Derivatives of dihydrobenzo[b][1,4]diazepine-2-one as antagonists of mglur2 ii

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

 

The present invention relates to compounds of General formula I

where X is a simple bond or etendering group, where in the case when X is a simple bond,

R1means langroup, halogen, lower alkyl, (C3-C6)cycloalkyl, (ness.)alkoxy, fluorine(ness.)alkoxy, fluorine(ness.)alkyl or means pyrrol-1-yl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of fluorine, chlorine, langroup, -(CH2)1-4-hydroxyl group, fluorine(ness.)of alkyl, lower alkyl, -(CH2n- (ness.)alkoxyl, -(CH2)n-C(O)OR", -(CH2)1-4-R NR'r", hydroxy(ness.)alkoxyl and -(CH2)n-CONR'R", or means phenyl, unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, lower alkyl, fluorine(ness.)of alkyl, (ness.)alkoxyl, fluorine(ness.)alkoxyl and langroup;

in the case when X is etendering group,

R1means phenyl, unsubstituted or substituted by 1-3 substituents,

selected from the group consisting of halogen, lower alkyl, fluorine(ness.)of alkyl, (C3-C6)cycloalkyl, (ness.)alkoxyl and fluorine(ness.)alkoxyl;

R2means R NR'r", fluorine(ness.)alkoxy or 3-oxopiperidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl, ring of which it is certainly substituted by R;

R' represents hydrogen, lower alkyl, (C3-C6)cycloalkyl, fluorine(ness.)alkyl or 2-(ness.)alkoxy(ness.)alkyl;

R indicates hydrogen, lower alkyl, (C3-C6)cycloalkyl, fluorine(ness.)alkyl, 2-(ness.)alkoxy(ness.)alkyl, -(CH2)2-4di(ness.)alkylamino, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy(ness.)alkyl;

Y represents-CH= or =N-;

R3means halogen, lower alkyl, fluorine(ness.)alkyl, (ness.)alkoxyl, langroup, -(CH2)n-C(O)OR", -(CH2)n-C(O)NR'r R" means or optionally substituted 5-membered aromatic heterocycle which may be substituted with halogen, fluorine(ness.)the alkyl, fluorine(ness.)alkoxyl, langroup, -(CH2)nNR'r R", -(CH2)n-C(O)OR", -(CH2)n-C(O)NR'r R", -(CH2)n-SO2NR'r R", -(CH2)n-C(NH2)=NR", hydroxyl, (ness.)alkoxyl, (ness.)alkylthiophene or lower alkyl, which is optionally substituted by fluorine, hydroxyl, (ness.)alkoxyl, langroup or carbamoyloximes;

n means 0, 1, 2, 3 or 4;

and their pharmaceutically acceptable additive salts.

It has been unexpectedly found that compounds of General formula I are antagonists of metabotropic glutamate receptors. The compounds of formula I differ valuable therapist is ical properties.

In the Central nervous system (CNS), the transmission of signals derived by the interaction of the neurotransmitter, sending neuron, with neuroreceptors.

L-Glutamic acid, the most common neurotransmitter in the Central nervous system, plays a crucial role in a large number of physiological processes. Glutamate-dependent receptors of stimuli are divided into two main groups. The first main group forms an adjustable ligands ion channels. Metabotropic glutamate receptors (mGluR) is the second main group and, in addition, belong to the family of receptors associated with G-protein.

At the present time famous eight different members of such mGluR and some of them even have subtypes. Based on the structural parameters of various influences on the synthesis of secondary metabolites and different affinity to low molecular weight chemical compounds these eight receptors can be subdivided into three subgroups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

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

D. the natives treatable indications in this regard are limited brain function, caused by operations bypass surgery or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, pregnancy-induced hypoxia, cardiac arrest, and hypoglycemia. Other treatable indications are chronic and acute pain, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, a disease of unknown origin or parkinsonism caused by medicaments, as well as the condition in which associated with deficiency of glutamate manifestations, such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, the addiction to opiates, anxiety, vomiting, dyskinesia and depression.

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts by themselves and as pharmaceutically active substances, their getting medicines on the basis of the compounds according to the invention and the reception, as well as the use of compounds according to the invention for the regulation or prevention of diseases of the aforementioned type and, accordingly, to prepare the drugs.

The compounds of formula I may also be used in the form of their prodrugs. Examples are esters, N-oxides, esters with phosphoric Ki is lotay, esters glycemia, the conjugates of the glycerides and the like compounds. Prodrugs can add to the effectiveness of these compounds advantages in absorption, pharmacokinetics, distribution and transport to the brain.

All tautomeric forms of the compounds according to the invention are also covered by the invention.

Preferred are the compounds of formula I, where X means a simple link. Examples of preferred compounds are compounds where R1means trifluoromethyl, and especially those where R3is langroup, for example, the following connections:

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

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

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

4-[4-oxo-8-(2,2,2-triptoreline)-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile and

4-[8-(isopropylethylene)-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4](diazepin-2-yl]pyridine-2-carbonitrile.

Other preferred compounds are compounds where X is a simple bond, R1means trifluoromethyl and R3means optionally substituted 5-membered aromatic Goethe is Ozil, which may be substituted with halogen, fluorine(ness.)the alkyl, fluorine (ness.)alkoxyl, langroup, -(CH2)n-R NR'r", -(CH2)n-C(O)OR", -(CH2)n-C(O)NR'r R", -(CH2)n-SO2NR'r R", -(CH2)n-C(NH2)=NR", hydroxyl, (ness.)alkoxyl, (ness.)alkylthiophene or lower alkyl, which is optionally substituted by fluorine, hydroxyl, (ness.)alkoxyl, langroup or carbamoyloximes. Examples of such compounds are the following:

7-dimethylamino-4-[3-(3-methylisoxazol-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-dimethylamino-4-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-dimethylamino-4-(3-imidazol-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

4-[3-(3-methylisoxazol-5-yl)phenyl]-7-(methylpropylamine)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isobutylamino)-4-[3-(3-methylisoxazol-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isopropylethylene)-4-[3-(3-methylisoxazol-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isobutylamino)-4-(3-{5-[(isopropylethylene)methyl]-[1,2,3]triazole-1-yl}-phenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isopropylethylene)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-the n

7-(methylpropylamine)-4-(3-[1,2,3]triazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isobutylamino)-4-(3-[1,2,3]triazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

4-(3-imidazol-1-ylphenyl)-7-isobutylamino-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-dimethylamino-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-dimethylamino-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(methylpropylamine)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

4-[3-(5-hydroxymethyl-[1,3,4]thiadiazole-2-yl)phenyl]-7-(methylpropylamine)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it.

Also preferred are compounds where X is a simple bond and R1means chlorine, for example, the following connections:

8-chloro-7-isobutylamino-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(methylpropylamine)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(isopropylethylene)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(isobutylamino)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-[3-(5-dimethyl isomethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

4-[3-(5-azetidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-8-chloro-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

4-[3-(5-azetidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-8-chloro-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(isobutylamino)-4-[3-(5-piperidine-1-ylmethyl-[1,2,3]triazole-1-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(isopropylethylene)-4-(3-{5-[(isopropylethylene)methyl]-[1,2,3]triazole-1-yl)phenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-(3-{5-[(isobutylamino)methyl]-[1,2,3]triazole-1-yl}phenyl)-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-isopropylamino-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(isobutylamino)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-(3-imidazol-1-ylphenyl)-7-isobutylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(ethylmethylamino)-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(ethylmethylamino)-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it.

Other preferred compounds are those where X is a simple bond and R1is langroup.

Examples of such compounds are the following:

8 diethylamino-2-[3-(3-methylisoxazol-5-yl)phenyl]-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile and

2-[3-(3-methylisoxazol-5-yl)phenyl]-4-oxo-8-piperidine-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile.

Further preferred are those compounds of formula I, where R3means optionally substituted 5-membered aromatic heterocycle which may be substituted with halogen, fluorine(ness.)the alkyl, fluorine(ness.)alkoxyl, langroup, -(CH2)n-R NR'r", -(CH2)n-C(O)OR", -(CH2)n-C(O)NR'r R", -(CH2)n-SO2NR'r R", -(CH2)n-C(NH2)=NR", hydroxyl, (ness.)alkoxyl, (ness.)alkylthiophene or lower alkyl, which is optionally substituted by fluorine, hydroxyl, (ness.)alkoxyl, langroup or carbamoyloximes.

Especially preferred are such compounds of formula I where R 3is optionally substituted 5-membered aromatic heterocycle selected from the group consisting of thiazolyl, oxazolyl, isoxazolyl, imidazolyl 2N-pyrazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]thiadiazolyl and [1,3,4]oxadiazolyl. Examples of such compounds are the following:

7-dimethylamino-8-phenylethynyl-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-(2-forfinal)-4-(3-[1,2,3]triazole-1-ylphenyl)-7-(2,2,2-triptoreline)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(ethylmethylamino)-8-methyl-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-dimethylamino-8-methyl-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isobutylamino)-8-methyl-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isobutylamino)-8-methyl-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

4-(3-{5-[(cyclopropylamino)methyl]-[1,2,3]triazole-1-yl}phenyl)-7-(isobutyl-methylamino)-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it.

Are preferred and other compounds, where R2means-N(CH3)2or pyrrolidine. Also preferred compounds where R2is isopropylamino, isopropylethylene, isobutylamino or isobutylmethylxanthine.

Preferred compounds of formula I in the volume of the IU of the present invention are, in addition, and such, where R3means langroup or optionally substituted 5-membered aromatic heterocycle which may be substituted by-CH2HE or-CH2N(CH3)2.

The term "lower alkyl"used in the present description, means the remains of saturated hydrocarbons with straight or branched chain containing 1 to 7 carbon atoms, preferably 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and the like.

The term "(ness.)alkoxyl" means the residue of lower alkyl, implying the above definition, linked through an oxygen atom. Examples of residues "(ness.)alkoxyl" include methoxy, ethoxy, isopropoxy and the like.

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

The term "fluorine(ness.)alkyl" means the remainder of the lower alkyl in which one or more hydrogen atoms may be replaced by fluorine.

The term "fluorine(ness.)alkoxyl" means the remainder of (ness.)alkoxyl, keeping in mind the above definition, in which one or more hydrogen atoms may be replaced by fluorine.

The term "(3-C6)cycloalkyl" means cycloalkyl group containing 3-6 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "(ness.)allylthiourea" means the residue of lower alkyl, with the mind the above definition, linked through a sulfur atom, for example methylsulfonyl.

The expression "five-membered aromatic heterocycle" includes furan, thiophene, thiazole, pyrrole, imidazole, pyrazole, oxazole, isoxazol, triazole, oxadiazole, thiadiazole and tetrazole. Preferred heterocycles are 1,2,3-triazole, 1,2,4-triazole, isoxazol, 1,3-oxazole, 1,3-thiazole, 1,3,4-oxadiazole or imidazole.

"Optionally substituted traveler" means that the group may or may not be substituted by one or more, preferably one or two, substituents, independently selected from a specific group.

The term "pharmaceutically acceptable additive salt" refers to any salt derived from an inorganic or organic acid or base.

Compounds of General formula I and their pharmaceutically acceptable salts can be obtained according to methods that include (a) the interaction of the compounds of formula II

with the compound of the formula IV or IVa

or

where R is alkyl, preferably ethyl or butyl,

to obtain the compounds of formula III

which is then subjected to removal of the protection of the amino group and cyclization to obtain the compounds of formula

where R1 , R2, R3X and Y are as described above

and, if it is desired, the compound obtained is transformed into pharmaceutically acceptable additive salt.

According to the scheme And compounds of General formula I, in which X, Y, R1, R2and R3are as described above, can be obtained from compounds of General formula II, using the reaction sequence of acylation-unprotect-cyclization.

For example, the interaction of compounds of General formula II with dioxanone IV, in which Y and R3are as described above, in an inert solvent, for example toluene or xylene, at elevated temperature, preferably between 80 and 160°C, leads to compounds of General formula III.

Alternatively, compounds of General formula III can also be obtained, for example, by the reaction of compounds of General formula II with difficult β-ketefian (General formula IVa), in which Y and R3are as described above, using the same conditions as described for the reaction with dioxanone.

Then the decomposition of tert-butoxycarbonyl (Boc) protective groups in compounds of formula III and concomitant cyclization obtained after removal of the protecting connection lead to the desired compounds of General formula I. Any other suitable protective group for aminor PPI, for example Fmoc (9-fluorenylmethoxycarbonyl) or benzyloxycarbonyl (Z), can be an alternative used instead of tert-butoxycarbonyl.

Stage unlocks the cyclization can be carried out by treating compounds of General formula III using, for example, acid BrëNSTEMI, such as triperoxonane acid, in an inert solvent, such as dichloromethane (DCM). The reaction is preferably carried out at a temperature between 0 and 50°C. May be advantageous to use the anisole or 1,3-dimethoxybenzene as an acceptor of carbocations in the reaction mixture.

According to scheme B, compounds of General formula II in which R1means phenyl, optionally substituted as described above for compounds where X is a simple bond, and R2is such as described above can be obtained in different ways depending on the nature of R1from improsoned General formula V in which R2is the same as described above. As shown in scheme B, the key step is the reaction mix by Suzuki to obtain the compounds of General formula VIa.

Compounds of General formula II in which R1, R2and X are as described above, can be obtained according to scheme B when restoring the nitro group in compounds of General formula VIa in am is nogroup. Recovery may be, for example, carried out using gaseous hydrogen in the presence of a suitable catalyst, such, for example, a Nickel catalyst or Raney palladium on coal. Another possible method of recovery uses douglaston tin (SnCl2·N2O) in ethanol at a temperature between 70 and 80° (as described in Tetrahedron Lett. 1984, 25, 839), or alternatively in polar aprotic solvents such as dimethylformamide (DMF), dimethylacetamide (DMA) or N-organic (NMP) and the like, optionally in the presence of bases, such as pyridine or triethylamine and the like, at temperatures between 0 and 80°C. Another suitable method involves the use of powdered zinc in the presence of ammonium chloride in proton solvents, such as water or ethanol, at temperatures between 20 and 80°C. Specific conditions for obtaining corresponding compounds of General formula II can be found in the experimental part.

Compounds of General formula V in which R2is such as described above can be obtained in different ways depending on the individual balance R2:

As shown in scheme V, compound B1 can be obtained from commercially available 5-chloro-2-nitroaniline by eadirova the Oia, you get a synthetic intermediate derived A1, which can then be protected to obtain a compound B1.

Phase iodination can be carried out, for example, when using odnoklavishnogo iodine in acetic acid in the presence of sodium acetate. The reaction can be, for example, carried out at temperatures between 20 and 80°C.

Protection of the amine function can be applied to a number of commercially available starting compounds, or compounds synthesized by any person skilled in the art, to obtain the corresponding 2-nitroaniline General formula VII in which X is a simple bond and R1is the same as described above. This transformation leads to a key intermediate compounds of General formula VIb, specific conditions for obtaining the corresponding compounds used in this invention can be found in the experimental part.

One of the possibilities to protect the amine function is, for example, reaction of compounds of General formula VII with di(tert-butyl)carbonate 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 between 20 and 60°C.

Alternative protection of the amino group can be achieved when the intermediate isocyanate of purembrace compounds of General formula VII diphosgene, preferably in aprotic solvents, such as ethyl acetate, or 1,4-dioxane, at temperatures from 0 to 100°and further processing isocyanate tert-butanol, in solvents such as dichloromethane or 1,2-dichloroethane and the like, at temperatures between 20 and 85°to obtain the desired compounds of General formula VIb.

Another suitable way to implement this stage of protection is intermediate formation of di(tert-butoxy)carbonyl derivative by treatment of compounds of General formula VII di(tert-butyl)carbonate in the presence of dimethylaminopyridine (DMAP) in an aprotic solvent, such as tetrahydrofuran and the like, followed by selective removal of one tert-butoxycarbonyl group by acidification BrëNSTEMI, as, for example, triperoxonane acid, in an aprotic solvent, such as dichloromethane, chloroform or 1,2-dichloroethane, at temperatures between 0 and 20°With, the result is the desired compounds of General formula VIb.

According to scheme G, the compounds of General formula VII, in which R1means pyrrol-1-yl, optionally substituted as described above, X is a simple bond and R is chlorine, can be obtained from the known 5-chloro-2-nitro-1,4-phenylenediamine[registration number Chemical Abstracts CAS-No. 26196-45-2] by selective condenser and the amino group in position 4 with a suitable substituted 2,5-dimethoxytetrahydrofuran General formula VIII, as described in J.Heterocycl. Chem. 1988, 25, 1003.

The reaction is preferably carried out in an acidic medium such as acetic acid or propionic acid and the like, at temperatures between 40 and 100°C. the Specific conditions for the respective compounds can be found in the experimental part.

The corresponding substituted 2,5-dimethoxytetrahydrofuran General formula VIII, in which Ra, Rband Rcare as described above in the General demand for derivatives pyrrol-1-yl, are either commercially available or are synthesized from the appropriately substituted furan, as shown in the diagram D. the Respective substituents may optionally be protected with suitable protective groups known to the person skilled in the art, or alternatively may be introduced after synthesis of the pyrrole rings. Two-stage sequence consists of the reaction of furan with bromine in methanol at low temperature, for example, -35°C, followed by treatment with a base, such as triethylamine and the like or potassium carbonate, or sodium bicarbonate, and the like. The resulting 2.5-dimethoxytetrahydrofuran General formula VIII, where Ra, Rband Rcare as described above, can be restored by catalytic gidir the cation preferably in methanol using a catalyst, as, for example, palladium on coal or Nickel Raney catalyst and the like, to the desired 2,5-dimethoxytetrahydrofuran General formula VIII. An example of this reaction sequence can be found in Tetrahedron 1971, 27, 1973-1996.

The specific conditions of synthesis of individual compounds can be found in the experimental part.

As shown in scheme E, compounds of formula VIc, in which R2attached via a nitrogen atom and is such as described above, can be obtained from the intermediates of General formula VIb, the synthesis of which can be found in the experimental part, by nucleophilic substitution reaction with the corresponding amines in the presence of a suitable base.

The reaction is preferably carried out in polar aprotic solvent, such as dimethylformamide, N-organic or dimethylsulfoxide and the like. The base can be selected from spatially-obstructed amines, such as triethylamine or base Hunya, alcoholate, such as methylate and tert-butyl sodium, or hydrides, e.g. sodium hydride. The reaction can be carried out at temperatures between 20 and 110°depending on the individual synthesized compounds.

According to the scheme W Conn is in General formula II, where R1is the same as described above for compounds where X is etendering group, can be obtained in various ways from IDataReader compounds of formula V, depending on the nature of R1and R2. As shown in scheme G, the transformation can be, for example, carried out

a) by direct attachment R1-alcantarilha Deputy to the compound of General formula V with a combination of type Sonogashira to obtain the compounds of General formula VId, followed by reduction of the nitro group or

b) by two-stage combinations type Sonogashira, when the first trimethylsilylacetamide undergoes combination with a compound of General formula V to obtain after desirelove using sodium hydroxide in methanol intermediate compound X, which can then be converted in the second combination type Sonogashira with a suitable reagent R1-I, R1-Br or R1-OSO2CF3in compounds of General formula VId, the restoration of the nitro group leads to the desired compounds of General formula II.

The exact conditions to obtain the corresponding compounds can be found in the experimental part.

According to the scheme C dioxanonane and β-keto-ester structural units of General formula IV and IVa can be obtained by methods known specifications the sheet in this area, from the corresponding derivatives of carboxylic acids R3-COR, free acids, complex methyl or ethyl esters and anhydrides of the acids. The exact conditions for obtaining the corresponding compounds can be found in the experimental part.

Pharmaceutically acceptable salts can be easily obtained according to methods which are in themselves known, taking into account the nature of the connection, turn into salt. Inorganic or organic acids, such as 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, p-toluensulfonate and the like, are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I.

The compounds of formula I and their pharmaceutically acceptable salts are antagonists of metabotropic glutamate receptors 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 and memory impairment. Other treatable indications are restricted brain function caused by surgery is mi bypass or transplant, poor blood supply to the brain, spinal cord injuries, head injuries, pregnancy-induced hypoxia, cardiac arrest, and hypoglycemia. Other treatable indications are acute and chronic pain, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, a disease of unknown origin or parkinsonism caused by medicaments, as well as the condition in which associated with deficiency of glutamate manifestations, such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychosis, addiction to opiates, anxiety, vomiting, dyskinesia and depression.

The compounds of formula I and their pharmaceutically priemlemye salts can be used as medicines, for example, in the form of pharmaceutical preparations. Pharmaceutical drugs can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be carried out through the rectum, for example, in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or the organic carriers for preparation of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and similar substances can be applied, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and similar substances; depending on the nature of the active substance carriers, however, are not usually required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like compounds. Adjuvants, such as alcohols, polyols, glycerine, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of the formula I, but, as a rule, they are not needed. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like substances.

Additionally, the pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizers, wetting means, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffers, mA is kirousis funds 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 object of the present invention, as a method of obtaining such medicines, which includes mixing one or more compounds of the formula I or their pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances in herbal dosage form together with one or more therapeutically inert carriers.

The dosage may vary within wide limits and, of course, is matched to the individual requirements in each particular case. Typically, the effective dose for oral or parenteral administration is 0.01-20 mg/kg/day dose of 0, 1-10 mg/kg/day is preferred for all of the above indications. Daily dose for an adult weighing 70 kg, are, respectively, 0.7 to 1400 mg per day, preferably between 7 and 700 mg per day.

The present invention relates also to the use of compounds of the formula I and their pharmaceutically acceptable salts for the preparation of pharmaceutical preparations, in particular for the regulation or prevention of acute and/or chronic never the logical violations of the aforementioned type.

Compounds of the present invention are antagonists of receptors mGlu group II.

The following table lists some typical values of inhibition constants (Ki) preferred compounds.

ConnectionKimGlu2 (µm)
3-(8-Dimethylamino-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile0,030
8-(2,3-Differenl)-7-dimethylamino-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,070

ConnectionKimGlu2 (µm)
8-Chloro-7-[(2-methoxyethyl)methylamino]-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,025
8-Chloro-7-dimethylamino-4-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,023
8-Chloro-7-dimethylamino-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,030
8-(2-Forfinal)-4-[3-(3-methylisoxazol-5-yl)phenyl]-7-(2,2,2-triptoreline)-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,03
8-Chloro-7-dimethylamino-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he 0,039
8-Chloro-7-(methylpropylamine)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,030
8-Chloro-7-(diethylamino)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,044
8-Chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)-phenyl]-7-pyrrolidin-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-he0,019
8-Chloro-7-(cyclopropylamino)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-he0, 16
8-Chloro-7-dimethylamino-4-(3-pyrazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he0, 11
7-Dimethylamino-4-[3-(3-morpholine-4-ylmethyl-isoxazol-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he0, 125
7-Dimethylamino-4-[3-(2-methylsulfonylamino-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-he0,019
4-[8-(Cyclopropanemethylamine)-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile0,005
4-[3-(5-Cyclopropylmethyl-[1,2,3]triazole-1-yl)-phenyl]-7-dimethylamino-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,049
4-[4-Oxo-8-(2,2,2-triptoreline)-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,]diazepin-2-yl]pyridine-2-carbonitrile 0,004
3-[7-Methyl-8-(methylpropylamine)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile0,025
8-Chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)-phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,02
8 Diethylamino-2-[3-(3-methylisoxazol-5-yl)phenyl]-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile0,009

ConnectionKimGlu2 (µm)
4-[3-(5-Azetidin-1-ylmethyl-[1,2,3]triazole-1-yl)-phenyl]-8-chloro-7-(methylpropylamine)-1,3-dihydro-benzo[b][1,4]diazepin-2-he0,015
8-Chloro-4-[3-(5-hydroxymethyl-[ 1,2,4]triazole-1-yl)-phenyl]-7-(isobutylamino)-1,3-dihydro-benzo[b][1,4]diazepin-2-he0,089
7-(Methylpropylamine)-4-(3-[1,2,4]triazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,027
7-(Isobutylamino)-4-(3-[1,2,4]triazole-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-he0,012
8-Chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isobutylamino)-1,3-dihydro-benzo[b][1,4]diazepin-2-he0,003
8-Chloro-7-dimethylamino-4-[3-(2-ethylaminomethyl-4-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,48
7-Dimethylamino-4-[3-(5-hydroxymethyl-[1,3,4]thiadiazole-2-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,017
7-Dimethylamino-4-[3-(2-methyl-5-preprocessor-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-he0,046
4-[3-(5-Hydroxymethyl-[1,3,4]thiadiazole-2-yl)phenyl]-7-(methylpropylamine)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-he0,008

Binding of [3H]-LY354740 on mGlu2 subjected to transfection of the cell membranes of Chinese hamster ovary (Cho)

Transfection and cell culture

cDNA encoding a protein of rat mGlu2 receptor in pBluescript II, received from Professor S. Nakanishi (Kyoto, Japan) and was subcloned into the eukaryotic expressing vector pcDNA I-amp from the company Invitrogen (NV Leek, the Netherlands). This vector design (pcD1mGR2) were subjected to joint transfection with the plasmid psvNeo that encodes a gene of resistance to neomycin, in cells SNO using a modified method with calcium phosphate as described by Chen & Okayma (1988). Cells were kept in modified Dulbecco environment Needle with a decreased amount of L-glutamine (final concentration 2 mm) and 10% cialisbuynow amniotic calf serum from the company Gibco BRL (Basel, Switzerland). Selection was performed in the presence of G-418 (final concentration of 1000 µg/ml). Clones identified with p the power of reverse transcription of 5 μg total RNA, then was carried out by polymerase chain reaction using specific primers of the mGlu2 receptor 5'-atcactgcttgggtttctggcactg-3' and 5'-agcatcactgtgggtggcataggagc-3' in 60 ml of Tris-HCl (rn), 15 mm (NH4)2SO4, 2 mm MgCl2, 25 units/ml Taq polymerase, using 30 cycles of annealing at 60°C for 1 minute, elongation at 72°C for 30 seconds and denaturation 1 min at 95°C.

Preparation of membranes

Cells, cultured as described above were collected and washed three times with cold phosphate buffered saline (SFR) and frozen at -80°C. the Precipitate is re-suspended in cold 20 mm buffer HEPES-NaOH containing 10 mm ethylenediaminetetraacetic acid (EDTA) (pH 7.4), and homogenized using Polytron (Kinematica AG, Littau, Switzerland) for 10 seconds at 10,000 rpm After centrifugation for 30 minutes at 4°the precipitate was washed once with the same buffer, and once cold 20 mm buffer HEPES-NaOH, containing 0, 1 ml EDTA (pH 7.4). The protein content was measured using the method of the Pier (Socochim, Lausanne, Switzerland), using as a standard bovine serum albumin.

Binding of [3H]-LY354740

After thawing, the membranes re-suspended in cold 50 mm buffer Tris-HCl containing 2 mm MgCl2and 2 mm CaCl2(pH 7) buffer (buffer for binding). The final concentration of the membranes in the experiments was 25 µg b the LCA/ml Experiments on the inhibition was performed with membranes, incubated with 10 nm [3H]-LY354740 at room temperature for 1 hour in the presence of different concentrations of the investigated compounds. After incubation the membranes were filtered on glass fiber filters Whatmann GF/C and washed 5 times with cold buffer for binding. I have not measured any specific binding in the presence of 10 μm DCG IV. After migration filters in plastic tubes containing 10 ml scintillation fluid Ultima gold (Packard company. Zurich, Switzerland), was measured radioactivity in a liquid scintillation counter Tri-Carb 2500 TR (Packard company. Zurich, Switzerland).

The results of the analysis.

Curves of inhibition was approximatively using a four-parameter logistic equation, giving values of Kiand the ratios of the hill.

EXAMPLES

Standard methods And

Getting 4-iodine-2-nitroaniline by iodination of 2-nitroaniline [according to Wilson, Gerald J.; Hunt, Frederick S. Aust. 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)was added over 60 minutes odnogolosy iodine (59-66 ml, 1,125-to 1.25 mol) in acetic acid (300 ml). The reaction mixture was heated to a predetermined temperature before until thin layer chromatography (the SH) did not full the educt, was stirred another 30 minutes at 23°With, then slowly diluted with water (1000 ml), which led to the separation of the crystalline product. Stirring is continued for 1 hour and the product was filtered, washed from acetic acid and dried in vacuum at 60°C.

Example A1

5-Chloro-4-iodine-2-nitrophenylamino

Specified in the title compound was obtained from 5-chloro-2-nitroaniline when ionirovanii using odnoklavishnogo iodine in acetic acid/sodium acetate in accordance with the standard method And (80°). The product was obtained in the form of a solid orange color.

Mass spectrometry (MS) with ionization by electron impact (EI) 298 (M+and 300 [(M+2)+]; tPL202-203°C (decomp.).

Standard method In

Obtain tert-butyl ester (2-nitrophenyl)karbinovykh acids from 2-nitroanilines

Method a (2-nitroanilines). To a solution of diphosgene (4,1 ml, 34.1 mmole) in ethyl acetate (40 ml) at 0°C was added a solution of 2-nitroaniline (45,5 mmole) in ethyl acetate (200-500 ml) and the mixture is boiled under reflux for 18 hours. The solvent was removed in vacuum, received solid brown color, which is triturated with hot hexane (200 ml). The solid was filtered and the filtrate was concentrated under reduced pressure, was obtained pure 2-nitrophenylhydrazine in a solid yellow color is the same. This substance is a mixture of excess tert-butanol in methylene chloride was boiled under reflux for 2.5 hours. After removal of the solvent remained solid orange color, which was purified by column chromatography on silica gel, elwira hexane/ethyl acetate, was obtained tert-butyl ether (2-nitrophenyl)carbamino acid in a solid yellow color.

Method b (from 2-nitroanilines). To a mixture of 2-nitroaniline (142 mmole) and cesium carbonate (55,5 g, 170 mmol) in 2-butanone (740 ml) was added dropwise a solution of di-tert-BUTYLCARBAMATE (Re2O) (37,8 g, 173 mmole) in 2-butanone (170 ml) and the resulting mixture was stirred at 50-80°until, while according to TLC did not fully develop. 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). The combined hexane layers were washed with brine (200 ml) and all water layers are re-extracted with hexane (300 ml). All combined hexane layers were dried over magnesium sulfate, filtered and the solvent was removed in vacuum, received solid orange color, which was purified by column chromatography on silica gel, using as eluent hexane/ethyl acetate, was obtained tert-butyl ether (2-nitrophenyl)carbamino KIS is the notes in the form of a solid yellow color.

Method (2-nitroanilines). To a solution of 2-nitroaniline (550 mmol) and 4-dimethylaminopyridine (DMAP) (1.22 g, 10 mmol) in tetrahydrofuran (1000 ml) at 23°was added dropwise over 70 minutes, the solution Vos2(246 g, 1128 mmol) in tetrahydrofuran (500 ml) and stirring was continued at 23°C for 75 minutes. The entire mixture was evaporated to dryness and dried in high vacuum, received a solid dark brown color. This substance was dissolved in dichloromethane (1100 ml), cooled to 0°and added dropwise triperoxonane acid (84 ml, 1100 mmol). The mixture was stirred 2 hours at 0°C, poured into chilled to the temperature of ice saturated sodium bicarbonate solution, was extracted with dichloromethane, washed with brine and dried over magnesium sulfate. After removal of solvent in vacuo received solid dark brown color that was applied to silica gel and was purified by column chromatography, elwira hexane/ethyl acetate, was obtained tert-butyl ether (2-nitrophenyl)carbamino acid in a solid yellow color.

Method d (2-nitroacetanilide). To a solution of 2-nitroacetanilide (100 mmol) and DMAP (122 mg, 1 mmol) in tetrahydrofuran (100 ml) at 23°was added dropwise over 15 minutes a solution of BOC2On (22,92 g, 105 mmol) in tetrahydrofuran (100 ml) and peremeci is the W continued at 23° With up until TLC indicated full conversion of the original substance. The entire mixture was evaporated to dryness and dried in high vacuum, received solid residue color from yellow to dark brown. This substance was dissolved in tetrahydrofuran (200 ml) and was added dropwise 25%ammonium hydroxide (77 ml, 500 mmol). The mixture was stirred at 23°up until TLC indicated full conversion was poured into 1 n hydrochloric acid, was extracted with ethyl acetate, the organic layer was washed with a saturated solution of sodium bicarbonate and with brine, dried over magnesium sulfate. After removal of solvent in vacuo remained solid color from yellow to brown, which was usually pure enough for further transformations, or if it were applied to silica gel and was purified by column chromatography using as eluent hexane/ethyl acetate, was obtained tert-butyl ether (2-nitrophenyl)carbamino acid in a solid yellow color.

Example B1

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

Specified in the title compound was obtained via isocyanate of 5-chloro-4-iodine-2-nitrophenylamino (example A1) (7.0 g, 23,45 mmole) in reaction with diphosgene (2,12 ml, to 17.6 mmole) in ethyl acetate (30 ml) and subsequent processing of tert-butanol (10 ml) in dichloromethane (100 ml) according to standard methods (method a). The product was obtained in a solid yellow color (7,1 g, 76%).

MS (EI) 398 (M+and 400 [(M+2)+]; tPL82-84°C.

Example B2

tert-Butyl ether (4,5-dichloro-2-nitrophenyl)carbamino acid

Specified in the title compound was obtained through di(tert-butoxycarbonyl) derived from commercially available 4,5-dichloro-2-nitroaniline (15 g, 72.5 mmole) and Vos2On (32,4 g, 148,5 mmole) followed by treatment with 2 EQ. triperoxonane acid in dichloromethane according to the standard method (method b). The product was obtained in a solid brown color (21,63 g, 97%).

MS ionization sputtering with the formation of negative ions (ISN) 305 [(M-N)-]; tPL68-73°C.

Example B3

tert-Butyl ester (5-fluoro-2-nitro-4-triptoreline)carbamino acid

Specified in the title compound was obtained through di(tert-butoxycarbonyl) derived from 5-fluoro-2-nitro-4-triptoreline obtained from commercially available 4-amino-2-fermentatively upon acetylation with acetic anhydride in toluene at 23°, nitrovanie% nitric acid at a temperature of from 10 to 23°and dezazetilirovanie 2 N. sodium hydroxide in tetrahydrofuran at 50°With (to 5.21 g of 23.2 mmole) and Vos2O (10,63 g, 48.7 per mmole), then spent processing 2 EQ. triperoxonane acid in dichloromethane according to the about the standard method (method b). The product was obtained in the form of a solid light-yellow color (6,33 g, 84%).

MS (ISN) 323 [(M-N)-]; tPL104°C.

Example B4

tert-Butyl ester [4-iodine-2-nitro-5-(2,2,2-triptoreline)phenyl]carbamino acid

Specified in the title compound was obtained through di(tert-butoxycarbonyl) derived from 4-iodine-2-nitro-5-(2,2,2-triptoreline)phenylamine [obtained by mixing 5-chloro-4-iodine-2-nitrophenylamino (example A1) (of 8.95 g, 30 mmol), 2,2,2-triptoreline (30 ml) and potassium hydroxide (4,36 g, 66 mmol) in dimethyl sulfoxide (DMSO) (60 ml) at 23°C for 35 days] (10, 41 g, 29 mmol) and Vos2O (12,87 g, 59 mmol) followed by treatment with 2 EQ. triperoxonane acid in dichloromethane according to the standard method (method b). The product was obtained in a solid yellow color (13,34 g, 100%).

MC (ISN) 461(M-H)-].

Example B5

tert-Butyl ester (5-chloro-2-nitro-4-triptoreline)carbamino acid

Specified in the title compound was obtained through di(tert-butoxycarbonyl) derived from commercially available 5-chloro-2-nitro-4-triptoreline [CAS-No. 35375-74-7](22,61 g, 94 mmole) and Vos2On (42,06 g, 193 mmole) followed by treatment with 2 EQ. triperoxonane acid in dichloromethane according to the standard method (method b). The product was obtained in a solid yellow color (31,82 g, 99%).

MS (ISN)339, 1 [(M-H)-] 341 [(M+2-N)-]; tPL113-115°C.

Example 6

tert-Butyl ester (5-chloro-4-fluoro-2-nitrophenyl)carbamino acid

Specified in the title compound was obtained through di(tert-butoxycarbonyl) derived from commercially available 3'-chloro-4'-fluoro-6'-nitroacetanilide [CAS-No. 81962-58-5] (59 g, 254 mmole) and Vos2On (58,13 g, 266 mmol) followed by treatment with ammonium hydroxide (25%, of 77.5 ml, 507 mmol) according to standard methods (method g). The product was obtained in a solid yellow color (73,53 g, 100%).

MS (ISN) 289 [(M-H)-] 291 [(M+2-N)-]; tPL73-74°C.

Example 7

tert-Butyl ether [2-nitro-5-(2,2,2-triptoreline)-4-triptoreline]carbamino acid

Specified in the title compound was obtained through di(tert-butoxycarbonyl) derived from 4-iodine-2-nitro-5-(2,2,2-triptoreline)phenylamine [obtained by mixing 5-chloro-4-iodine-2-nitrophenylamino (example A1), 2,2,2-triptoreline and potassium hydroxide in dimethyl sulfoxide at 23°With over 32.5 days] and Vos2Oh, followed by treatment with 2 EQ. triperoxonane acid in dichloromethane according to the standard method (method b). The product was obtained in a solid yellow color (18,955 g).

MS (ISN) 403[(M-N)-].

Example B8

tert-Butyl ester (5-chloro-4-methyl-2-nitrophenyl)carbamino acid

Specify the OU in the title compound was obtained through di(tert-butoxycarbonyl) derived from commercially available 5-chloro-4-methyl-2-nitroaniline (10.0 g, 53,6 mmole) and Boc2O (23.9 g, 109 mmol) followed by treatment with 2 EQ. triperoxonane acid in dichloromethane according to the standard method (method b). After column chromatography (toluene/ethyl acetate 19:1) received solid yellow (14.6 g, 95%).

MS (ISN) 285,1 [(M-N)-].

Example B9

tert-Butyl ester (4-cyan-5-fluoro-2-nitrophenyl)carbamino acid

Specified in the title compound was obtained through di(tert-butoxycarbonyl) derived from 4-cyan-5-fluoro-2-nitroaniline (24,9 g, 137 mmol) [Ohmori and other J.Med. Chem.1994, 37, 467-475] and Vos2O (61,5 g, 282 mmole) followed by treatment with 2 EQ. triperoxonane acid in dichloromethane according to the standard method (method b). After column chromatography (hexane/ethyl acetate 4:1) received solid light yellow (14.5 g, 39%).

MS (ISN) 280,1 [(M-N)-].

Standard methods With

Obtain tert-butyl ester 5-N-substituted-(2-nitrophenyl)karbinovykh acids

tert-Butyl ester (5-chloro - or fluoro-2-nitrophenyl)carbamino acid was mixed with the desired amine optional with dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-organic or tetrahydrofuran and/or diisopropylethylamine or triethylamine at a temperature of from 23 to 130°until, while according to TLC did not show complete absence of the original half-life the reed or fluoride. The reaction mixture was cooled to 23°C, poured into ice water, the precipitate was filtered, 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 with brine, dried over sodium sulfate. After filtration and removal of solvent in vacuo received a technical product, which was purified by column chromatography on silica gel, using as eluent hexane/ethyl acetate. Got cleaned specified in the title of the product.

Example C1

tert-Butyl ester (4-chloro-5-dimethylamino-2-nitrophenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4,5-dichloro-2-nitrophenyl)carbamino acid (example B2) (3.0 g, 9.77 mmole) and dimethylamine (5,6 N. in ethanol, to 8.7 ml, and 48.8 mmole) in dimethyl sulfoxide (35 ml) at 23°according to the standard procedure C. the Product was obtained in a solid yellow color (2,81 g).

MS ionization sputtering with the formation of positive ions (ISP) 316 [(M+N)+] 318 [(M+2+N)+]; tPL136-138°C.

Example C2

tert-Butyl ester (5-dimethylamino-4-iodine-2-nitrophenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (399 mg,1 mmol) and dimethylamine (5,6 N. in ethanol, of 0.36 ml, 2 mmole) in tetrahydrofuran (3 ml) at 65°C for 18 hours in a sealed tube according to the standard procedure C. the Product was obtained in a solid yellow color (386 mg).

MS (EI) 407 (M+); tPL120-122°C.

Example C3

tert-Butyl ester {4-chloro-5-[(2-methoxyethyl)methylamino]-2-nitrophenyl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4,5-dichloro-2-nitrophenyl)carbamino acid (example B2) (of 3.07 g, 10 mmol), N-(2-methoxyethyl)methylamine (2,43 ml, 23 mmole) and triethylamine (of 4.2 ml, 30 mmol) in dimethyl sulfoxide (20 ml) at 23°according to the standard procedure C. the Product was obtained as brown oil (3.57 g).

MS (ISP) 360 [(M+N)+] 362 [(M+2+N)+].

Example C4

tert-Butyl ester (5-dimethylamino-2-nitro-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-fluoro-2-nitro-4-triptoreline)carbamino acid (example B3) (of 1.62 g, 5.0 mmol) and dimethylamine (5,6-called ethanol, 4,47 ml, 25.0 mmol) in dimethyl sulfoxide (10 ml) at 23°according to the standard procedure C. the Product was obtained in a solid yellow color (1.48 g).

MS (ISN) 348 [(M-N)-]; tPL110°C.

Example C5

tert-Butyl ester [4-chloro-5-(ethylmethylamino)-2-nitrophenyl]carbamino acid

MS (ISP) 330,3 [(M+N)+]; tPL94°C.

Example C6

tert-Butyl ester [4-chloro-5-(methylpropylamine)-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4,5-dichloro-2-nitrophenyl)carbamino acid (example B2) (3.0 g, 9.77 mmole) and N-methylpropylamine (2.50 g, a 34.2 mmole) in dimethyl sulfoxide (30 ml) at room temperature according to standard procedure C. the Product was obtained in the form of a solid pale brown (3.58 g).

MS (ISP) 344,3 [(M+N)+]; tPL68°C.

Example C7

tert-Butyl ester [4-chloro-5-(diethylamino)-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4,5-dichloro-2-nitrophenyl)carbamino acid (example B2) (3.0 g, 9.77 mmole) and diethylamine (3.57 g, and 48.8 mmole) in dimethyl sulfoxide (35 ml) at 60°according to the standard procedure C. the Product was obtained in a solid yellow color (2,63 g).

MS (ISP) 344,3 [(M+N)+]; tPL95°C.

Example C8

tert-Butyl ester (4-chloro-2-nitro-5-pyrrolidin-1-ylphenyl)carbamino acid

Specified in the title of a connection is Uchali from tert-butyl ether (4,5-dichloro-2-nitrophenyl)carbamino acid (example B2) and pyrrolidine in dimethyl sulfoxide at 23° According to the standard method C. the Product was obtained in a solid yellow color (6,65 g).

MS (ISP) 342 [(M+N)+] 344 [(M+2+N)+]; tPL157-158°C.

Example C9

tert-Butyl ester [4-chloro-5-(cyclopropylamino)-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4,5-dichloro-2-nitrophenyl)carbamino acid (example B2) (of 3.07 g, 10 mmol), hydrochloride of cyclopropanemethylamine (3,22 g, 30 mmol) and triethylamine (6,97 ml, 50 mmol) in dimethyl sulfoxide (30 ml) at 23°according to the standard procedure C. the Product was obtained in a solid yellow color (3.25 g).

MS (ISP) 342,2 [(M+N)+] 344 [(M+2+N)+]; tPL104-106°C.

Example C10

tert-Butyl ether (2-nitro-5-pyrrolidin-1-yl-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-2-nitro-4-triptoreline)carbamino acid (example B5) (for 6.81 g, 20 mmol) and pyrrolidine (of 8.27 g, 100 mmol) in dimethyl sulfoxide (70 ml) at 23°according to the standard procedure C. the Product was obtained in a solid yellow color (7,35 g).

MS (ISN) 374 [(M-N)-]; tPL138-141°C.

Example C11

tert-Butyl ester (5-dimethylamino-4-fluoro-2-nitrophenyl)carbamino acid

Specified in the title compound was obtained from tert-b is delovogo ether (5-chloro-4-fluoro-2-nitrophenyl)carbamino acid (example B6) (4.94 g, 17 mmol) and dimethylamine (40% in water, 7.9 M, 10.9 ml, 86 mmol) in dimethyl sulfoxide (35 ml) at 23°according to the standard procedure C. the Product was obtained in a solid yellow color (4,93 g).

MS (ISP) 303 [(M+N)+]; tPL144-148°C.

Example C12

tert-Butyl ester (4-chloro-2-nitro-5-piperidine-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4,5-dichloro-2-nitrophenyl)carbamino acid (example B2) and piperidine in dimethyl sulfoxide at 23°according to the standard procedure C. the Product was obtained in a solid yellow color (1,173 g).

MS (ISP) 356 [(M+N)+]358 [(M+2+N)+]; tPL132-133°C.

Example C13

tert-Butyl ester (4-fluoro-2-nitro-5-pyrrolidin-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-4-fluoro-2-nitrophenyl)carbamino acid (example B6) (of 5.81 g, 20 mmol) and pyrrolidine (of 8.27 ml, 100 mmol) in dimethyl sulfoxide (40 ml) at 23°according to the standard procedure C. the Product was obtained in a solid yellow color (6.42 per g).

MS (ISP) 326 [(M+N)+]; tPL188-193°C.

Example C14

tert-Butyl ether (5 azetidin-1-yl-4-chloro-2-nitrophenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4,5-dichloro-2-nitrophenyl)carb is inovas acid (example B2) (6,14 g, 20 mmol), azetidine (2,33 ml, 34 mmole) and triethylamine (of 8.4 ml, 60 mmol) in dimethyl sulfoxide (40 ml) at 23°according to the standard procedure C. the Product was obtained in the form of a solid orange color (5,85 g).

MC (EI) 327 (M+) and 329 [(M+2)+].

Example C15

tert-Butyl ether (5 azetidin-1-yl-2-nitro-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-2-nitro-4-triptoreline)carbamino acid (example B5), azetidine and triethylamine in dimethyl sulfoxide at 23°according to the standard procedure C. the Product was obtained in a solid yellow color (6,925 g).

MS (ISN) 360 [(M-N)-].

Example C16

tert-Butyl ester of [5-(cyclopropanemethylamine)-2-nitro-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-2-nitro-4-triptoreline)carbamino acid (example B5) (5,11 g, 15 mmol), hydrochloride of cyclopropanemethylamine (vs. 5.47 g, 45 mmol) and triethylamine (10.5 ml, 75 mmol) in dimethyl sulfoxide (50 ml) at 23°according to the standard procedure C. the Product was obtained in a solid yellow color (5.73 g).

MS (ISN) 388 [(M-N)-]; tPL51°C.

Example C17

tert-Butyl ester of [5-(cyclopropylamino)-2-nitro-4-triptoreline]carbonintensity

Specified in the title compound was obtained from tert-butyl ether (5-chloro-2-nitro-4-triptoreline)carbamino acid (example B5) (3,40 g, 10 mmol), hydrochloride of cyclopropanemethylamine (3,22 g, 30 mmol) and triethylamine (6,97 ml, 50 mmol) in dimethyl sulfoxide (50 ml) at 23°according to the standard procedure C. the Product was obtained in a solid yellow color (3,74 g).

MS (ISP) 374,2 [(M+N)+].

Example C18

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

Specified in the title compound was obtained from tert-butyl ether (2-chloro-2'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid (example D3) (9,568 g, approximately 26 mmol) and dimethylamine (60% in water, 12 ml) in dimethyl sulfoxide (87 ml) at 23°according to the standard procedure C. the Product was obtained in a solid yellow color (4,54 g).

MS (ISP) 376.3 on [(M+N)+].

Example C19

tert-Butyl ester (5-dimethylamino-4-methyl-2-nitrophenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-4-methyl-2-nitrophenyl)carbamino acid (example B8) (3.5 g, 12.2 mmole) and dimethylamine (11 ml, 33% in ethanol, 61,0 mmol) in dimethyl sulfoxide (35 ml) at 50°according to the standard procedure C. the Product was obtained in a solid yellow color (3.50 g, 97%).

MS (ISP) 296,3 [(M+N)+].

Example C20

tert-Butyl ester (4-cyan-5-dimethylamino-2-nitrophenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-fluoro-2-nitrophenyl)carbamino acid (example B9) (2.0 g, 7, 11 mmole) and dimethylamine (6.3 ml, 33% in ethanol, 35,0 mmol) in dimethyl sulfoxide (30 ml) at room temperature according to standard procedure C. the Product was obtained in a solid yellow color (1,87 g, 86%).

MS (ISP) 307,3 [(M+N)+].

Example C21

tert-Butyl ester [4-methyl-5-(methylpropylamine)-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-4-methyl-2-nitrophenyl)carbamino acid (example B8) (3.5 g, 12.2 mmole) and N-methylpropylamine (6.5 ml, 61,0 mmol) in dimethyl sulfoxide (35 ml) at 55°according to the standard procedure C. the Product was obtained as yellow oil (to 3.89 g, 98%).

MC (ISP) 324,4[(M+H)+].

Example C22

tert-Butyl ester of [5-(ethylmethylamino)-4-methyl-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-4-methyl-2-nitrophenyl)carbamino acid (example B8) (3.5 g, 12.2 mmole) and N-ethylmethylamine (5.5 ml, 61,0 mmol) in dimethyl sulfoxide (35 ml) at 55°according to the standard procedure C. the Product was obtained in a solid yellow color (3.58 g, 95%).

MS (ISP) 310,3 [(M+H) +].

Example C23

tert-Butyl ester [4-chloro-5-(isopropylethylene)-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4,5-dichloro-2-nitrophenyl)carbamino acid (example B2) (5.0 g, 16.3 mmole) and N-isopropylbenzylamine (5,95 g, 81,4 mmole) in dimethyl sulfoxide (50 ml) at 75°according to the standard procedure C. the Product was obtained in a solid yellow color (4,07 g, 73%).

MS (ISP) 344,3 [(M+N)+].

Example C24

tert-Butyl ester [4-chloro-5-(isobutylamino)-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4,5-dichloro-2-nitrophenyl)carbamino acid (example B2) (5.0 g, 16.3 mmole) and N-isobutylamine (7,09 g, 81,4 mmole) in dimethyl sulfoxide (50 ml) at room temperature according to standard procedure C. the Product was obtained as brown oil (5,79 g, 99%).

MS (ISP) 358,2 [(M+N)+].

Example C25

tert-Butyl ester (4-cyan-2-nitro-5-pyrrolidin-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-fluoro-2-nitrophenyl)carbamino acid (example B9) (2.0 g, 7, 11 mmole) and pyrrolidine (2,94 ml, 35,6 mmole) in dimethyl sulfoxide (30 ml) at room temperature according to standard procedure C. the Product was obtained in the form of a solid yellow what about the color (1.97 g, 83%).

MC (ISN) 331,2 [(M-H)-].

Example s

tert-Butyl ester [4-cyan-5-(methylpropylamine)-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-fluoro-2-nitrophenyl)carbamino acid (example B9) (1,95 g, 6,93 mmole) and N-methyl-Propylamine (and 3.72 ml, or 34.7 mmole) in dimethyl sulfoxide (20 ml) at room temperature according to standard procedure C. the Product was obtained in a solid yellow color (1.75 g, 75%).

MS (ISN) TO 333.3 [(M-N)-].

The example On 27

tert-Butyl ester (4-cyan-5-diethylamino-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-fluoro-2-nitrophenyl)carbamino acid (example B9) (1,95 g, 6,93 mmole) and N,N-diethylamine (of 3.60 ml, or 34.7 mmole) in dimethyl sulfoxide (20 ml) at room temperature according to standard procedure C. the Product was obtained in a solid yellow color (1.78 g, 77%).

MS (ISN) 333,2 [(M-N)-].

Example s

tert-Butyl ester [4-cyan-5-(isopropylethylene)-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-fluoro-2-nitrophenyl)carbamino acid (example B9) (1,95 g, 6,93 mmole) and N-isopropyl-N-methylamine (of 3.60 ml, or 34.7 mmole) in dimethyl sulfoxide (30 ml) at room temperature according to standard techniques is C. The product was obtained in a solid yellow color (1.84 g, 79%).

MS (ISN) TO 333.3 [(M-N)-].

Example s

tert-Butyl ester [4-cyan-5-(isobutylamino)-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-fluoro-2-nitrophenyl)carbamino acid (example B9) (1,95 g, 6,93 mmole) and N-isobutyl-N-methylamine (3,02 g, to 34.7 mmole) in dimethyl sulfoxide (20 ml) at room temperature according to standard procedure C. the Product was obtained in a solid yellow color (1,87 g, 77%).

MS (ISN) 347,4 [(M-N)-].

Example C30

tert-Butyl ester (4-cyan-2-nitro-5-piperidine-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-fluoro-2-nitrophenyl)carbamino acid (example B9) (2.0 g, 7, 11 mmole) and piperidine (3,51 ml, 35,6 mmole) in dimethyl sulfoxide (20 ml) at room temperature according to standard procedure C. the Product was obtained in a solid yellow color (1,94 g, 79%).

MS (ISN) 345,3 [(M-N)-].

Example A31

tert-Butyl ester (4-chloro-5-isobutylamino-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4,5-dichloro-2-nitrophenyl)carbamino acid (example B2) (3.0 g, 9.7 mmole) and isobutylamine (3.57 g, and 48.8 mmole) in dimethyl sulfoxide (20 ml) at 55°Soglasno standard method C. The product was obtained in a solid brown color (of 2.26 g, 67%).

MS (ISP) 344,2 [(M+N)+].

Example C32

tert-Butyl ester of [5-(methylpropylamine)-2-nitro-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-2-nitro-4-triptoreline)carbamino acid (example B5) (4,00 g of 11.7 mmole), N-methylpropylamine (1.89 ml, to 17.6 mmole) and triethylamine (5,73 ml, 41, 1 mmole) in dimethyl sulfoxide (30 ml) at room temperature according to standard procedure C. the Product was obtained in a solid yellow color (Android 4.04 g, 91%).

MS (ISP) 378,3 [(M+N)+].

Example s

tert-Butyl ester of [5-(isobutylamino)-2-nitro-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-2-nitro-4-triptoreline)carbamino acid (example B5) (4,00 g of 11.7 mmole), N-isobutylamine (1.54 g, to 17.6 mmole) and triethylamine (5,73 ml, 41,1 mmole) in dimethyl sulfoxide (30 ml) at room temperature according to standard procedure C. the Product was obtained in a solid yellow color (4,18 g, 91%).

MS (ISN) 390,3 [(M-N)+].

Example S

tert-Butyl ester of [5-(isopropylethylene)-2-nitro-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-2-neither the ro-4-triptoreline)carbamino acid (example B5) (4,00 g, an 11.7 mmole), N-isopropylacrylamide (3,67 ml of 35.2 mmole) and triethylamine (5,73 ml, 41,1 mmole) in dimethyl sulfoxide (30 ml) at 50°according to the standard procedure C. the Product was obtained in a solid yellow color (3,27 g, 74%).

MS (ISN) 376.3 ON [(M-N)-].

Example s

tert-Butyl ester of [5-(isobutylamino)-4-methyl-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-4-methyl-2-nitrophenyl)carbamino acid (example B8) (3,01 g, 10.5 mmole) and N-isobutylamine (4,56 g, 52,3 mmole) in dimethyl sulfoxide (30 ml) at 55°according to the standard procedure C. the Product was obtained as yellow oil (1.84 g, 52%).

MS (ISN) 336,3 [(M-N)-].

Example C36

tert-Butyl ester (4-methyl-2-nitro-5-pyrrolidin-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-4-methyl-2-nitrophenyl)carbamino acid (example B8) (3,01 g, 10.5 mmole) and pyrrolidine (4,33 ml, 52,3 mmole) in dimethyl sulfoxide (30 ml) at 55°according to the standard procedure C. the Product was obtained in a solid yellow color (3,27 g, 97%).

MS (ISN) 320,3 [(M-N)-]; tPL145°C.

Example S

tert-Butyl ester (4-chloro-5-isopropylamino-2-nitrophenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4,5-d is chloro-2-nitrophenyl)carbamino acid (example B2) (5.0 g, 16.3 mmole) and Isopropylamine (7,0 ml, 81,4 mmole) in dimethyl sulfoxide (35 ml) at 55°according to the standard procedure C. the Product was obtained in a solid brown color (3,95 g, 73%).

MS (ISP) 330,2 [(M+N)+].

Example S

tert-Butyl ether (5 isobutylamino-2-nitro-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-chloro-2-nitro-4-triptoreline)carbamino acid (example B5) (5,00 g, 14.7 mmole), isobutylamine (of 7.36 ml, 73,4 mmole) in dimethyl sulfoxide (35 ml) at room temperature according to standard procedure C. the Product was obtained in a solid yellow color (5,39 g, 97%).

MS (ISN) 376.3 ON [(M-N)-].

Standard method D

Obtain tert-butyl ester (4-aryl-2-nitrophenyl)karbinovykh acids by the direct combination of Suzuki tert-butyl ester (4-iodine-2-nitrophenyl)karbinovykh acids airborne acids

A mixture of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (3.0 mmole), airborne acid (4.5 mmole) and PdCl2(PPh3) (2 mol.%) boiled under reflux B1,4-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 (Ph3R)4Pd (3 mol.%) in 1,2-dimethoxyethane (30 ml); it is also possible with the triethylamine is m (9.0 mmol), Pd(OAc)2(3 mol.%), PPh3(6 mol.%) in dimethylformamide (10 ml) at 100°] up until according to TLC did not show complete conversion of the iodide. The mixture was transferred into a separating funnel, was added water (25 ml) and product was extracted with diethyl ether or ethyl acetate (3×30 ml). The combined organic layers were then washed with brine (50 ml) and dried over sodium sulfate. After removal of the solvent left a brown residue, which was purified by column chromatography on silica gel, elwira cyclohexane/diethyl ether or cyclohexane/ ethyl acetate, has been specified in the title compound.

Example D1

tert-Butyl ether (2-dimethylamino-2',3'-debtor-5-nitrobiphenyl-4-yl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-4-iodine-2-nitrophenyl)carbamino acid (example C2) and 2,3-diperpanjang acid according to the standard method D. the Product was obtained in a solid yellow color (3,096 g).

MS (ISN) 392 [(M-N)-].

Example D2

tert-Butyl ether [2'-fluoro-5-nitro-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [4-iodine-2-nitro-5-(2,2,2-triptoreline)phenyl]carbamino acid (example B4) and 2-ftorpolimernoj acid according to the SNO standard method D. The product was obtained in a solid yellow color (1.39 g).

MS (ISP) 491 [(M+N)+]; tPL73-75°C.

Example D3

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

Specified in the title compound was obtained from tert-butyl ether (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (30 g, 75,3 mmole) and 2-ftorpolimernoj acid (13,82 g, 98,8 mmole) according to the standard method D. the Product was obtained as a resinous substance yellow (1.39 g).

MS (ISN) 365 [(M-N)-].

Standard method E

Obtain tert-butyl ester (4-aryl-2-nitrophenyl)karbinovykh acids by combining Suzuki tert-butyl ester (4-iodine-2-nitrophenyl)karbinovykh acids with bis(pinacolato)diboron and subsequent reaction with guidarelli

A mixture of tert-butyl methyl 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 complete conversion of the iodide according to TLC [cf. Tetr. Lett.1997, 38, 3841-3844]. After addition of halodrol (4.0 mmole), PdCl2(PPh3)2(3 mol.%) and 2 M sodium carbonate solution (7.5 ml) and the mixture was stirred at 100°up until TLC indicated full conversion of the intermediate complex ester of boric acid. A mixture of TRANS who wore into a separating funnel, was added water (30 ml) and the product was extracted with diethyl ether or ethyl acetate (3×50 ml). The combined organic layers were washed with brine (100 ml) and dried over sodium sulfate. After removal of the solvent was obtained brown residue, which was purified by column chromatography on silica gel, elwira cyclohexane/diethyl ether or cyclohexane/ethyl acetate, has been specified in the title compound.

Standard method F

Getting 5-chloro-2-nitro-4-pyrrol-1-ilfenomeno by condensation of 5-chloro-2-nitro-1,4-phenylenediamine with 2.5-dimethoxytetrahydrofuran [cf. J.Heterocycl. Chem. 1988, 25, 1003-1005]

A mixture of 5-chloro-2-nitro-1,4-phenylenediamine (4,69 g, 25 mmol), 2,5-dimethoxy-tetrahydrofuran (26-32,5 mmole) in acetic acid (150 ml) was stirred at 60 to 120°up until TLC indicated full conversion of the phenylenediamine. After cooling to 23°the mixture was poured into brine (500 ml) and was extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with brine (300 ml) and dried over MgSO4. Removal of the solvent led to a brown residue, which was purified by column chromatography on silica gel, elwira cyclohexane/ethyl acetate, has been specified in the title compound.

Standard method G

Obtaining 2,5-dimethoxy what hydrofuran by the synthesized furan methanol [cf. Tetrahedron 1971, 27, 1973-1996]

To a solution of furan (177,5 mmole) in a mixture of anhydrous diethyl ether (54 ml) and absolute methanol (79 ml) at -35°With added gradually with stirring bromide (10.0 ml, 195 mmol) in methanol (105 ml). The reaction mixture was stirred for 30 minutes, saturated with gaseous NH3to pH 8 and gave the mixture to warm to 23°C. was Poured into a mixture of ice and water, was extracted with diethyl ether (3×400 ml), washed with brine, dried over sodium sulfate. After evaporation of the solvent left a yellow liquid, which was purified by distillation under vacuum, has been specified in the title compound.

The standard technique N

Obtain tert-butyl ester (4-quinil-2-nitrophenyl)karbinovykh acids through a combination of on Sonogashira tert-butyl ester (4-iodine-2-nitrophenyl)karbinovykh acid derivative of acetylene, also through a combination of on Sonogashira tert-butyl ester (4-ethinyl-2-nitrophenyl)karbinovykh acids with guidarelli

A mixture of halide compounds (3.0 to 4.5 mmole), acetylene derivative (3.0 to 4.5 mmole), triethylamine (13.5 mmol), PdCl2(PPh3)2(5 mol.%) and PPh3(to 2.5 mol.%) in tetrahydrofuran (12 ml) [in the case of poorly soluble substances could be added dimethylformamide (12 ml)] was stirred for 20 minutes at 23°injecting argon. Was added Cul (1.2 m is l%) and continued stirring at 60° C in argon atmosphere up until TLC indicated full conversion of the least significant component [cf. J.Org. Chem. 1998, 63, 8551]. The mixture was transferred into a separating funnel, was added 5% citric acid (50 ml) and product was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (50 ml) and with brine (50 ml), then dried over MgSO4. Removal of the solvent led to a yellow residue, which was purified by column chromatography on silica gel, elwira hexane/ethyl acetate, and/or triturated with hexane or water-ethanol, has been specified in the title compound.

Example H1

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

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-4-iodine-2-nitrophenyl)carbamino acid (example C2) (386 mg, 0.97 mmole) and phenylacetylene (149 mg, of 1.46 mmole) according to the standard method N. The product was obtained in the form of a solid orange color (370 mg).

MS (EI) 381 (M+); tPL141-149°C.

Standard method J

Obtain tert-butyl ester (2-AMINOPHENYL)karbinovykh acids by restoring tert-butyl ester (2-nitrophenyl)karbinovykh acids

Method A. Catalytic hydrogenation

The mixture NIT is soedineniya (1.0 mmol) in methanol or ethanol and tetrahydrofuran (1:1, about 20 ml) [or only in ethyl acetate for chlorinated aromatic compounds] and 10%palladium on coal (20 mg), Nickel Raney catalyst (20 mg) or 5%platinum on coal intensively stirred at 23°C in an atmosphere of hydrogen until, while according to TLC did not observe a complete chemical transformation. The catalyst was filtered, thoroughly washed with methanol or ethanol and tetrahydrofuran (1:1) [or ethyl acetate], the solvent was removed in vacuum, has been specified in the title compound, which was usually pure enough for further transformations, but if necessary could be recrystallized from hot hexane.

Method B. Recovery using SnCl2·2H2O

The mixture of nitro compounds (1.0 mmol) and SnCl2·2H2About (5.0 mmol) was stirred either in ethanol (30 ml) at 70-80°With or an alternative in pyridine (3 ml) and dimethylformamide (12 ml) at 23°in argon atmosphere up until according to TLC did not observe a complete chemical transformation [cf. Tetr. Lett.1984, 25, 839]. Established in the reaction mixture a pH of 8 by adding saturated sodium bicarbonate solution and was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent led to the solid substance, yellow, which if necessary, can be purified by column chromatography on silica gel.

The way century. Recovery using zinc and ammonium chloride

To a mixture of nitro compounds (1.0 mmol) in ethanol/tetrahydrofuran/saturated solution of ammonium chloride (1:1:1, 30 ml) was added zinc dust (3.0 mmole) and the mixture was stirred at 70°in argon atmosphere up until according to TLC did not complete chemical transformation. Water processing were performed as described in method B.

Example J1

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

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-dimethylamino-2-nitrophenyl)carbamino acid (example C1) (2.76 g, a total of 8.74 mmole) when restoring SnCl2·2H2O according to the standard procedure J (method b). The connection was received in the form of a solid orange color (2.3 g).

MS (ISP) 286 [(M+N)+] 288 [(M+2+N)+]; tPL96-101°C.

Example J2

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

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-2-nitro-4-phenylethylene)carbamino acid (example H1) when restoring SnCl2·2H2O according to the standard procedure J (method b). Connected to the ies received in the form of a solid brown color (1,927 g).

MS (ISP) 352 [(M+N)+].

Example J3

tert-Butyl ester (5-amino-2-dimethylamino-2',3'-diferuloyl-4-yl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-dimethylamino-2',3'-debtor-5-nitrobiphenyl-4-yl)carbamino acid (example D1) when restoring SnCl2·2H2O according to the standard procedure J (method b). The product was obtained in the form of a solid orange color (2,206 g).

MS (ISP) 364 [(M+N)+].

Example J4

tert-Butyl ether {2-amino-4-chloro-5-[(2-methoxyethyl)methylamino]phenyl}-carbamino acid

Specified in the title compound was obtained from tert-butyl ester {4-chloro-5-[(2-methoxyethyl)methylamino]-2-nitrophenyl}carbamino acid (example C3) (of 3.46 g, 9,62 mmole) when restoring SnCl2·2H2O according to the standard procedure J (method b). The compound was obtained in a solid yellow color (2.25 g).

MS (ISP) 330 [(M+N)+] 332 [(M+2+N)+]; tPL112°C.

Example J5

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

Specified in the title compound was obtained from tert-butyl ether [2'-fluoro-5-nitro-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid (example D2) when the hydrogenation in prisutstvie% Pd/C according to the standard procedure J (method a). The product was obtained in the form of Targovishte gray (1,17 g).

MC (ISP) 401(M+H)+].

Example J6

tert-Butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-2-nitro-4-triptoreline)carbamino acid (example C4) when the hydrogenation in prisutstvie% Pd/C according to the standard procedure J (method a). The compound was obtained as an amorphous yellow substance (1,34 g).

MS (ISP) 320 [(M+N)+].

Example J7

tert-Butyl ether [2-amino-4-chloro-5-(ethylmethylamino)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [4-chloro-5-(ethylmethylamino)-2-nitrophenyl]carbamino acid (example C5) (3.0 g, which is 9.09 mmole) when restoring SnCl2·2H2O according to the standard procedure J (method b). The connection was received in the form of a solid pale brown (2.64 g).

MS (ISP) 300,3 [(M+N)+]; tPL81°C.

Example J8

tert-Butyl ether [2-amino-4-chloro-5-(methylpropylamine)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [4-chloro-5-(methylpropylamine)-2-nitrophenyl]carbamino acid (example C6) (3.15 g, 9,16 mmole) when restoring SnCl2·2H2O according to the standard procedure J (method b). The connection was received in the form of a solid pale brown is th color (2.58 g).

MS (ISP) 314,3 [(M+H)+]; tPL92°C.

Example J9

tert-Butyl ether [2-amino-4-chloro-5-(diethylamino)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [4-chloro-5-(diethylamino)-2-nitrophenyl]carbamino acid (example C7) (2.25 g, is 6.54 mmole) when restoring SnCl2·H2O according to the standard procedure J (method b). The connection was received in the form of a solid orange color (1.55 g).

MS (ISP) 314,3 [(M+N)+]; tPL110°C.

Example J10

tert-Butyl ether (2-amino-4-chloro-5-pyrrolidin-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-chloro-2-nitro-5-pyrrolidin-1-ylphenyl)carbamino acid (example C8) when restoring SnCl2·2H2About according to the standard procedure J (method b). The compound was obtained in a solid red color (4,80 g).

MS (ISP) 312 [(M+N)+] 314 [(M+2+N)+]; tPL136-138°C.

Example J11

tert-Butyl ether [2-amino-4-chloro-5-(cyclopropylamino)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [4-chloro-5-(cyclopropylamino)-2-nitrophenyl]carbamino acid (example C9) (3.2 g, 9,36 mmole) when restoring SnCl2·H2O according to the standard procedure J (method b). Was soedineniya in a solid brown color (2.00 d).

MS (ISP) 312 [(M+N)+] 314 [(M+2+N)+].

Example J12

tert-Butyl ether (2-amino-5-pyrrolidin-1-yl-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-nitro-5-pyrrolidin-1-yl-4-triptoreline)carbamino acid (example C10) (7,35 g, 19,75 mmole) by hydrogenation with 10% Pd/C according to the standard procedure J (method a). The connection was received in the form of a solid light orange color (6.75 g).

MS (ISP) 346 [(M+N)+]; tPL101-103°C.

Example J13

tert-Butyl ether (2-amino-5-dimethylamino-4-forfinal)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-4-fluoro-2-nitrophenyl)carbamino acid (example C11) (4,88 g, 16 mmol) by hydrogenation with 10% Pd/C according to the standard procedure J (method a). The compound was obtained in a solid green color (4,55 g).

MS (ISP) 270 [(M+N)+]; tPL120-123°C.

Example J14

tert-Butyl ether (2-amino-4-chloro-5-piperidine-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-chloro-2-nitro-5-piperidine-1-ylphenyl)carbamino acid (example 12) when restoring SnCl2·2H2O according to the standard procedure J (method b). The connection was received in the form of a solid light brown is th color (747 mg).

MS (ISP) 326 [(M+N)+] 328 [(M+2+N)+]; tPL149-151°C.

Example J15

tert-Butyl ether (2-amino-4-fluoro-5-pyrrolidin-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-fluoro-2-nitro-5-pyrrolidin-1-ylphenyl)carbamino acid (example C13) (6,37 g, 20 mmol) by hydrogenation with 10% Pd/C according to the standard procedure J (method a). The connection was received in the form of a solid gray color (of 5.92 g).

MS (ISP) 296 [(M+N)+]; tPL75-76°C.

Example J16

tert-Butyl ether (2-amino-5-azetidin-1-yl-4-chlorophenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5 azetidin-1-yl-4-chloro-2-nitrophenyl)carbamino acid (example 14) by hydrogenation with 5% Pt/C according to the standard procedure J (method a). The compound was obtained in a solid white color (3,664 g).

MS (ISP) 298 [(M+N)+] and 300 [(M+2+N)+]; tPL176-179°C.

Example J17

tert-Butyl ether (2-amino-5-azetidin-1-yl-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5 azetidin-1-yl-2-nitro-4-triptoreline)carbamino acid (example 15) by hydrogenation with 5% Pt/C according to the standard procedure J (method a). The compound was obtained in a solid white color (5,173 g).

MS (ISP) 33 [(M+N) +]; tPL166-167°C.

Example J18

tert-Butyl ether [2-amino-5-(cyclopropanemethylamine-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [5-(cyclopropanemethylamine)-2-nitro-4-triptoreline)carbamino acid (example C16) (5,66 g, 14.5 mmole) when restoring SnCl2·2H2O according to the standard procedure J (method b). The compound was obtained in a solid yellow color (4.7 g).

MS (ISP) 360 [(M+N)+]; tPL56°C.

Example J19

tert-Butyl ether [2-amino-5-(cyclopropylamino)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [5-(cyclopropylamino)-2-nitro-4-triptoreline]carbamino acid (example 17) (3,74 g, 9,96 mmole) when restoring SnCl2·2H2O according to the standard procedure J (method b). The connection was received in the form of semi-solid substances orange (2.00 d).

MC (ISP) 346,4 [(M+H)+].

Example J20

tert-Butyl ester (5-amino-2-dimethylamino-2'-forbiden-4-yl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-dimethylamino-2'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid (example 18) (4,54 g, 12,1 mmole) by hydrogenation with 10% Pd/C according to the standard method J (with whom persons). The product was obtained in the form of a solid light brown color (3,324 g).

MC (ISP) 346,4 [(M+N)+].

Example J21

tert-Butyl ether [2-amino-5-(2,2,2-triptoreline)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-nitro-5-(2,2,2-triptoreline)-4-triptoreline]carbamino acid (example B7) by hydrogenation with 5% Pt/C according to the standard procedure J (method a). The compound was obtained in a solid yellow color (17,374 g).

MC (ISP) 375 [(M+N)+].

Example J22

tert-Butyl ether (2-amino-5-dimethylamino-4-were)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-4-methyl-2-nitrophenyl)carbamino acid (example C19) (3,22 g of 10.9 mmole) by hydrogenation with 10% Pd/C according to the standard procedure J (method a). The product was obtained in the form of a solid gray color (2,05 g, 58%).

MC (ISP) 266,3 [(M+N)+]; tPL78°C.

Example J23

tert-Butyl ether (2-amino-4-cyan-5-dimethylaminophenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-dimethylamino-2-nitrophenyl)carbamino acid (example 20) (3,9 g, 12.7 mmole) when restoring using SnCl2·H2O according to the standard procedure J (method b). The product was obtained in the de solid pale brown (2,05 g, 58%).

MS (ISP) 277.2 M. [(M+N)+]; tPL120°C.

Example J24

tert-Butyl ether [2-amino-4-methyl-5-(methylpropylamine)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [4-methyl-5-(methylpropylamine)-2-nitrophenyl]carbamino acid (example C21) (3,59 g, 11.1 mmole) by hydrogenation with 10% Pd/C according to the standard procedure J (method a). The product was obtained as solid Magenta (3,23 g, 99%).

MS (ISP) 294,4 [(M+N)+].

Example J25

tert-Butyl ether [2-amino-5-(ethylmethylamino)-4-were]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [5-(ethylmethylamino)-4-methyl-2-nitrophenyl]carbamino acid (example 22) (3.28 g, 10.6 mmole) by hydrogenation with 10% Pd/C according to the standard procedure J (method a). The product was obtained as solid Magenta (2,94 g, 99%).

MS (ISP) 280,3 [(M+N)+].

Example J26

tert-Butyl ether [2-amino-4-chloro-5-(isopropylethylene)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [4-chloro-5-(isopropylethylene)-2-nitrophenyl]carbamino acid (example C23) (4,07 g, 11.8 mmole) when restoring using SnCl2·2H2O according to the standard procedure J (method b). The product was obtained as a solid substance pale-coric is avago color (is 3.08 g, 83%).

MS (ISP) 314,3 [(M+N)+]; tPL116°C.

Example J27

tert-Butyl ether [2-amino-4-chloro-5-(isobutylamino)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [4-chloro-5-(isobutylamino)-2-nitrophenyl]carbamino acid (example C24) (of 5.55 g of 15.5 mmole) when restoring using SnCl2·2H2O according to the standard procedure J (method b). The product was obtained in the form of a solid pale brown (3.98 g, 78%).

MS (ISP) 328,3 [(M+N)+].

Example J28

tert-Butyl ether (2-amino-4-cyan-5-pyrrolidin-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-cyan-2-nitro-5-pyrrolidin-1-ylphenyl)carbamino acid (example C25) (1,82 g of 5.48 mmole) when restoring using SnCl2·2H2O according to the standard procedure J (method b). The connection was received in the form of a solid pale brown (1.27 g, 77%).

MS (ISP) 303,2 [(M+N)+].

Example J29

tert-Butyl ether [2-amino-4-cyan-5-(methylpropylamine)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [4-cyan-5-(methylpropylamine)-2-nitrophenyl]carbamino acid (example C) (1.64 g, 4,90 mmole) when restoring using SnCl2·2H2O according to the standard the first method J (method b). The product was obtained in the form of oil is dark red (1.24 g, 83%).

MS (ISP) 305,3 [(M+N)+].

Example J30

tert-Butyl ether (2-amino-4-cyan-5-diethylaminophenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-diethylamino-2-nitrophenyl)carbamino acid (example On 27) (1.66 g, 4,96 mmole) when restoring using SnCl2·2H2O according to the standard procedure J (method b). The product was obtained in the form of not-quite-white solid (1,38 g, 91%).

MS (ISP) 305,3 [(M+N)+]; tPL151°C.

Example J31

tert-Butyl ether [2-amino-4-cyan-5-(isopropylethylene)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [4-cyan-5-(isopropylethylene)-2-nitrophenyl]carbamino acid (example C) (1.73 g, of 5.17 mmole) when restoring using SnCl2·2H2O according to the standard procedure J (method b). The product was obtained in the form of not-quite-white solid (1.56 g, 99%).

MS (ISP) 305,3 [(M+N)+]; tPL77°C.

Example J32

tert-Butyl ether [2-amino-4-cyan-5-(isobutylamino)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [4-cyan-5-(isobutylamino)-2-nitrophenyl]carbamino acid (example C) (1,76 g of 5.05 mmole) when restoring with what label SnCl 2·2H2O according to the standard procedure J (method b). The product was obtained in the form of a solid light brown color (1.55 g, 96%).

MS (ISP) 319,5 [(M+N)+]; tPL88°C.

Example J33

tert-Butyl ether (2-amino-4-cyan-5-piperidine-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-cyan-2-nitro-5-piperidine-1-ylphenyl)carbamino acid (sample C30) (2,08 g, 5,71 mmole) when restoring using SnCl2·2H2O according to the standard procedure J (method b). The connection was received in the form of not-quite-white solid (1,67 g, 99%).

MS (ISP) 317,2 [(M+N)+]; tPL86°C.

Example J34

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

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-isobutylamino-2-nitrophenyl)carbamino acid (example A31) (1,93 g, 5,61 mmole) when restoring using SnCl2·2H2O according to the standard procedure J (method b). The compound was obtained in a solid brown color (1,30 g, 74%).

MC (ISP) 314,3 [(M+H)+].

Example J35

tert-Butyl ether [2-amino-5-(methylpropylamine)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [5-(methylpropylamine)-2-nitro-4-Tr is formationl]carbamino acid (example S32) (of 3.78 g, 10.0 mmole) by hydrogenation with 10% Pd/C according to the standard procedure J (method a). The connection was received in the form of oil red (3,40 g, 98%).

MS (ISP) 248,4 [(M+N)+].

Example J36

tert-Butyl ether [2-amino-5-(isobutylamino)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [5-(isobutylamino)-2-nitro-4-triptoreline]carbamino acid (example C) (3.88 g, to 9.91 mmole) by hydrogenation with 10% Pd/C according to the standard procedure J (method a). The compound was obtained as orange oil (2.70 g, 75%).

MS (ISP) 362,3 [(M+N)+].

Example J37

tert-Butyl ether [2-amino-5-(isopropylethylene)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [5-(isopropylethylene)-2-nitro-4-triptoreline]carbamino acid (example C) (2,98 g of 7.90 mmole) by hydrogenation with 10% Pd/C according to the standard procedure J (method a). The compound was obtained as orange oil (2,42 g, 88%).

MS (ISP) 348,5 [(M+N)+].

Example J38

tert-Butyl ether [2-amino-5-(isobutylamino)-4-were]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [5-(isobutylamino)-4-methyl-2-nitrophenyl]carbamino acid (example C) (1.48 g, 4,39 mmole) in the hydrogenation of c 1% Pd/C according to the standard procedure J (method a). The compound was obtained in a solid white color (1.08 g, 80%).

MS (ISP) 308,3 [(M+N)+]; tPL71°C.

Example J39

tert-Butyl ether (2-amino-4-methyl-5-pyrrolidin-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (4-methyl-2-nitro-5-pyrrolidin-1-ylphenyl)carbamino acid (example C36) (3,27 g, 10.2 mmole) by hydrogenation with 10% Pd/C according to the standard procedure J (method a). The connection was received in the form of a solid pale brown (2,48 g, 83%).

MS (ISP) 292,3 [(M+N)+]; tPL115°C.

Example J40

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

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-isopropylamino-2-nitrophenyl)carbamino acid (example C) (3.75 g, 11.3 mmole) when restoring using SnCl2·H2O according to the standard procedure J (method b). The compound was obtained in a solid brown color (2,90 g, 86%).

MS (ISP) 303,3 [(M+N)+].

Example J41

tert-Butyl ether [2-amino-5-(isobutylamino)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [5-(isobutylamino)-2-nitro-4-triptoreline]carbamino acid (example C) (5,28 g 13,99 mmole) by hydrogenation with 10% Pd/C solenostomidae method J (method a). The connection was received in the form of a solid pale yellow color (3,69 g, 76%).

MS (ISP) 348,5 [(M+N)+]; tPL141°C.

The following examples relate to the generation ethyl or tert-butyl esters of 3-aryl-3-oxopropionate acids (General formula IVa), which serve as building blocks for the synthesis of target compounds (synthesis scheme C):

The standard technique To

Method a). Getting 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 arylcarboxylic acids and the potassium salt of ethyl or tert-butyl ester of malonic acid [CAS-No. 6148-64-7 and 75486-33-8] when reacted with triethylamine and magnesium chloride in acetonitrile at a temperature from 0 to 23°as described in Synthesis 1993, 290. If this reaction was used free arylcarbamoyl acid, its to reaction with the salt of malonic acid activated by treatment with etelcharge.com and triethylamine in tetrahydrofuran/acetonitrile at 0°C.

Method b). Obtain tert-butyl ester 3-aryl-3-oxopropionate acids

Alternative tert-butyl ester 3-aryl-3-oxopropionate acids were obtained from complex methyl or ethylaniline esters in the processing of the lithium derivative of tert-butyl acetate [obtained about what abode tert-butyl acetate by diisopropylamide lithium in tetrahydrofuran at -78° S] in the presence of tert-butyl lithium according to Synthesis 1985, 45. If the product contained after treatment residual starting material, it could be removed by selective saponification with lithium hydroxide in tetrahydrofuran/methanol/water at 23°C.

The way in). Obtaining 3-aryl-3-oxopropionate acids

3-Aryl-3-oxopropionate acid obtained from the acid chlorides arylcarboxylic acids and bis(trimethylsilyl)malonate when reacted with triethylamine and lithium bromide in acetonitrile at 0°according to Synth. Commun. 1985, 15, 1039 (method B1) or with n-BuLi in diethyl ether at temperatures from -60°0°according to Synthesis 1979, 787 (method B2).

Example K1

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

Specified in the title compound was obtained from 3-[1,2,3]triazole-1-eventing acid, obtained by boiling under reflux methyl ester 3-azidobenzoyl acid [CAS-No. 93066-93-4] trimethylsilylacetamide with subsequent saponification aqueous sodium hydroxide in boiling alcohol, when activating etelcharge.com/triethylamine and the reaction with the potassium salt of ethylmalonate in the presence of triethylamine and magnesium chloride in acetonitrile according to the standard method (method a). The product was obtained in the form of a solid light-yellow color (2,22 g).

MS (EI) 259 (M+); tPL72-74°C.

Note the R K2

tert-Butyl ether 3-(3-tianfeng)-3-oxopropanoic acid

Specified in the title compound was obtained from methyl ester 3-lambertini acid [CAS-No. 13531-48-1] when processing the lithium derivative of tert-butylate according to the standard procedure K (method b). The connection was received in the form of semi-solid oily substance light brown color.

MS (EI) 245 (M+).

Example K3

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

Specified in the title compound was obtained from ethyl ether 2-cialisonlinenow acid [CAS-No. 58481-14-4] when processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The connection was received in the form of a solid light brown color (of 7.70 g).

MS (ISN) 245 [(M-N)-].

Example K4

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

Specified in the title compound was obtained from ethyl ester 3-(3-methylisoxazol-5-yl)benzoic acid [obtained by the reaction of ethyl ester of 3-ethynylbenzene acid [CAS-No.178742-95-5] with a mixture of N-chlorosuccinimide, acetaldoxime, triethylamine and a catalytic amount of pyridine in chloroform at 50°according to Tetrahedron 1984, 40, 2985-2988] when processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The floor connection is made in a solid yellow color (2,54 g).

MS (ISP) 302 [(M+N)+]; tPL50-56°C.

Example K5

tert-Butyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl)propionic acid

Specified in the title compound was obtained from methyl ester (RS)-3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]benzoic acid [obtained using the following sequence of reactions. i) Methyl ether 3-azidobenzoyl acid [CAS-No. 93066-93-4] (15,55 g, 88 mmol) and (RS)-tert-butultimately-[3-(tetrahydropyran-2-yloxy)prop-1-inyl]silane [CAS-No. 135294-85-8] (33,50 g, 132 mmole) was heated at 60°within 10 days. ii) the resulting substance (or 48.2 g, 88 mmol) was stirred in tetrabutylammonium (300 ml, 1 M in tetrahydrofuran) at 70°C for 6 days and then boiled under reflux in 1 N. hydrochloric acid (400 ml) for 2 hours. iii) the resulting substance (16,15 g, 74 mmole) was stirred in methanol (400 ml) and concentrated sulfuric acid (30 ml) at 23°C for 11 days. iv) a Part of the obtained substances (4,60 g, 19.7 mmole) was subjected to reaction with 3,4-dihydro-2H-Piran (or 2.67 ml of 29.5 mmole) and a catalytic amount of p-TsOH·H2O in dichloromethane (38 ml) at 23°C for 20 hours] (6.20 g, 19.5 mmole) when handling the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The product was obtained as yellow oil (of 8.47 g).

MS (SP) 402 [(M+N) +].

Example K6

tert-Butyl ester 3-[2-(3-methylisoxazol-5-yl)pyridin-4-yl]-3-oxopropanoic acid

Specified in the title compound was obtained from methyl ester of 2-(3-methylisoxazol-5-yl)isonicotinic acid [obtained by (i) reaction of methyl ether 2-madisoncounty acid [CAS-No. 134579-47-8] trimethylsilylacetamide according to the standard method H; (ii) desilicious by reaction with a catalytic amount of potassium carbonate in methanol at 0°C for 4 hours; (iii) cyclopentadiene using a mixture of N-chlorosuccinimide, acetaldoxime, triethylamine and a catalytic amount of pyridine in chloroform at 50°according to Tetrahedron 1984, 40, 2985-2988] when processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The compound was obtained in a solid brown color (of 5.17 g).

MS (EI) 302 (M+); tPL59-67°C.

Example C7

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

Specified in the title compound was obtained from methyl ester 3-(2-methyl-2H-pyrazole-3-yl)benzoic acid [obtained by (i) reaction of 1-(3-bromophenyl)-3-dimethylaminopropane [CAS-No. 163852-04-8] methylhydrazine in ethanol at 23°C for 2.5 days; (ii) chromatographic separation of the obtained isomers; (iii) processing of pure isomer of n-BuLi in those whom rageragerage at -78° C for 1 hour and then mixed with a stream of carbon dioxide and subsequent esterification with methanol and concentrated sulfuric acid at 23°C for 48 hours] by treatment with lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The compound was obtained as yellow oil (5,96 g).

MS (EI) 300 (M+).

Example K8

tert-Butyl ester 3-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-3-oxopropanoic acid

Specified in the title compound was obtained from methyl ester 3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)benzoic acid [obtained from the methyl ester of 3-azidobenzoyl acid according to the stages of the synthesis (i)-(iii), as described in obtaining the substance from example K5, and the reaction of the obtained product with thionyl chloride in tetrahydrofuran at a temperature 0-23°C for 1 hour and subsequent addition of dimethylamine (7.9 M in water) and stirring at 23-70°C for 1 hour] (2 14 g, by 8.22 mmole) when handling the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The compound was obtained as yellow oil (2,90 g).

MS (ISP) 345 [(M+N)+].

Example K9

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

Specified in the title compound was obtained from methyl ester 3-(3-methoxymethyl Sasol-5-yl)benzoic acid [obtained by the reaction of ethyl ester of 3-ethynylbenzene acid [CAS-No. 178742-95-5] with a mixture of N-chlorosuccinimide, 2-methoxyacetanilide [CAS-No. 71494-93-4], triethylamine and a catalytic amount of pyridine in chloroform at 50°according to Tetrahedron 1984, 40, 2985-2988] when processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The compound was obtained as a yellow liquid (1,548 g).

MS (EI) 331 (M+).

Example K10

tert-Butyl ether (RS)-3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl}propionic acid

Specified in the title compound was obtained from methyl ester (RS)-3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]benzoic acid [obtained using the following sequence of reactions: (i) a mixture of methyl ester of 3-thiocarbamoylation acid [CAS-No. 106748-27-0] (7,8 g), 1,3-dichloro-2-propanone (8,4 g) and sodium bicarbonate (8,4 g) in 1,4-dioxane (180 ml) was heated at 60°C for 24 hours. The reaction mixture was cooled to 20°and was added to a stirred solution of sodium methylate (5.4 g) in methanol (200 ml). Stirring was continued for 0.5 hours. The mixture was poured into cooled to the temperature of the ice 2 N. hydrochloric acid (200 ml) and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuum. The residue was led from dichloromethane/hexane, obtained methyl ester 3-(hydroxymethyl shall eazol-2-yl)benzoic acid (7.5 g) in the form of crystals, light brown, tPL115-117°With; (ii) a mixture of the obtained material (7.5 g), dihydropyran (4,1 ml) and hydrate p-toluenesulfonic acid (0,19 g) in ethyl acetate (50 ml) was stirred at 20°C for 1 hour. The solution was diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and with brine, dried over sodium sulfate and evaporated in vacuum. The remaining oily substance was purified by chromatography on silica gel using ethyl acetate/hexane (1:2) as eluent, received the methyl ester of (RS)-3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]benzoic acid (9.6 g) in the form of oil is pale-yellow] (3.5 g, 11 mmol) in processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The connection was received in the form of oil, pale yellow (3.8 g).

MS (ISP) 418,2 [(M+N)+].

Example C

tert-Butyl ether (RS)-3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)oxazol-2-yl]phenyl}propionic acid

Specified in the title compound was obtained from methyl ester (RS)-3-[4-(tetrahydropyran-2-intoximeter)oxazol-2-yl]benzoic acid [obtained using the following sequence of reactions: (i) a mixture of methyl ester of 3-carbamoylating acid [CAS-No. 106748-24-7] (17.9 g) and 1,3-dichloro-2-propanone (14.0 g) was heated at 140°C for 1.5 hours. The mixture was cooled to 20°and carefully added koncentrira is nnow sulfuric acid (12 ml). The mixture was stirred 10 minutes and then poured into a mixture of ice water. The product was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuum. The residue was chromatographically on silica gel, using as eluent ethyl acetate/hexane (1:1), was obtained methyl ester 3-(4-chlormethiazole-2-yl)benzoic acid (11.8 g) in the form of oil pale yellow color. MS (ISP) 252,2 [(M+N)+]. ii) the Solution obtained above substances (7.6 g) and monohydrate of lithium hydroxide (5.0 g) in dimethyl sulfoxide (30 ml) was heated at 60°C for 7 hours. The cooled reaction mixture was poured into a mixture of ice water and the mixture was extracted with diethyl ether. The aqueous layer was acidified to pH 1 with the addition of 6 N. hydrochloric acid and the precipitate was collected by filtration and was led from dichloromethane/hexane. Pale-yellow crystals (5.5 g) was dissolved in dimethyl sulfoxide (25 ml) and after addition of N,N,N',N'-tetramethylguanidine (4,4 ml) and iodotope bromide (2.2 ml) and the mixture was stirred for 1 hour at 20°C. were Added ethyl acetate and the mixture is then washed with water, 1 N. hydrochloric acid and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuum. The residue was chromatographically on silica gel, using as eluent ethyl acetate/hexane (1:1)and purified cont the CT was led from diethyl ether/hexane, received methyl ester 3-(4-hydroxymethylimidazole-2-yl)benzoic acid (2.1 g) as white crystals, tPL118-119°With. iii) the Mixture obtained substances (2.1 g), dihydropyran (1.2 ml) and hydrate p-toluenesulfonic acid (0.1 g) in ethyl acetate (15 ml) was stirred for 1 hour at 20°C. the Solution was diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and with brine, dried over sodium sulfate and evaporated in vacuum. The remainder in the form of oil was purified by chromatography on silica gel, using as eluent ethyl acetate/hexane (1:2), was obtained methyl ester of (RS)-3-[4-(tetrahydropyran-2-intoximeter)oxazol-2-yl]benzoic acid (3.5 g) in the form of oil is pale-yellow] (3.5 g, 11 mmol) in processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The compound obtained in the form of oil, pale yellow (3.8 g).

MS (ISP) 402,5 [(M+N)+].

Example K12

tert-Butyl ether (RS)-3-oxo-3-{3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl)propionic acid

Specified in the title compound was obtained from methyl ester (RS)-3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]benzoic acid [obtained using the following sequence of reactions. (i) Ethyl ester of 4-(3-bromophenyl)-2,4-dioxolane acid [CAS-No. 151646-31-0] (of 7.55 g, 23 mmole) and hydroxylamine hydrochloride (4,74 g,68 mmol) was boiled under reflux in ethanol for 1 hour. ii) Obtained ester (5,94 g, 20 mmol) was reduced by lithium aluminum hydride (761 mg, 20 mmol) in tetrahydrofuran at -10°C for 1 hour. iii) the resulting alcohol (4,90 g, 19 mmol) was subjected to reaction with 3,4-dihydro-2H-Piran and a catalytic amount of hydrate p-toluenesulfonic acid in dichloromethane at 23°C for 20 hours. iv) Obtained a simple tetrahydropyranyloxy ether (5,24 g, 15 mmol) was treated with n-butyllithium at 78°C for 45 minutes, and then the flow of carbon dioxide. v) Received technical acid was stirred in methyl alcohol (90 ml) and concentrated sulfuric acid (6.5 ml) at 50°C for 12 hours. vi) the Obtained substance (2,01 g, 8,62 mmole) was subjected to reaction with 3,4-dihydro-2H-Piran (1,17 ml, 12.9 mmole) and a catalytic amount of hydrate p-toluenesulfonic acid in dichloromethane (17 ml) at 23°C for 5 hours] (2,44 g, 7.7 mmole) when handling the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The compound was obtained as yellow oil (of 3.06 g).

MS (ISP) 402 [(M+N)+].

Example K13

tert-Butyl ether (RS)-3-{3-[3-methyl-4-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}-3-oxopropanoic acid

Specified in the title compound was obtained from methyl ester (RS)-3-[3-methyl-4-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]benzoic acid [obtained is by using the following sequence of reactions. (i) Ethyl ester (3-bromophenyl)-3-oxopropanoic acid [CAS-No. 21575-91-7], pyrrolidin and trimethylsilyltriflate in benzene was boiled under reflux for 16 hours (Org.Synth. 53, 59). ii) Obtained ethyl ester 3-(3-bromophenyl)-3-pyrrolidin-1-elkrylova acid was subjected to reaction with nitroethane, phosphorus oxychloride and triethylamine at 23°With. iii) Obtained ethyl ester 5-(3-bromophenyl)-3-methylisoxazol-4-carboxylic acid was reduced by lithium aluminum hydride in tetrahydrofuran at -10°C for 1 hour. iv) is Obtained [5-(3-bromophenyl)-3-methylisoxazol-4-yl]methanol was subjected to reaction with 3,4-dihydro-2H-Piran and a catalytic amount of hydrate p-toluenesulfonic acid in dichloromethane at 23°C for 20 hours. v) Obtained a simple tetrahydropyranyloxy ether was treated with n-butyllithium at -78°C for 45 minutes, and then the flow of carbon dioxide. vi) Received technical acid was stirred in methyl alcohol and concentrated sulfuric acid at 50°C for 18 hours. vii) Obtained methyl ester 3-(hydroxymethyl-3-methylisoxazol-5-yl)benzoic acid was subjected to reaction with 3,4-dihydro-2H-Piran and a catalytic amount of hydrate p-toluenesulfonic acid in dichloromethane at 23°C for 1 hour] when processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). Product floor is Ali in the form of oil is light yellow in color (972 mg).

MS (EI) 416(M+H)+].

Example K14

tert-Butyl ether (RS)-3-{3-[2-methyl-5-(tetrahydropyran-2-intoximeter)-2H-pyrazole-3-yl]phenyl)-3-oxopropanoic acid

Specified in the title compound was obtained from methyl ester (RS)-3-[2-methyl-5-(tetrahydropyran-2-intoximeter)-2H-pyrazole-3-yl]benzoic acid [obtained using the following sequence of reactions. (i) Ethyl ester of 4-(3-bromophenyl)-2,4-dioxolane acid [CAS-No. 151646-31-0] (6,135 g, 21 mmol), methylhydrazine (1,296 ml, 25 mmol) and HCl (4 M in dioxane, and 6.25 ml, 25 moles) in ethanol (35 ml) was boiled under reflux for 1.5 hours. ii) Obtained ethyl ester 5-(3-bromophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (7,02 g, an increase of 22.7 mmole) was reduced by lithium aluminum hydride (862 mg, an increase of 22.7 mmole) in tetrahydrofuran (60 ml) at -10°C for 1 hour. iii) Obtained [5-(3-bromophenyl)-1-methyl-1H-pyrazole-3-yl]methanol (6,34 g, 24 mmole) was subjected to reaction with 3,4-dihydro-2H-Piran (of 3.25 ml, 36 mmol) and catalytic amount of hydrate p-toluenesulfonic acid in dichloromethane (50 ml) at 23°C for 23 hours. iv) is Obtained (RS)-[5-(3-bromophenyl)-1-methyl-3-(tetrahydropyran-2-intoximeter)-1H-pyrazole (8,64 g, 25 mmol) was treated with n-butyllithium at -78°C for 45 minutes, then the flow of carbon dioxide. v) Received technical acid was stirred in methanol (90 ml) and concentrated sulfuric acid (6.5 ml) at 50#x000B0; C for 5 hours. vi) the Obtained methyl ester 3-(5-hydroxymethyl-2-methyl-2H-pyrazole-3-yl)benzoic acid (3,41 g, 13,85 mmole) was subjected to reaction with 3,4-dihydro-2H-Piran (1.75 ml, 20,77 mmole) and a catalytic amount of hydrate p-toluenesulfonic acid in dichloromethane (28 ml) at 23°C for 18 hours] (3,93 g, 11.9 mmole) when handling the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The substance was obtained as yellow oil (4,90 g).

MC (ISP) 415(M+H)+].

Example K15

tert-Butyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl)propionic acid

Specified in the title compound was obtained from methyl ester (RS)-3-[5-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]benzoic acid[obtained from the methyl ester of (Z)-3-(gidroksilaminami)benzoic acid [CAS-No. 91186-80-0] when processing an N-chlorosuccinimide, a catalytic amount of pyridine in chloroform and subsequent addition of (RS)-tetrahydro-2-(2-propenyloxy)-2H-Piran and slow addition of triethylamine in chloroform at 23°] when processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The substance was obtained as yellow oil (3.00 g).

MS (ISN) 400,5 [(M-N)-].

Example C

tert-Butyl ester 3-oxo-3-(3-pyrazole-1-ylphenyl)propionic acid

Indicated the data in the title compound was obtained from methyl ester 3-pyrazole-1-yl-benzoic acid [CAS-No. 168618-35-7] when processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The compound was obtained as yellow oil (5,00 g).

MS (EI) 286 (M+).

Example R17

tert-Butyl ether (RS)-3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)pyrazole-1-yl]phenyl}propionic acid

Specified in the title compound was obtained from methyl ester (RS)-3-[4-(tetrahydropyran-2-intoximeter)pyrazole-1-yl]benzoic acid [obtained using the following sequence of reactions. i) a Mixture of methyl ester hydrochloride 3-hydrazinobenzene acid [CAS-No. 167626-26-8] (15,14 g, 75 mmol), benzyl ester 2-cyan-3 - ethoxyacrylate acid [CAS-No. 32016-27-6] (17,36 g, 75 mmol) and triethylamine (10.5 ml, 75 mmol) in isopropanol (115 ml) was boiled under reflux for 1.5 hours. ii) Obtained benzyl ether of 5-amino-1-(3-ethoxycarbonylphenyl)-1H-pyrazole-4-carboxylic acid (26,0 g, 74 mmole) was heated with isopentylamine (30 ml, 225 mmol; 10 ml) in tetrahydrofuran (200 ml) for 22 hours. iv) Obtained benzyl ester 1-(3-ethoxycarbonylphenyl)-1H-pyrazole-4-carboxylic acid (18,98 g, 56 mmol) was first made in the presence of Pd/C (10% Pd/C, 600 mg, 1 mol.%) in ethyl acetate (350 ml) and tetrahydrofuran (250 ml) at 23°C for 16 hours. iv) Obtained 1-(3-ethoxycarbonylphenyl)-1H-pyrazole-4-carboxylic acid (13,70 g, 55,6 mmole) was restored using BH ·SMe2(28,46 ml, 278,2 mmole) in tetrahydrofuran (364 ml) at 5-23°C for 16 hours. v) Obtained methyl ester 3-(4-hydroxymethylimidazole-1-yl)benzoic acid (10,66 g, 45,9 mmole) was subjected to reaction with 3,4-dihydro-2H-Piran (6,24 ml, 68.9 mmole) and a catalytic amount of hydrate p-toluenesulfonic acid in dichloromethane (91 ml) at 23°C for 22 hours] (14,18 g, 44,8 mmole) when handling the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The substance was obtained as yellow oil ($15.87 with g).

MS (ISN) 399 [(M-N)-].

Example K18

tert-Butyl ether (RS)-3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionic acid

Specified in the title compound was obtained from methyl ester (RS)-3-[4-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]benzoic acid [obtained using the following sequence of reactions. i) Methyl ester (Z)-3-(gidroksilaminami)benzoic acid [CAS-No. 91186-80-0] was treated with N-chlorosuccinimide, a catalytic amount of pyridine in chloroform, followed by addition of tert-butyl methyl ether (E)-3-pyrrolidin-1-elkrylova acid [CAS-No. 340257-76-3] and slow addition of triethylamine in chloroform at 23°With. ii) Obtained tert-butyl ester 3-(3-ethoxycarbonylphenyl)isoxazol-4-carboxylic acid was stirred in formic acid at 50#x000B0; C for 18 hours. iii) the Obtained 3-(3-ethoxycarbonylphenyl)isoxazol-4-carboxylic acid was recovered using BH3·SMe2in tetrahydrofuran at 5-23°C for 16 hours. iv) Obtained methyl ester 3-(4-hydroxymethylimidazole-3-yl)benzoic acid was subjected to reaction with 3,4-dihydro-2H-Piran and a catalytic amount of hydrate p-toluenesulfonic acid in dichloromethane at 23°C for 1 hour] when processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The product was obtained as yellow oil (1,817 g).

MS (ISN) 400 [(M-N)-].

Example C

tert-Butyl ether (RS)-3-{3-[2-methyl-4-(tetrahydropyran-2-intoximeter)-2H-pyrazole-3-yl]phenyl}-3-oxopropanoic acid

Specified in the title compound was obtained from methyl ester (RS)-3-[2-methyl-4-(tetrahydropyran-2-intoximeter)-2H-pyrazole-3-yl]benzoic acid [obtained using the following sequence of reactions. i) 3-Bromobenzoate and methyl ether 3-isopropylaminocarbonyl acid [CAS-No. 89895-40-9] was subjected to the reaction in toluene and triethylamine according to Synthesis 1982, 318. ii) Obtained methyl ester 2-(3-bromobenzoyl)-3-isopropylaminocarbonyl acid reacted with methylhydrazine in diethyl ether at 23°according to Synthesis 1982, 318. iii) Obtained methyl ester 5-(3-bromophenyl)-1-methyl-1H-pyrazole-4-carbon is th acid was reduced by lithium aluminum hydride in tetrahydrofuran at -10° C for 1 hour. iv) is Obtained [5-(3-bromophenyl)-1-methyl-1H-pyrazole-4-yl]methanol was subjected to reaction with 3,4-dihydro-2H-Piran and a catalytic amount of hydrate p-toluenesulfonic acid in dichloromethane at 23°C for 20 hours. v) is Obtained (RS)-5-(3-bromophenyl)-1-methyl-4-(tetrahydropyran-2-intoximeter)-1H-pyrazole was treated with n-butyllithium at -78°C for 45 minutes, then the flow of carbon dioxide. vi) Received technical acid was stirred in methyl alcohol and concentrated sulfuric acid at 50°C for 18 hours. vii) Obtained methyl ester 3-(4-methoxymethyl-2-methyl-2H-pyrazole-3-yl)benzoic acid was subjected to the reaction with 1 M solution trichromate boron in dichloromethane at a temperature from -78 to 23°C for 1 hour. viii) the technical bromide was subjected to reaction with potassium acetate in dimethylformamide at 60°C for 30 minutes. ix) the technical acetate was subjected to reaction with a solution of sodium methylate in methyl alcohol at 23°C for 20 minutes. x) is Obtained methyl ester 3-(4-hydroxymethyl-2-methyl-2H-pyrazole-3-yl)benzoic acid was subjected to reaction with 3,4-dihydro-2H-Piran and a catalytic amount of monohydrate p-toluenesulfonic acid in dichloromethane at 23°C for 1 hour] when processing the lithium derivative of tert-butyl acetate according to standard methods (ways is b). The product was obtained in a solid yellow color (11,106 g).

MC (ISN) 413(M-H)-].

Example C

tert-Butyl ether (RS)-3-oxo-3-(3-{2-[2-(tetrahydropyran-2-yloxy)ethyl]-2H-pyrazole-3-yl}phenyl)propionic acid

Specified in the title compound was obtained from methyl ester (RS)-3-{2-[2-(tetrahydropyran-2-yloxy)ethyl]-2H-pyrazole-3-yl}benzoic acid [obtained by the following reactions. i) Carried out the reaction of 1-(3-bromophenyl)-3-dimethylaminopropane [CAS-No. 163852-04-8] 2-hydroxyethylhydrazine in ethanol at 23°C for 2.5 days. ii) the mixture of pyrazoles (12,36 g, 35,19 mmole) was subjected to reaction with 3,4-dihydro-2H-Piran (4,79 ml, 52,8 mmole) and a catalytic amount of monohydrate p-toluenesulfonic acid in dichloromethane (70 ml) at 23°C for 20 hours. iii) Performing a chromatographic separation of the obtained isomers. iv) Pure isomer (7,35 g, 73.7 mmole) was treated with n-butyllithium (13,08 ml of 20.9 mmole) in tetrahydrofuran (42 ml) at -78°C for 45 minutes, then the flow of carbon dioxide. v) is Obtained (RS)-3-{2-[2-(tetrahydropyran-2-yloxy)ethyl]-2H-pyrazole-3-yl}benzoic acid (4,56 g, a 14.1 mmole) was subjected to reaction with potassium bicarbonate (2,89 g of 28.8 mmole) and idestam the stands (0,99 ml, 15.9 mmole) in dimethylformamide (29 ml) at 23°2 hours] (2,96 g, 8,96 mmole) when handling the lithium derivative of tert-butyl acetate according to the article Hartnoll method (method b). The product was obtained as yellow oil (3.00 g).

MC (ISP) 415(M+H)+].

Example C

tert-Butyl ether (RS)-3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,2,3]triazole-1-yl}phenyl)propionic acid

Specified in the title compound was obtained from methyl ester (RS)-3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,2,3]triazole-1-yl}benzoic acid [obtained using the following sequence of reactions. i) Methyl ether 3-azidobenzoyl acid [CAS-No. 93066-93-4] and (RS)-tert-butultimately-[4-(tetrahydropyran-2-yloxy)-buta-1-inyl]silane [CAS-No. 198411-20-0] was heated at 60°within 10 days. ii) the resulting material was stirred in tetrabutylammonium (1M in tetrahydrofuran) at 70°C for 6 days and then boiled under reflux in 1 N. hydrochloric acid for 2 hours. iii) the Obtained 3-[5-(2-hydroxyethyl)-[1,2,3]triazole-1-yl]benzoic acid was stirred in methyl alcohol and concentrated sulfuric acid at 23°C for 11 days. iv) Obtained methyl ester 3-[5-(2-hydroxyethyl)-[1,2,3]triazole-1-yl]benzoic acid was subjected to reaction with 3,4-dihydro-2H-Piran and a catalytic amount of monohydrate p-toluenesulfonic acid in dichloromethane at 23°C for 20 hours] when processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The product was obtained as yellow oil (6,748 g).

MS (ISP) 416(M+H) +].

Example C

Ethyl ester of (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)pyrazole-1-yl]phenyl}propionic acid

Specified in the title compound was obtained from (RS)-3-[5-(tetrahydropyran-2-yl-oxymethyl)pyrazole-1-yl]benzoic acid [obtained using the following sequence of reactions. i) a Mixture of 3-hydrazinobenzene acid [CAS-No. 38235-71-1], ethyl ester of 4-dimethylamino-2-exabot-3-ene acid [CAS-No. 67751-14-8] acetic acid was boiled under reflux in the course of 15.5 hours. ii) Obtained ethyl ester of 2-(3-carboxyphenyl)-2H-pyrazole-3-carboxylic acid was stirred with di-tert-butylacetate of dimethylformamide in toluene at 80°C for 45 hours iii) Obtained ethyl ester of 2-(3-tert-butoxycarbonylmethyl)-2H-pyrazole-3-carboxylic acid omilami using 3 N. of sodium hydroxide in tetrahydrofuran at 0-23°C for 16 hours. iv) Obtained 2-(3-tert-butoxycarbonylmethyl)-2H-pyrazole-3-carboxylic acid was recovered using NR3·SMe2in tetrahydrofuran at 5-23°C for 18 hours. v) Obtained tert-butyl ether 3-(5-hydroxymethyluracil-1-yl)benzoic acid (3,188 g, are 11.62 mmole) was stirred in formic acid (22 ml) at 50°C for 5 hours. vi) Received technical acid was stirred in methanol (50 ml) with thionyl chloride (1,54 ml, each holding 21.25 mmole) at 23°C for 6.5 hours is. vii) Obtained methyl ester 3-(5-hydroxymethyluracil-1-yl)benzoic acid (2,84 g, 12.2 mmole) was subjected to reaction with 3,4-dihydro-2H-Piran (of 1.66 ml, and 18.3 mmole) and a catalytic amount of monohydrate p-toluenesulfonic acid in dichloromethane (25 ml) at 23°C for 3 days. viii) Obtained methyl ester of (RS)-3-[5-(tetrahydropyran-2-intoximeter)pyrazole-1-yl]benzoic acid (2,926 g, a 9.25 mmole) omilami 6 N. sodium hydroxide (5 ml) in tetrahydrofuran (20 ml) at 23°within 3 hours] (1.90 g, 6.3 mmole) when activated with ethyl ether of Harborview acid (0.63 ml, 6.6 mmole) and triethylamine (1 ml, 7.0 mmol) in tetrahydrofuran (9 ml)/acetonitrile (7 ml) at 0°C for 2 hours and further reacted with the potassium salt of monoethylene ester of malonic acid (2.15 g, 12.6 mmole), magnesium chloride (1.5 g, 15.8 mmole) and triethylamine (2.9 ml, 20.8 mmole) when 0-23°C for 2 days according to a standard method (method a). The connection was received in the form of oil is light yellow in color (1,124 g).

MS (ISP) 373,4 [(M+N)+].

Example C

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

Specified in the title compound was obtained from 3-[1,2,3]triazole-1-eventing acid[obtained by boiling under reflux methyl ester 3-azidobenzoyl acid [CAS-No. 93066-93-4] trimethylsilylacetamide and subsequent saponification is one sodium hydroxide in boiling ethanol] (10.0 g, 52,86 mmole) when activating etelcharge.com/triethylamine and the reaction with the potassium salt of mono-tert-butyl ester of malonic acid in the presence of triethylamine and magnesium chloride in acetonitrile according to the standard method (method a). The compound was obtained as orange oil (11,55 g).

MS (ISP) 288 [(M+N)+].

Example K24

tert-Butyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,4]triazole-1-yl]phenyl}propionic acid

Specified in the title compound was obtained from methyl ester (RS)-3-[5-(tetrahydropyran-2-intoximeter)-[1,2,4]triazole-1-yl]benzoic acid [obtained using the following sequence of reactions. i) Methyl ester 3-(1H-1,2,4-triazole-1-yl)benzoic acid [CAS-No. 167626-27-9] (39,4 g, 194 mmole) was heated in a 36% formaldehyde-water (250 ml) in an autoclave for 41 hours at 150°C. Crystallization from water and ethyl acetate/hexane (1:1) resulted in a solid substance, light brown (24.3 g, 54%) with tPL164°With. ii) the Obtained compound (24.3 g, 104 mmole) was subjected to reaction with 3,4-dihydro-2H-Piran (29.3 ml, 320 mmol) and catalytic amount of monohydrate p-toluenesulfonic acid in dichloromethane (360 ml)/tetrahydrofuran (300 ml) at 23°C for 20 hours. After purification using column chromatography on silica gel (toluene/ethyl acetate 1:1) got the oil light brown] 16.6 g, 52,3 mmole) when handling the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The connection was received in the form of oil pale yellow (14.3 g, 68%).

MS (ISN) 400,4 [(M-N)-].

Example C

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

Specified in the title compound was obtained from methyl ester 3-[1,2,4]triazole-1-eventing acid [CAS-No. 167626-27-9] when processing the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The connection was received in the form of liquid orange (2,41 g).

MS (EI) 287 (M+].

Example C

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

Specified in the title compound was obtained from methyl ester 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] while boiling under reflux in concentrated sulfuric acid/methanol] in the processing of the lithium derivative of tert-butyl acetate according to the standard procedure K (method b). The connection was received in the form of oil orange-brown color.

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

Example C

tert-Butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]propionic acid

a) Methyl ester of 3-(4-hydroxymethylimidazole-2-yl)benzoic acid

<> A mixture of methyl ester of 3-thiocarbamoylation acid (7.8 g), 1,3-dichloro-2-propanone (8,4 g) and sodium bicarbonate (8,4 g) in 1,4-dioxane (180 ml) was heated at 60°C for 24 hours. The reaction mixture was cooled to 20°and was added to a stirred solution of sodium methylate (5.4 g) in methanol (200 ml). Stirring was continued for 0.5 hours. The mixture was poured into cooled to the temperature of the ice 2 N. hydrochloric acid (200 ml) and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated in vacuum. The residue was led from dichloromethane/hexane, obtained methyl ester 3-(4-hydroxymethylimidazole-2-yl)benzoic acid (7.5 g) in the form of crystals light brown, tPL115-117°C.

b) Methyl ester of 3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]benzoic acid

The mixture of substances obtained in section a) (7.5 g), dihydropyran (4, 1 ml) and hydrate p-toluenesulfonic acid (0, 19 g) in ethyl acetate (50 ml) was stirred at 20°C for 1 hour. The solution was diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and with brine, dried over sodium sulfate and evaporated in vacuum. The obtained oily residue was purified by chromatography on silica gel, using as eluent ethyl acetate/hexane (1:2), was obtained methyl ester 3-[4-(tetrahydropyran-2-intoximeter)enous the l-2-yl]benzoic acid (9.6 g) in the form of oil pale yellow color.

C) tert-Butyl ether 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]propionic acid

The sample obtained in section (b) (3.3 grams), was treated with the lithium derivative of tert-butyl acetate according to the standard procedure K (method b)was obtained tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]propionic acid (3.25 g) in the form of oil pale yellow color.

MS (ISP) 418,2 [(M+N)+].

Example C

tert-Butyl ester 3-oxo-3-[3-(2-bromo-1,1-dimethoxymethyl)phenyl]propionic acid

a) Methyl ester of 3-(2-bromo-1,1-dimethoxymethyl)benzoic acid

A mixture of 3-(2-bromoacetyl)benzoic acid [CAS-No. 62423-73-8] (2,43 g), hydrate 4-toluenesulfonic acid (0,38 g) and trimethylboron ether orthomorphisms acid (5.5 ml) in methyl alcohol (40 ml) was boiled under reflux for 20 hours. The cooled solution was diluted with ethyl acetate (0.15 l), washed with 5% sodium bicarbonate solution and saline solution, dried and evaporated in vacuum, was obtained methyl ester 3-(2-bromo-1,1-dimethoxymethyl)benzoic acid (3.0 g) in the form of oil pale yellow color.

b) tert-Butyl ether 3-oxo-3-[3-(2-bromo-1,1-dimethoxymethyl)phenyl]propionic acid

Methyl ester 3-(2-bromo-1,1-dimethoxymethyl)benzoic acid (3.9 g) was treated with lithium derivative of tert-butyl acetate according to a standard method To method b), received tert-butyl ester 3-oxo-3-[3-(2-bromo-1,1-dimethoxymethyl)phenyl]propionic acid (2.8 g) as a yellow oil.

Example K29

tert-Butyl ester 3-oxo-3-[3-(2-methoxazole-4-yl)phenyl]propionic acid

a) 3-(2-Methoxazole-4-yl)benzoic acid

A mixture of 3-(2-bromoacetyl)benzoic acid (2,43 g) and ndimethylacetamide (1.77 g) was heated with stirring at 130°C for 40 minutes. The mixture was cooled and was diluted with water (30 ml) and the precipitate was collected by filtration, was obtained 3-(2-methoxazole-4-yl)benzoic acid (1.51 g) as a solid brown color.

b) Methyl ester of 3-(2-methoxazole-4-yl)benzoic acid

A solution of 3-(2-methoxazole-4-yl)benzoic acid (1.42 g) in a mixture of methanol (30 ml), and 4 N. HCl/Et2O (6 ml) was heated at 40°C for 4 hours. The solution was evaporated in vacuum and the remaining oil was stirred with water (30 ml), was established pH of the mixture to about 6 by adding a saturated solution of sodium bicarbonate. The precipitate was isolated by filtration, was obtained methyl ester 3-(2-methoxazole-4-yl)benzoic acid (1.18 g) as a solid light brown color.

MS (ISP) 218,2 [(M+N)+].

C) tert-Butyl ether 3-oxo-3-[3-(2-methoxazole-4-yl)phenyl]propionic acid

Methyl ester 3-(2-methoxazole-4-yl)benzoic acid (1,02 g) was treated with lithium deposition is the major tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-oxo-3-[3-(2-methoxazole-4-yl)phenyl]propionic acid (1.50 g) in the form of oil pale yellow color.

Example C

tert-Butyl ester 3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]thiadiazole-2-yl]phenyl}propionic acid

a) Methyl ester of 3-(N'-tert-butoxycarbonylamino)benzoic acid

A mixture of methyl ester of 3-(N'-tert-butoxycarbonylmethylene)benzoic acid (1.47 g) and reagent Lawesson (1,62 g) in toluene (30 ml) was heated at 70°C for 1.5 hours. The mixture was concentrated in vacuo and then subjected to chromatography on silica gel, using as eluent ethyl acetate/hexane (1:2), was obtained methyl ester 3-(N'-tert-butoxycarbonylamino)benzoic acid (1.31 g) as a solid yellow color, MS (ISP) 328,3 [(M+NH4)+].

b) Triptorelin methyl ester 3-hydrazinecarbothioamide acid

A solution of methyl ester of 3-(N'-tert-butoxycarbonylamino)benzoic acid (0,93 g) in triperoxonane acid (9 ml)/anisole (2 ml) was stirred at 0°C for 1 hour. The solvents are evaporated in vacuum, received technical triptorelin methyl ester 3-hydrazinecarbothioamide acid (0,98 g) as a crystallizing oil.

C) Methyl ester of 3-(5-hydroxymethyl-[1,3,4]thiadiazole-2-yl)what antinoi acid

A mixture of triptoreline methyl ester 3-hydrazinecarbothioamide acid (0,49 g) and the hydrochloride of the ethyl ester of 2-chloroacetonitrile (0,47 g) in ethanol (6 ml) was heated at 80°C for 2.5 hours. The mixture was diluted with ethyl acetate and washed with 1 N. hydrochloric acid and with brine. The organic layer was dried and evaporated. The remainder in the form of an oil (0.8 g) was dissolved in methyl alcohol (5 ml), was added sodium methylate (0.08 g) and the solution was heated for half an hour at 65°C. the Mixture was diluted with ethyl acetate and washed with 1 N. hydrochloric acid and with brine. The organic layer was dried and evaporated and the residue was led from ethyl acetate/hexane, obtained methyl ester 3-(5-hydroxymethyl-[1,3,4]thiadiazole-2-yl)benzoic acid (0.15 g) as a solid white, MS (ISP) 251,2 [(M+N)+].

d) Methyl ester of 3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]thiadiazole-2-yl]benzoic acid

A mixture of methyl ester of 3-(5-hydroxymethyl-[1,3,4]thiadiazole-2-yl)benzoic acid (7.8 g), dihydropyran (5.6 ml) and hydrate p-toluenesulfonic acid (0,59 g) in ethyl acetate (80 ml) was stirred for 1 hour at 20°C. the Solution was diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and saline solution, dried and evaporated in vacuum. The remainder in the form of oil was purified by chromatography on silica gel, using as eluent utilized the t/hexane (1:2), received the methyl ester of 3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]thiadiazole-2-yl]benzoic acid (5,85 g) in the form of oil pale yellow color.

d) tert-Butyl ether 3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]thiadiazole-2-yl]phenyl}propionic acid

Methyl ester of 3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]thiadiazole-2-yl]benzoic acid (5,85 g) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]thiadiazole-2-yl]phenyl}propionic acid (8,9 g) in the form of oil pale yellow color.

Example C

tert-Butyl ester 3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]thiadiazole-2-yl}phenyl)propionic acid

a) Methyl ester of 3-[5-(2-hydroxyethyl)-[1,3,4]thiadiazole-2-yl]benzoic acid

A mixture of triptoreline methyl ester 3-hydrazinecarbothioamide acid (0.45 g) and ethyl ester hydrochloride 3-hydroxypropionitrile (0.35 g) in pyridine (5 ml) was heated at 100°for 1.5 hours the Mixture was diluted with ethyl acetate and washed with 1 N. hydrochloric acid and with brine. The organic layer was dried and evaporated, the residue in the form of oil was chromatographically on silica gel, using as eluent ethyl acetate/hexane (1:1), was obtained methyl ester 3-[5-(2-hydroxyethyl)-[1,3,4]thiadiazol the-2-yl]benzoic acid (0,37 g) as a solid white color, MS (ISP) 265,3 [(M+N)+].

b) Methyl ester of 3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]thiadiazole-2-yl}-benzoic acid

A mixture of methyl ester of 3-[5-(2-hydroxyethyl)-[1,3,4]thiadiazole-2-yl]benzoic acid (1.86 g), dihydropyran (0.95 ml) and hydrate p-toluenesulfonic acid (0,13 g) in ethyl acetate (25 ml) was stirred for 1 hour at 20°C. the Solution was diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and saline solution, dried and evaporated in vacuum. The remainder in the form of oil was purified by chromatography on silica gel, using as eluent ethyl acetate/hexane (1:2), was obtained methyl ester 3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]thiadiazole-2-yl}benzoic acid (1.60 g) in the form of oil pale yellow color.

C) tert-Butyl ether 3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]thiadiazole-2-yl}phenyl)propionic acid

Methyl ester of 3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]thiadiazole-2-yl}benzoic acid (1.60 g) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b)was obtained tert-butyl ester 3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]thiadiazole-2-yl}phenyl)propionic acid (2.1 g) in the form of oil pale yellow color.

Example C

tert-Butyl ester 3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]oxadiazol-2-yl]phenyl}propionic acid

a) Methyl EF the p 3-(5-hydroxymethyl-[1,3,4]oxadiazol-2-yl)benzoic acid

A mixture of methyl ester of 3-hydrazinecarbothioamide acid (0.97 g) and the hydrochloride of the ethyl ester of 2-chloroacetonitrile (0.95 g) in ethanol (20 ml) was heated at 80°C for 1 hour. The mixture was diluted with ethyl acetate and washed with 1 N. hydrochloric acid and with brine. The organic layer was dried and evaporated, the residue in the form of oil (1.1 g) was dissolved in dimethylformamide (4 ml). After addition of potassium acetate (0,59 g) and iodotope potassium (0.07 g) and the mixture was stirred 0.5 hour at 100°C. After cooling to 20°With added methanol (10 ml) and sodium methylate (0.14 g) and stirring continued for 0.5 hours at 65°C. the Mixture was diluted with ethyl acetate and washed with 1 N. hydrochloric acid and with brine. The organic layer was dried and evaporated and the residue was led from ethyl acetate/hexane, obtained methyl ester 3-(5-hydroxymethyl-[1,3,4]oxadiazol-2-yl)benzoic acid (0,72 g) as a solid white, MS (ISP) 235,3 [(M+N)+].

b) Methyl ester of 3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]oxadiazol-2-yl]-benzoic acid

A mixture of methyl ester of 3-(5-hydroxymethyl-[1,3,4]oxadiazol-2-yl)benzoic acid (9.8 g), dihydropyran (7.7 ml) and hydrate p-toluenesulfonic acid (0.8 g) in ethyl acetate (100 ml) was stirred for 1 hour at 20°C. the Solution was diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and saline solution, su the or and was evaporated. The remainder in the form of oil was purified by chromatography on silica gel, using as eluent ethyl acetate/hexane (1:2), was obtained methyl ester 3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]oxadiazol-2-yl]benzoic acid (12,6 g) in the form of oil pale yellow color.

C) tert-Butyl ether 3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]oxadiazol-2-yl]phenyl} propionic acid

Methyl ester of 3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]oxadiazol-2-yl]benzoic acid (12,6 g) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-oxo-3-(3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]oxadiazol-2-yl]phenyl} propionic acid (17.0 g) in the form of oil pale yellow color.

Example C

tert-Butyl ester 3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]oxadiazol-2-yl}phenyl)propionic acid

a) Methyl ester of 3-[5-(2-hydroxyethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid

A mixture of technical methyl ester 3-hydrazinecarbothioamide acid (2,90 g) and ethyl ester hydrochloride 3-hydroxypropionitrile (2.76 g) in pyridine (10 ml) was heated for 2 hours at 100°C. the Mixture was diluted with ethyl acetate and washed with 1 N. hydrochloric acid and with brine. The organic layer was dried and evaporated, the residue in the form of oil led from diethyl which first aired, received the methyl ester of 3-[5-(2-hydroxyethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid (2.5 g) as a solid white, MS (ISP) 249,1[(M+N)+].

b) Methyl ester of 3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1.3.4]oxadiazol-2-yl}-benzoic acid

A mixture of methyl ester of 3-[5-(2-hydroxyethyl)-[1,3,4]oxadiazol-2-yl]benzoic acid (7,45 g), dihydropyran (4,1 ml) and hydrate p-toluenesulfonic acid (0,57 g) in ethyl acetate (80 ml) was stirred 2 hours at 20°C. the Solution was diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and saline solution, dried and evaporated in vacuum. The remainder in the form of oil was purified by chromatography on silica gel, using as eluent ethyl acetate/hexane (1:2), was obtained methyl ester 3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]oxadiazol-2-yl}benzoic acid (8.2 g) in the form of oil pale yellow color.

C) tert-Butyl ether 3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]oxadiazol-2-yl}phenyl)propionic acid

Methyl ester of 3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]oxadiazol-2-yl}benzoic acid (8.2 g) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]oxadiazol-2-yl}-phenyl)propionic acid (11.6 g) in the oil is pale yellow in color.

p> Example C

tert-Butyl ether 3-(3-oxazol-4-ylphenyl)-3-oxopropanoic acid

a) Methyl ester of 3-oxazol-4-eventing acid

A mixture of 3-(2-bromoacetyl)benzoic acid (1,94 g) and formamide (1.08 g) was heated with stirring for 3 hours at 130°C. the Mixture was distributed between ethyl acetate and brine solution, the organic layer was dried and evaporated, the residue in the form of oil was dissolved in a mixture of methanol (30 ml), and 4 N. HCl/Et2O (8 ml).

After holding at 20°C for 18 hours the solution was concentrated in vacuum, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saline solution, dried and evaporated. The residue was chromatographically on silica gel, using as eluent ethyl acetate/hexane (1:3), was obtained methyl ether C-oxazol-4-eventing acid (0.85 grams) in the form of not-quite-white solid, MS (ISP) to 204.1 [(M+N)+].

b) tert-Butyl ether 3-(3-oxazol-4-ylphenyl)-3-oxopropanoic acid

Methyl ether 3-oxazol-4-eventing acid (0.85 grams) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-(3-oxazol-4-ylphenyl)-3-oxopropanoic acid (1,46 g) in the form of oil pale yellow color.

Example K35

tert-Butyl ester 3-oxo-3-(3-thiazol-4-ylphenyl)propionic acid

a) Methyl ether is-thiazole-4-eventing acid

A solution of 3-(2-bromoacetyl)benzoic acid (1.22 g) and thioformate (0,46 g) in ethanol (5 ml) was heated at 80°C for 1 hour. The mixture was distributed between ethyl acetate and brine solution and the organic layer was dried and evaporated. The remainder in the form of oil was dissolved in a mixture of methanol (20 ml), and 4 N. HCl/Et2O (5 ml). After holding at 20°C for 18 hours the solution was concentrated in vacuum, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saline solution, dried and evaporated. The residue was chromatographically on silica gel, using as eluent ethyl acetate/hexane (1:3), was obtained methyl ether 3-thiazole-4-eventing acid (0,98 g) in the form of not-quite-white solid, MS (ISP) 220,2 [(M+N)+].

b) tert-Butyl ether 3-oxo-3-(3-thiazol-4-ylphenyl)propionic acid

Methyl ether 3-thiazole-4-eventing acid (0,91 g) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-oxo-3-(3-thiazol-4-ylphenyl)propionic acid (1.54 g) in the form of oil pale yellow color.

Example C

tert-Butyl ester 3-[3-(5-methoxazole-4-yl)phenyl]-3-oxopropanoic acid

a) Methyl ester 3-tert-butoxycarbonylamino acid

Dimethyltotal (67,9 g) was treated with lithium production is diversified tert-butyl acetate according to the standard procedure K (method b), received technical methyl ester 3-tert-butoxycarbonylamino acid (74,5 g) in the form of oil pale yellow color.

b) Methyl ester of 3-propenylbenzene acid

To a stirred solution of methyl ester 3-tert-butoxycarbonylamino acid (11.1 g) and iodotope bromide (2.2 ml) in dimethylformamide (40 ml) was added at 0°With portions of sodium hydride (55%dispersion in mineral oil, 1.4 g). Stirring is continued at 0°C for 15 minutes and at 20°C for 30 minutes. The mixture was distributed between ethyl acetate and brine solution, was established pH 7 by adding 3 N. hydrochloric acid. The organic layer was dried and evaporated. The residue was stirred in a mixture of dichloromethane (30 ml) and triperoxonane acid (30 ml) for 40 minutes at 20°C. After evaporation of the solvent solution of the residue in ethyl acetate was extracted with cooled to the temperature of ice saturated solution of sodium carbonate and aqueous extracts were immediately acidified 3 N. hydrochloric acid and was extracted with ethyl acetate. The solvent and the extract is evaporated and the residue was heated in a mixture of toluene (40 ml) and 3 N. hydrochloric acid (3 ml) at 100°C for 1 hour. The cooled mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saline solution, dried and evaporated, received methyl ether 3-about what inventing acid (a 3.87 g) in the form of a solid white color, MS (ISP) 193,2 [(M+N)+].

C) Methyl ester of racemic. 3-(2-bromopropionyl)benzoic acid

A mixture of methyl ester of 3-propenylbenzene acid (3.6 g) and copper bromide(2) (7,45 g) in ethyl acetate (45 ml) was boiled under reflux for 2 hours. Nerastvorimaya substance was filtered from the cooled mixture and the clear solution was washed with brine, dried and evaporated, received technical methyl ether racemic. 3-(2-bromopropionyl)benzoic acid (5.0 g) in the form of oil pale yellow color.

d) Methyl ester of 3-(5-methoxazole-4-yl)benzoic acid

Methyl ether racemic. 3-(2-bromopropionyl)benzoic acid (5,42 g) and formamide (3.6 ml) were heated together at 130°C for 5 hours. The mixture was distributed between ethyl acetate and brine solution, the organic layer was dried and evaporated and the residue in the form of oil was chromatographically on silica gel, using as eluent ethyl acetate/hexane (1:4), was obtained methyl ester 3-(5-methoxazole-4-yl)benzoic acid (2,52 g) as a solid white color.

d) tert-Butyl ether 3-[3-(5-methoxazole-4-yl)phenyl]-3-oxopropanoic acid

Methyl ester 3-(5-methoxazole-4-yl)benzoic acid (0.87 g) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-[3-(5-methoxazole-4-yl)F. the Nile]-3-oxopropanoic acid (1,46 g) in the form of oil pale yellow color.

Example kastrofylakas k37

tert-Butyl ester 3-[3-(2-methyl-5-preprocessor-4-yl)phenyl]-3-oxopropanoic acid

a) Methyl ester of 3-Penta-4-norbertines acid

To a stirred solution of methyl ester 3-tert-butoxycarbonylamino acid (11.1 g) and allylbromide (3.0 ml) in dimethylformamide (40 ml) was added by portions at 0°With sodium hydride (55%dispersion in mineral oil, 1.44 g). Stirring is continued for 20 minutes at 0°C and 30 minutes at 20°C. the Mixture was distributed between ethyl acetate and brine solution, was established pH 7 by the addition of 3 N. hydrochloric acid. The organic layer was dried and evaporated. The remainder in the form of oil was stirred in a mixture of dichloromethane (30 ml) and triperoxonane acid (30 ml) for 40 minutes at 20°C. the Solvents evaporated. A solution of the residue in ethyl acetate was extracted with cooled to the temperature of ice saturated solution of sodium carbonate and aqueous extracts were immediately acidified 3 N. hydrochloric acid and was extracted with ethyl acetate. The solvent and the extract is evaporated and the residue was heated in a mixture of toluene (40 ml) and 3 N. hydrochloric acid (2 ml) at 100°C for 1 hour. The cooled mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saline solution, dried and evaporated, received methyl ether C-Penta-4-norbertines acid (5,11 g) in the form m the SLA pale yellow color, MS (ISP) 236,2 [(M+NH4)+].

b) Methyl ester of racemic. 3-(2-bromopentane)benzoic acid

A sample of the methyl ester 3-Penta-4-norbertines acid (3,93 g) was first made in ethyl acetate (50 ml) in the presence of 5% Pd-C (190 mg) for 30 minutes at 20°C. the Catalyst was filtered, the solution was added copper bromide(2) (4.44 g) and the mixture is boiled under reflux for 1 hour. The insoluble substance was filtered from the cooled mixture and the clear solution is washed with 1 N. hydrochloric acid and with brine, dried and evaporated, received technical methyl ether racemic. 3-(2-bromopentane)benzoic acid (3.6 g) in the form of oil pale yellow color.

C) Methyl ester of 3-(2-methyl-5-preprocessor-4-yl)benzoic acid

A sample of the methyl ester of racemic. 3-(2-bromopentane)benzoic acid (1.50 g) and ndimethylacetamide (0,89 g) were heated together at 130°C for 15 hours. The mixture was distributed between ethyl acetate and brine solution, the organic layer was dried and evaporated and the residue in the form of oil was chromatographically on silica gel, using as eluent ethyl acetate/hexane (1:3), was obtained methyl ester 3-(2-methyl-5-preprocessor-4-yl)benzoic acid (0,47 g) in the form of oil is light yellow in color.

g) tert-Butyl ether 3-[3-(2-methyl-5-preprocessor-4-yl)phenyl]-3-oxopropanoic acid

Methyl ester 3-(2-methyl-5-preprocessor-4-yl)benzo is Noah acid (0,47 g) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-[3-(2-methyl-5-preprocessor-4-yl)phenyl]-3-oxopropanoic acid (0,58 g) in the form of butter, light brown.

Example C

tert-Butyl ester 3-[3-(5-methylthiazole-4-yl)phenyl]-3-oxopropanoic acid

a) Methyl ester of 3-(5-methylthiazole-4-yl)benzoic acid

The technical solution of the methyl ester of racemic. 3-(2-bromopropionyl)benzoic acid (2,71 g) and thioformate (1,83 g) in ethanol (20 ml) was boiled under reflux for 1 hour. The mixture was distributed between ethyl acetate and brine solution, the organic layer was dried and evaporated and the residue in the form of oil was chromatographically on silica gel using ethyl acetate/hexane (1:4) as eluent, was obtained methyl ester 3-(5-methylthiazole-4-yl)benzoic acid (2,41 g) as a solid white color.

b) tert-Butyl ether 3-[3-(5-methylthiazole-4-yl)phenyl]-3-oxopropanoic acid

A sample of the methyl ester of 3-(5-methylthiazole-4-yl)benzoic acid (1,05 g) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-[3-(5-methylthiazole-4-yl)phenyl]-3-oxopropanoic acid (1.9 g) in the form of oil pale yellow color.

Example C

tert-Butyl ester 3-[3-(2,5-dimethylthiazol-4-yl)phenyl]-3-oxopropanoic acid

a) Methyl ester of 3-(2,5-dimetallic the ol-4-yl)benzoic acid

A mixture of methyl ester racemic. 3-(2-bromopropionyl)benzoic acid (of 6.78 g) and thioacetamide (5,63 g) was heated at 130°C for 20 minutes. The mixture was distributed between ethyl acetate and water, the organic layer was dried and evaporated and the residue in the form of oil was chromatographically on silica gel, using as eluent ethyl acetate/hexane (1:4), was obtained methyl ester 3-(2,5-dimethylthiazol-4-yl)benzoic acid (equal to 4.97 g) as a yellow oil.

b) tert-Butyl ether 3-[3-(2,5-dimethylthiazol-4-yl)phenyl]-3-oxopropanoic acid

A sample of the methyl ester of 3-(2,5-dimethylthiazol-4-yl)benzoic acid (0,99 g) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b)was obtained tert-butyl ester 3-[3-(2,5-dimethylthiazol-4-yl)phenyl]-3-oxopropanoic acid (1.12 g) in the form of oil pale yellow color.

Example 40

tert-Butyl ester 3-oxo-3-[3-[5-methyl-4-(tetrahydropyran-2-intoximeter)thiazol-4-yl]phenyl]propionic acid

a) Methyl ester of 3-(2-hydroxymethyl-5-methylthiazole-4-yl)benzoic acid

A solution of methyl ester racemic. 3-(2-bromopropionyl)benzoic acid (2,71 g) and 2-(tert-BUTYLCARBAMATE)thioacetamide (2.1 g) in ethanol (20 ml) was boiled under reflux for 6 hours. The mixture was distributed between ethyl acetate and brine solution and the organic layer was dried and evaporated. Rast is the PR oily residue and sodium methylate (0.54 g) in methyl alcohol (20 ml) was stirred for 1 hour at 60° C. the Solution was diluted with ethyl acetate, washed with 1 N. hydrochloric acid and with brine, dried and evaporated, received methyl ester 3-(2-hydroxymethyl-5-methylthiazole-4-yl)benzoic acid (1,17 g) as white crystals, MS (ISP) 264,1 [(M+N)+].

b) Methyl ester of 3-[5-methyl-4-(tetrahydropyran-2-intoximeter)thiazol-4-yl]-benzoic acid

A mixture of methyl ester of 3-(2-hydroxymethyl-5-methylthiazole-4-yl)benzoic acid (1,05 g), dihydropyran (0,73 ml) and hydrate p-toluenesulfonic acid (0.07 g) in ethyl acetate (10 ml) was stirred for 1 hour at 20°C. the Solution was diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and saline solution, dried and evaporated. The remainder in the form of oil was purified by chromatography on silica gel, using as eluent ethyl acetate/hexane (1:3), was obtained methyl ester 3-[5-methyl-4-(tetrahydropyran-2-intoximeter)thiazol-4-yl]benzoic acid (1.45 g) in the form of oil pale yellow color.

C) tert-Butyl ether 3-oxo-3-[3-[5-methyl-4-(tetrahydropyran-2-intoximeter)-thiazol-4-yl]phenyl]propionic acid

Methyl ester of 3-[5-methyl-4-(tetrahydropyran-2-intoximeter)thiazol-4-yl]benzoic acid (1.45 g) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-oxo-3-[3-[5-methyl-4-(tetrahydropyran-2-intoximeter)thiazol-yl]phenyl]propionic acid (2,13 g) in the form of oil pale yellow color.

Example C

tert-Butyl ester 3-oxo-3-[3-[5-propyl-4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]propionic acid

a) Methyl ester of 3-(2-hydroxymethyl-5-methylthiazole-4-yl)benzoic acid

A sample of the methyl ester of racemic. 3-(2-bromopentane)benzoic acid (0,60 g) and 2-(tert-BUTYLCARBAMATE)thioacetamide (0.36 g) in ethanol (4 ml) was boiled under reflux for 5 hours. The mixture was distributed between ethyl acetate and 5% sodium bicarbonate solution, the organic layer was washed with brine, dried and evaporated. The solution of the oily residue and sodium methylate (0,13 g) in methyl alcohol (10 ml) was stirred for 30 minutes at 60°C. the Solution was diluted with ethyl acetate, washed with 1 N. hydrochloric acid and with brine, dried and evaporated, received methyl ester 3-(2-hydroxymethyl-5-methylthiazole-4-yl)benzoic acid (0,44 g) in the form of oil.

b) Methyl ester of 3-[5-propyl-4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]benzoic acid

Methyl ester 3-(2-hydroxymethyl-5-methylthiazole-4-yl)benzoic acid (0,38 g), dihydropyran (0,73 ml) and the hydrate p-toluenesulfonic acid (0.07 g) in ethyl acetate (10 ml) was stirred for 1 hour at 20°C. the Solution was diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and saline solution, dried and evaporated. The remainder in the form of oil was purified using chromatography naselesele, using as eluent ethyl acetate/hexane (1:3), was obtained methyl ester 3-[5-propyl-4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]benzoic acid (0.36 g) in the form of oil pale yellow color.

C) tert-Butyl ether 3-oxo-3-[3-[5-propyl-4-(tetrahydropyran-2-intoximeter)-thiazol-2-yl]phenyl]propionic acid

Methyl ester of 3-[5-propyl-4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]benzoic acid (0.34 g) was treated with lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-oxo-3-[3-[5-propyl-4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]propionic acid (0,42 g) in the form of oil pale yellow color.

Example C

tert-Butyl ester 3-oxo-3-[3-[2-methyl-5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]phenyl]propionic acid

a) Methyl ester of 3-(5-methyl bromide-2-methylthiazole-4-yl)benzoic acid

A mixture of methyl ester of 3-(2,5-dimethylthiazol-4-yl)benzoic acid (3,96 g), N-bromosuccinimide (3.13 g) and α,α'-bis(isobutyronitrile) (0.02 g) in carbon tetrachloride (60 ml) was boiled under reflux for 30 minutes. The cooled mixture was filtered and the solvent evaporated, received technical methyl ester 3-(5-methyl bromide-2-methylthiazole-4-yl)benzoic acid (6.2 g) in the form of oil.

b) Methyl ester of 3-(5-hydroxymethyl-2-methylthiazole-4-yl)benzoic key is lots

Methyl ester 3-(5-methyl bromide-2-methylthiazole-4-yl)benzoic acid was stirred in dimethylformamide (16 ml) with potassium acetate (2.35 g) for 20 minutes at 20°C. was Added methyl alcohol (32 ml) and sodium methylate (0,86 g) and stirring continued for 30 minutes at 50°C. the Mixture was distributed between ethyl acetate and brine solution and the organic layer was dried and evaporated. The remainder in the form of oil chromatographically on silica gel using ethyl acetate/hexane (1:1) as eluent, was obtained methyl ester 3-(5-hydroxymethyl-2-methylthiazole-4-yl)benzoic acid (with 2.93 g) as a solid white color.

C) Methyl ester of 3-[2-methyl-5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]benzoic acid

Methyl ester 3-(5-hydroxymethyl-2-methylthiazole-4-yl)benzoic acid (0,38 g), dihydropyran (2,01 ml) and the hydrate p-toluenesulfonic acid (0.21 g) in ethyl acetate (25 ml) was stirred for 1 hour at 20°C. the Solution was diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and saline solution, dried and evaporated. The remainder in the form of oil was purified by chromatography on silica gel, using as eluent ethyl acetate/hexane (1:3), was obtained methyl ester 3-[2-methyl-5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]benzoic acid (3.8 g) in the form of oil pale yellow color.

g) tert-Butyl ether 3-oxo-3-[3-[2-methyl-5-(tetrahydropyran-2-roximate the l)thiazol-4-yl]phenyl]propionic acid

Methyl ester of 3-[2-methyl-5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]benzoic acid was treated with the lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-oxo-3-[3-[2-methyl-5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]phenyl]propionic acid (of 5.45 g) in the form of oil pale yellow color.

Example C

tert-Butyl ester 3-oxo-3-{[5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]phenyl}propionic acid

a) Methyl ester of 3-(5-brometalia-4-yl)benzoic acid

A mixture of methyl ester of 3-(5-methylthiazole-4-yl)benzoic acid (2,40 g), N-bromosuccinimide (2,01 g) and α,α'-bis(isobutyronitrile) (0.02 g) in carbon tetrachloride (40 ml) was boiled under reflux for 30 minutes. The cooled mixture was filtered and the solvent evaporated, received technical methyl ester 3-(5-brometalia-4-yl)benzoic acid (3,36 g) in the form of oil.

b) Methyl ester of 3-(5-hydroxymethylimidazole-4-yl)benzoic acid

Methyl ester 3-(5-brometalia-4-yl)benzoic acid was stirred in dimethylformamide (10 ml) with potassium acetate (1.52 g) for 30 minutes at 20°C. was Added methyl alcohol (20 ml) and sodium methylate (0.84 g) and stirring continued for 30 minutes at 50°C. the Mixture was distributed between ethyl acetate and brine solution and the organic layer dried and evaporated. The remainder in the form of oil chromatographically on silica gel using ethyl acetate/hexane (1:2) as eluent, was obtained methyl ester 3-(5-hydroxymethylimidazole-4-yl)benzoic acid (1,43 g) as a solid white color.

C) Methyl ester of 3-[5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]benzoic acid

Methyl ester 3-(5-hydroxymethylimidazole-4-yl)benzoic acid (1.25 g), dihydropyran (0,84 ml) and the hydrate p-toluenesulfonic acid (0.10 g) in ethyl acetate (12 ml) was stirred 3 hours at 20°C. the Solution was diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and saline solution, dried and evaporated. The remainder in the form of oil was purified by chromatography on silica gel, using as eluent ethyl acetate/hexane (1:3), was obtained methyl ester 3-[5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]benzoic acid (1.60 g) in the form of oil pale yellow color.

g) tert-Butyl ether 3-oxo-3-{[5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]phenyl)propionic acid

Methyl ester of 3-[5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]benzoic acid was treated with the lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-oxo-3-{[5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]phenyl}propionic acid (2.3 g) in the form of oil pale yellow color.

Example K4

tert-Butyl ester 3-[3-(2-isopropyl-3H-imidazol-4-yl)phenyl]-3-oxopropanoic acid

a) Methyl ester of 3-dihydroxyacetophenone acid

A mixture of 3-(2-bromoacetyl)benzoic acid (2,43 g), DMSO (17 ml) and 48%Hydrobromic acid (3.4 ml) was heated for 30 minutes at 55°C. the Mixture was distributed between ethyl acetate and water and the organic layer was washed with brine and evaporated received methyl ether 3-dihydroxyacetophenone acid (1.06 g) as a solid white color.

b) Methyl ester of 3-(2-isopropyl-3H-imidazol-4-yl)benzoic acid

A solution of methyl ester 3-dihydroxyacetophenone acid (0.36 g) and 2-methylpropionamide aldehyde (of 0.24 ml) in 5%aqueous ammonia (6 ml) was heated for 1 hour at 100°C. the Mixture was evaporated in vacuo and a solution of the residue in a mixture of methanol (10 ml), and 4 N. HCl/Et2O (2 ml) was heated for 18 hours at 40°C. the Solution was concentrated in vacuum, diluted with ethyl acetate, washed with saturated sodium carbonate solution and with brine, dried and evaporated. The residue was chromatographically on silica gel, using as eluent ethyl acetate was obtained methyl ester 3-(2-isopropyl-3H-imidazol-4-yl)benzoic acid (0,37 g) in the form of oil pale yellow color.

C) tert-Butyl ether 3-[3-(2-isopropyl-3H-imidazol-4-yl)phenyl]-3-oxopropanoic acid

Methyl e is Il-3-(2-isopropyl-3H-imidazol-4-yl)benzoic acid was treated with the lithium derivative of tert-butyl acetate according to the standard procedure K (method b), received technical tert-butyl ester 3-[3-(2-isopropyl-3H-imidazol-4-yl)phenyl]-3-oxopropanoic acid (0.25 g) in the form of oil pale yellow color.

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

Standard method L

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

Method (a)

6-Aryl-2,2-dimethyl-[1,3]dioxin-4-ones were obtained from 3-aryl-3-oxopropanoic acid and catalytic amounts of concentrated sulfuric acid or triperoxonane acid (TFA) in isopropenylacetate at 23°according to Chem. Pharm. Bull. 1983, 31, 1896. The final products were purified by column chromatography on silica gel using hexane/ethyl acetate as eluent.

Method b)

6-Aryl-2,2-dimethyl-[1,3]dioxin-4-ones were obtained from tert-butyl esters of 3-aryl-3-oxopropionate acids during processing anhydride triperoxonane acid (TFAA) in a mixture triperoxonane acid and acetone at 23°according to Tetrahedron Lett. 1998, 39, 2253. The final products were purified by column chromatography on silica gel using hexane/ethyl acetate as eluent.

Example L1

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

3-(3-Tianfeng)-3-oxopropionate acid was obtained from 3-canbesold (828 is g, 5 mmol) and bis(trimethylsilyl)malonate (2,56 ml, 10 mmol) with n-butyllithium (1.6 M in hexane, 6,25 ml) in diethyl ether at a temperature of from -60 to 0°according to the standard procedure M (method B2). Technical product (1.04 g) was converted to the specified in the title compound under stirring in isopropenylacetate and triperoxonane acid according to the standard procedure L (method a). The product was obtained in the form of a solid light-yellow color (0.8 g).

MC (EI) 229 (M+); tPL138°C (decomp.).

Example L2

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

Specified in the title compound was obtained from tert-butyl ether 3-(2-lepirudin-4-yl)-3-oxopropanoic acid (example M10) under stirring triperoxonane acid/acetone with triperoxonane anhydride according to the standard procedure L (method b). The compound was obtained in a solid brown color (3,30 g).

MS (EI) 230 (M+); tPL132°C (decomp.).

Example L3

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

3-(3-Imidazol-1-ylphenyl)-3-oxopropionate acid was obtained from hydrochloride of 3-(1H-imidazol-1-yl)benzoyl chloride [obtained by treating 3-(1H-imidazol-1-yl)benzoic acid (J.Med. Chem. 1987, 30, 1342); CAS-No. [108035-47-8] thionyl chloride] and bis(trimethylsilyl)malonate with triethylamine and lithium bromide in acetonitrile at 0°according to the standard method (method B1). Technical product made in accordance to the title compound by stirring in isopropenylacetate and concentrated sulfuric acid according to the standard procedure L (method a). The connection was received in the form of semi-solid substances orange (617 mg).

MS (EI) 270 (M+).

Example L4

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

Specified in the title compound was obtained from tert-butyl ether 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example C) under stirring triperoxonane acid/acetone with triperoxonane anhydride according to the standard procedure L (method b). The connection was received in the form of a solid beige color (7,80 g).

MS (EI) 271 (M+); tPL144-147°C (decomp.).

Standard method M

Obtain tert-butyl ether {2-[3-aryl-3-oxopropionate]phenyl}-carbamino acid by the reaction of tert-butyl esters (2-AMINOPHENYL)karbinovykh acids with ethyl or tert-butyl esters of 3-aryl-3-oxopropanoic acid or 6-aryl-2,2-dimethyl-[1,3]dioxin-4-areas

A mixture of tert-butyl methyl ether (2-AMINOPHENYL)carbamino acid and 1.0 to 1.2 mmole) or (1.0 to 1.5 mmole) ethyl or tert-butyl ester 3-aryl-3-oxopropanoic acid or 6-aryl-2,2-dimethyl-[1,3]dioxin-4-it was heated in toluene (4-8 ml) at 80-120°until then, until TLC indicated the and full consumption, a smaller quantity of the component. The solution was allowed to cool to 23°C, after which the product is usually crystallized (in cases where crystallization occurred, it was caused by the addition of hexane or diethyl ether, alternative reaction mixture was directly subjected to column chromatography on silica gel). The solid precipitate was filtered, washed with diethyl ether or mixtures of diethyl ether/hexane and dried in vacuum, was obtained tert-butyl ester of {2-[3-aryl-3-oxopropionate]phenyl}karbinovykh acid, which was used directly in the next stage or, if necessary, purified by recrystallization or by column chromatography on silica gel.

Example M1

tert-Butyl ester {4-chloro-2-[3-(3-tianfeng)-3-oxopropionate]-5-dimethylaminophenyl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (0.5 mmole) and ethyl ester of 3-(3-tianfeng)-3-oxopropanoic acid [CAS-No. 62088-13-5; obtained from 3-canbesold according to standard methods, method a] (0.55 mmole) according to the standard method M Compound was obtained in a solid white color (160 mg).

MS (ISP) 457 [(M+N)+]; tPL159-163°C.

Example M2

tert-Butyl ester {4-chloro-5-dimethylamino-2-[3-OK is about-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (143 mg, 0.5 mmole) and ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example K1) (150 mg, of 0.58 mmole) according to the standard method M Compound was obtained in a solid beige color (160 mg).

MS (ISP) 499 [(M+N)+] 501 [(M+2+N)+]; tPL136-137°C.

Example M3

tert-Butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (143 mg, 0.5 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (250 mg, of 0.62 mmole) according to the standard method M Compound was obtained as yellow oil (257 mg).

MS (ISP) 613 [(M+N)+] 615 [(M+2+N)+].

Example M4

tert-Butyl ether {2-[3-(3-tianfeng)-3-oxopropionate]-5-dimethylamino-4-phenylethylene}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J2) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)Ben is onitrile (example L1) according to the standard method M The connection was received in the form of a solid orange (108 mg).

MS (ISP) 523[(M+N)+].

Example M5

tert-Butyl ether {5-dimethylamino-2-[3-oxo-3-(3-[1,2,3]triazole-1-yl-phenyl)propionamido]-4-phenylethylene}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J2) and ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example K1) according to the standard method M Compound was obtained in the form of a solid orange color (148 mg).

MS (ISP) 565 [(M+N)+].

Example M6

tert-Butyl ester (4-chloro-5-dimethylamino-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (143 mg, 0.5 mmole) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (450 mg, 0.75 mmole) according to the standard method M Compound was obtained in a solid white color (136 mg).

MS (ISP) 513 [(M+N)+] 515 [(M+2+N)+]; tPL109-114°C.

Example M7

tert-Butyl ether (RS)-[2-dimethylamino-2',3'-debtor-5-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl} propionamide)biphenyl-4-yl]CT the amine acid

Specified in the title compound was obtained from tert-butyl ether (5-amino-2-dimethylamino-2',3'-diferuloyl-4-yl)carbamino acid (example J3) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) according to the standard method M Compound was obtained in a solid yellow color (253 mg).

MS (ISP) 691 [(M+N)+].

Example M8

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

Specified in the title compound was obtained from tert-butyl ether (5-amino-2-dimethylamino-2',3'-diferuloyl-4-yl)carbamino acid (example J3) and ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example K1) according to the standard method M Compound was obtained in a solid yellow color (253 mg).

MS (ISP) 577 [(M+N)+].

Example M9

tert-Butyl ether {5-[3-(3-tianfeng)-3-oxopropionate]-2-dimethylamino-2',3'-diferuloyl-4-yl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-amino-2-dimethylamino-2',3'-diferuloyl-4-yl)carbamino acid (example J3) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example L1) according to the standard method M Compound was obtained in the form of solid substances is as yellow (145 mg).

MS (ISP) 535 [(M+N)+].

Example M10

tert-Butyl ester (4-chloro-5-dimethylamino-2-{3-[2-(3-methylisoxazol-5-yl)pyridin-4-yl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (143 mg, 0.5 mmole) and tert-butyl ester 3-[2-(3-methylisoxazol-5-yl)pyridin-4-yl]-3-oxopropanoic acid (example K6) (170 mg, of 0.56 mmole) according to the standard method M Compound was obtained in the form of solids brown (206 mg).

MS (ISP) 514 [(M+N)+] 516 [(M+2+N)+]; tPL181-183°C.

Example M11

tert-Butyl ester (4-chloro-5-[(2-methoxyethyl)methylamino]-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether {2-amino-4-chloro-5-[(2-methoxyethyl)methylamino]phenyl}carbamino acid (example J4) (165 mg, 0.5 mmole) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (165 mg, 0.55 mmole) according to the standard method M Compound was obtained as an amorphous yellow substance (207 mg).

MS (ISP) 557 [(M+N)+] 559 [(M+2+N)+].

Example M12

tert-Butyl ester (4-chloro-5-[(2-methoxyethyl)methylamino]-2-{3-[2-(3-methylisoxazol-5-yl)pyridin-4-yl]-3-oxopropionate}Fe is silt)carbamino acid

Specified in the title compound was obtained from tert-butyl ether {2-amino-4-chloro-5-[(2-methoxyethyl)methylamino]phenyl}carbamino acid (example J4) (165 mg, 0.5 mmole) and tert-butyl ester 3-[2-(3-methylisoxazol-5-yl)pyridin-4-yl]-3-oxopropanoic acid (example K6) (151 mg, 0.5 mmole) according to the standard method M Compound was obtained in a solid yellow color (190 mg).

MS (ISP) 558 [(M+N)+] 560 [(M+2+N)+]; tPL148°C.

Example M13

tert-Butyl ether (RS)-[4-chloro-5-[(2-methoxyethyl)methylamino]-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether {2-amino-4-chloro-5-[(2-methoxyethyl)methylamino]phenyl}carbamino acid (example J4) (165 mg, 0.5 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (200 mg, 0.5 mmole) according to the standard method M Compound was obtained as an amorphous yellow substance (160 mg).

MS (ISP) 657 [(M+N)+] 659 [(M+2+N)+].

Example M14

tert-Butyl ester {4-chloro-5-[(2-methoxyethyl)methylamino]-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether {2-amino-4-chloro-5-[(2-way shall Sitel)methylamino]phenyl}carbamino acid (example J4) (165 mg, 0.5 mmole) and ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example K1) (165 mg, 0.5 mmole) according to the standard method M Compound was obtained as an amorphous yellow substance (167 mg).

MS (ISP) 543 [(M+N)+] 545 [(M+2+N)+].

Example M15

tert-Butyl ester {4-chloro-2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-dimethylaminophenyl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (143 mg, 0.5 mmole) and tert-butyl ester 3-(2-lepirudin-4-yl)-3-oxopropanoic acid (example K3) (123 mg, 0.5 mmole) according to the standard method M Compound was obtained in a solid yellow color (155 mg).

MS (ISP) 458 [(M+N)+] 460 [(M+2+N)+]; tPL110°C.

Example M16

tert-Butyl ester (4-chloro-5-dimethylamino-2-{3-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (143 mg, 0.5 mmole) and tert-butyl ester 3-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]-3-oxopropanoic acid (example C7) (180 mg, 0.6 mmole) according to the standard method M Compound was obtained as an amorphous yellow substance (160 mg).

MS (ISP) 512 [(M+N)+ ] 514 [(M+2+N)+].

Example M17

tert-Butyl ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1.2.3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (160 mg, 0.5 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (201 mg, 0.5 mmole) according to the standard method M Compound was obtained as an amorphous yellow substance color (247 mg).

MS (ISP) 647 [(M+N)+].

Example M18

tert-Butyl ester (5-dimethylamino-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (160 mg, 0.5 mmole) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (151 mg, 0.5 mmole) according to the standard method M Compound was obtained as an amorphous yellow substance (94 mg).

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

Example M19

tert-Butyl ester (4-chloro-5-dimethylamino-2-{3-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-3-oxopropionate } phenyl)carbs the OIC acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (143 mg, 0.5 mmole) and tert-butyl ester 3-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-3-oxopropanoic acid (example K8) (172 mg, 0.5 mmole) according to the standard method M Compound was obtained as an amorphous yellow substance (176 mg).

MS (ISP) 556 [(M+N)+] 558 [(M+2+N)+].

Example M20

tert-Butyl ester (4-chloro-5-dimethylamino-2-{3-[3-(3-methoxymethylethoxy-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) and tert-butyl ester 3-[3-(3-methoxymethylethoxy-5-yl)phenyl]-3-oxopropanoic acid (example K9) according to the standard method M Compound was obtained in a solid yellow color (205 mg).

MS (ISP) 543 [(M+N)+] 545 [(M+2+N)+].

Example M21

tert-Butyl ether {2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-dimethylamino-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (319 mg, 1.0 mmol) and tert-butyl ester 3-(2-lepirudin-4-yl)-3-oxopropionate KIS is the notes (example K3) according to the standard method M The compound was obtained as an amorphous yellow substance (297 mg).

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

Example M22

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

Specified in the title compound was obtained from tert-butyl ether [5-amino-2'-fluoro-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid (example J5) (200 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl-[1,3]dioxin-4-it (example L3) (160 mg, 0.5 mmole) according to the standard method M Compound was obtained as an amorphous substance brown (167 mg).

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

Example M23

tert-Butyl ether [2'-fluoro-5-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [5-amino-2'-fluoro-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid (example J5) (200 mg, 0.5 mmole) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (160 mg, of 0.53 mmole) according to the standard method M Compound was obtained in a solid white color (40 mg).

MS (ISN) 626 [(M-N)-]; tPL121-123°C.

Example M24

tert-Butyl ether [2'-fluoro-5-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]-2-(2,2,2-triptoreline)biphenyl-4-yl]the carbs the OIC acid

Specified in the title compound was obtained from tert-butyl ether [5-amino-2'-fluoro-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid (example J5) (200 mg, 0.5 mmole) and ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example K1) (150 mg, 0.57 mmole) according to the standard method M Compound was obtained in the form of solid light yellow (110 mg).

MS (ISP) 614 [(M+N)+]; tPL54-56°C.

Example M25

tert-Butyl ether (RS)-[2'-fluoro-5-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamido)-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [5-amino-2'-fluoro-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid (example J5) (200 mg, 0.5 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (220 mg, 0.55 mmole) according to the standard method M Compound was obtained as yellow oil (100 mg).

Example M26

tert-Butyl ether (RS)-[4-chloro-5-(ethylmethylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3 ]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(ethylmethylamino)phenyl]carbamino acid (example J7) (300 mg, 1.0 mmol who) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (402 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance in yellow (500 mg).

MS (ISP) 627,1 [(M+N)+].

Example M27

tert-Butyl ether (RS)-[4-chloro-5-(methylpropylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(methylpropylamine)phenyl]carbamino acid (example J8) (310 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (402 mg, 1.0 mmol) according to the standard method M Compound was obtained in the form foamy substance in yellow (410 mg).

MC (ISP) 641,3 [(M+H)+].

The example covered by M28

tert-Butyl ether (RS)-[4-chloro-5-(diethylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(diethylamino)phenyl]carbamino acid (example J9) (310 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (402 mg, 1.0 mmol) according to the standard method M Compound was obtained in the form foamy substance in yellow (530 mg).

MS (ISP) 641,3 [(M+N)+].

Example M29

tert-Butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (143 mg, 0.5 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl)propionic acid (example K12) (201 mg, 0.5 mmole) according to the standard method M Compound was obtained as foamy substance in yellow (530 mg).

MS (ISP) 613,1 [(M+N)+] 615 [(M+2+N)+].

Example M30

tert-Butyl ether (RS)-[4-chloro-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-5-pyrrolidin-1-ylphenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-pyrrolidin-1-ylphenyl)carbamino acid (example J10) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) according to the standard method M Compound was obtained as foamy substance in yellow (228 mg).

MS (ISP) 639 [(M+N)+] 641 [(M+2+N)+].

Example M31

tert-Butyl ester (5-dimethylamino-2-{3-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]-3-oxoprop is ynylamine}-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (160 mg, 0.5 mmole) and tert-butyl ester 3-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]-3-oxopropanoic acid (example C7) (150 mg, 0.5 mmole) according to the standard method M Compound was obtained as foamy substance in yellow (90 mg).

MS (ISP) 546,2 [(M+N)+].

Example M32

tert-Butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-{3-[3-methyl-4-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}-3-oxopropionate)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) and tert-butyl methyl ether (RS)-3-{3-[3-methyl-4-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}-3-oxopropanoic acid (example K13) according to the standard method M Compound was obtained in the form of a solid light-yellow color (187 mg).

MS (ISN) 626 [(M-N)-] 628 [(M+2-N)-].

Example m

tert-Butyl ether (RS)-[4-chloro-5-(cyclopropylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(cyclopropylamino)phenyl]carbamino acid(example J11) (156 mg, 0.5 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (250 mg, of 0.62 mmole) according to the standard method M Compound was obtained in a solid yellow color (215 mg).

MS (ISN) 637,1 [(M-N)-] 639 [(M+2-N)-]; tPL47-49°C.

Example M

tert-Butyl ester (5-dimethylamino-2-{3-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (160 mg, 0.5 mmole) and tert-butyl ester 3-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-3-oxopropanoic acid (example K8) (172 mg, 0.5 mmole) according to the standard method M Compound was obtained as an amorphous yellow substance (195 mg).

MS (ISN) 588 [(M-N)-].

Example M35

tert-Butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-{3-[2-methyl-5-(tetrahydropyran-2-intoximeter)-2H-pyrazole-3-yl]phenyl}-3-oxopropionate)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (200 mg, 0.7 mmole) and tert-butyl methyl ether (RS)-3-{3-[2-methyl-5-(tetrahydropyran-2-intoximeter)-2H-pyrazole-3-yl]phenyl}-3-ox is propionic acid (example K14) according to the standard method M The compound was obtained as an amorphous yellow substance (329 mg).

MS (ISN) 624,0 [(M-N)-] 626 [(M+2-N)-].

Example M36

tert-Butyl ether {2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-pyrrolidin-1-yl-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-pyrrolidin-1-yl-4-triptoreline)carbamino acid (example J12) (173 mg, 0.5 mmole) and tert-butyl ester 3-(2-lepirudin-4-yl)-3-oxopropanoic acid (example K3) (150 mg, and 0.61 mmole) according to the standard method M Compound was obtained in a solid yellow color (140 mg).

MC (ISP) 518(M+H)+].

Example M37

tert-Butyl ether (RS)-[2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-5-pyrrolidin-1-yl-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-pyrrolidin-1-yl-4-triptoreline)carbamino acid (example J12) (173 mg, 0.5 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (250 mg, of 0.62 mmole) according to the standard method M Connection received the form of a foamy substance orange (168 mg).

MS (ISP) 673 [(M+N)+].

Example M38

tert-Butyl ether (RS)-[5-dimethylamino-4-the Thor-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-forfinal)carbamino acid (example J13) (269 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (401 mg, 1.0 mmol) according to the standard method M Compound was obtained as an amorphous yellow substance color (417 mg).

MS (ISN) 595 [(M-N)-].

Example m

tert-Butyl ester (5-dimethylamino-2-{3-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-3-oxopropionate}-4-forfinal)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-forfinal)carbamino acid (example J13) (269 mg, 1.0 mmol) and tert-butyl ester 3-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-3-oxopropanoic acid (example K8) (344 mg, 1.0 mmol) according to the standard method M Compound was obtained as an amorphous yellow substance (211 mg).

MC (ISN) 538(M-H)-].

Example M40

tert-Butyl ether (RS)-[5-dimethylamino-4-fluoro-2-(3-oxo-3-{3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-forfinal)carbamino acid (example J13) (269 mg, 1.0 mmol) and tert-butyl is Thira (RS)-3-oxo-3-{3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}propionic acid (example K12) (401 mg, 1.0 mmol) according to the standard method M Compound was obtained as an amorphous yellow substance (360 mg).

MS (ISN) 595 [(M-H)-].

Example M41

tert-Butyl ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}propionamide)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (565 mg, or 1.77 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}propionic acid (example K12) (710 mg, or 1.77 mmole) according to the standard method M Compound was obtained as an amorphous yellow substance (721 mg).

MS (ISN) 645 [(M-H)-].

Example M42

tert-Butyl ether (RS)-[5-dimethylamino-4-fluoro-2-(3-oxo-3-{3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-forfinal)carbamino acid (example J13) (269 mg, 1.0 mmol) and tert-butyl ester 3-[3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as an amorphous yellow substance (273 mg).

MS (ISP) 497 [(M+N)+].

Example M

Tr is t-Butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionic acid (example K15) according to the standard method M Compound was obtained as foamy substance in yellow (232 mg).

MS (ISN) 611,1 [(M-N)-] 613 [(M+2-N)-].

Example M44

tert-Butyl ether (RS)-[4-chloro-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-5-piperidine-1-ylphenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-piperidine-1-ylphenyl)carbamino acid (example J14) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]-phenyl}propionic acid (example K5) according to the standard method M Compound was obtained as foamy substances orange (257 mg).

MS (ISP) 653,2 [(M+N)+] 655 [(M+2+N)+].

Example M45

tert-Butyl ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionamide)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (PR which measures J6) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionic acid (example K15) according to the standard method M The connection was received in the form of penoobraznogo substance of light-yellow color (224 mg).

MS (ISP) 647,2 [(M+N)+].

Example M46

tert-Butyl ester {4-chloro-5-dimethylamino-2-[3-oxo-3-(3-pyrazole-1-ylphenyl)propionamido]phenyl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) and tert-butyl ester 3-oxo-3-(3-pyrazole-1-ylphenyl)propionic acid (example C) according to the standard method M Compound was obtained in the form of a solid light-yellow color (135 mg).

MS (ISP) 498 [(M+N)+] and 500 [(M+2+N)+]; tPL148-149°C.

Example m

tert-Butyl ether {2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-4-fluoro-5-pyrrolidin-1-ylphenyl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-fluoro-5-pyrrolidin-1-ylphenyl)carbamino acid (example J15) and tert-butyl ester 3-(2-lepirudin-4-yl)-3-oxopropanoic acid (example K3) according to the standard method M Compound was obtained in a solid yellow color (196 mg).

MS (ISP) 518 [(M+N)+]; tPL231°C (decomp.).

Example M48

tert-Butyl ester (4-fluoro-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropylidene)-5-pyrrolidin-1-ylphenyl)carbamino acid

Specified in the title is connected to the e was obtained from tert-butyl ether (2-amino-4-fluoro-5-pyrrolidin-1-ylphenyl)carbamino acid (example J15) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) according to the standard method M Compound was obtained in the form of solid light yellow (126 mg).

MS (ISP) 468 [(M+N)+]; tPL186°C.

Example M49

tert-Butyl ether (RS)-[4-fluoro-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-5-pyrrolidin-1-ylphenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-fluoro-5-pyrrolidin-1-ylphenyl)carbamino acid (example J15) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) according to the standard method M Compound was obtained in the form of a viscous orange oil (268 mg).

MS (ISP) 623 [(M+N)+].

Example M50

tert-Butyl ether {5-azetidin-1-yl-4-chloro-2-[3-(2-lepirudin-4-yl)-3-oxopropionate]phenyl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-azetidin-1-yl-4-chlorophenyl)carbamino acid (example J16) and tert-butyl ester 3-(2-lepirudin-4-yl)-3-oxopropanoic acid (example BC) according to the standard method M Compound was obtained in a solid yellow color (142 mg).

MS (ISP) 470 [(M+N)+] 472 [(M+2+N)+]; tPL168°C (decomp.).

Example M51

tert-Butyl ether (RS)-[2-(3-oxo-3-{3-[5-(tetrahydropyran-2-yl-oxymethyl)isoxazol-3-yl]phenyl} propion the laminitis)-5-pyrrolidin-1-yl-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-pyrrolidin-1-yl-4-triptoreline)carbamino acid (example J12) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionic acid (example K15) according to the standard method M Compound was obtained as foamy substance in yellow (522 mg).

MS (ISN) 671,2 [(M-N)-].

Example M52

tert-Butyl ether {5-azetidin-1-yl-2-[3-(2-lepirudin-4-yl)-3-oxo-propionamido]-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-azetidin-1-yl-4-triptoreline)carbamino acid (example J17) and tert-butyl ester 3-(2-lepirudin-4-yl)-3-oxopropanoic acid (example K3) according to the standard method M Compound was obtained in the form of a solid light-yellow color (131 mg).

MS (ISP) 470 [(M+N)+]; tPL166-167°C.

Example M53

tert-Butyl ether (5 azetidin-1-yl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-azetidin-1-yl-4-triptoreline)carbamino acid (example J17) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) according to the standard method M The compound was obtained as foamy substance of light-yellow color (218 mg).

MS (ISN) 557,2 [(M-N)-]; tPL83-84°C.

Example M54

tert-Butyl ether (RS)-[5-azetidin-1-yl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-azetidin-1-yl-4-triptoreline)carbamino acid (example J17) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) according to the standard method M Compound was obtained as foamy substance in yellow (450 mg).

MS (ISN) 657,1 [(M-N)-]; tPL76-77°C.

Example M55

tert-Butyl ether {5-dimethylamino-2-[3-oxo-3-(3-pyrazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (319 mg, 1.0 mmol) and tert-butyl ester 3-oxo-3-(3-pyrazole-1-ylphenyl)propionic acid (example C) (286 mg, 1.0 mmol) according to the standard method M Compound was obtained as an amorphous yellow substance (485 mg).

MS (ISN) 530 [(M-N)-].

Example M56

tert-Butyl ether {5-dimethylamino-2-[3-about the co-3-(3-[1,2,4]triazole-4-ylphenyl)propionamido]-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (383 mg, 1.2 mmole) and ethyl ester of 3-oxo-3-(3-[1,2,4]triazole-4-ylphenyl)propionic acid [CAS-No. 335255-97-5] (259 mg, 1.0 mmol) according to the standard method M Compound was obtained in a solid yellow color (290 mg).

MS (ISP) 533,3 [(M+N)+]; tPL58-62°C.

Example m

tert-Butyl ether {5-dimethylamino-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl-[1,3]dioxin-4-it (example 3) according to the standard method M Compound was obtained as orange oil (238 mg).

MS (ISP) 432 [(M+N)+].

Example M58

tert-Butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)pyrazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (429 mg, 1.5 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)pyrazole-1-yl]phenyl}propionic acid (example R17) (601 mg, 1.5 to the mole) according to the standard method M The compound was obtained as an amorphous yellow substance (710 mg).

MS (ISN) 610 [(M-N)-] 612 [(M+2-N)-].

Example m

tert-Butyl ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)pyrazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (479 mg, 1.5 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)-pyrazole-1-yl]phenyl}propionic acid (example R17) (601 mg, 1.5 mmole) according to the standard method M Compound was obtained as amorphous substances pink (641 mg).

MS (ISN) 644 [(M-N)-].

Example M60

tert-Butyl ether (RS)-[5-dimethylamino-2-(3-{3-[3-methyl-4-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}-3-oxopropylidene)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) and tert-butyl methyl ether (RS)-3-{3-[3-methyl-4-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}-3-oxopropanoic acid (example K13) according to the standard method M Compound was obtained in the form of oil red (424 mg).

MS (ISN) 626 [(M-N)-].

Example M61

tert-Bout levy ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionamide)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionic acid (example K18) according to the standard method M Compound was obtained in the form of solid light yellow (145 mg).

MS (ISP) 647 [(M+N)+].

Example M62

tert-Butyl ether (RS)-(5-dimethylamino-2-{3-[3-(2-methylsulfonylamino-1-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (319 mg, 1.0 mmol) and tert-butyl ester 3-[3-(2-methylsulfonylamino-1-yl)phenyl]-3-oxopropanoic acid [CAS-No. 335256-01-4] (432 mg, 1.3 mmole) according to the standard method M Compound was obtained as an amorphous substance, light brown (493 mg).

MS (ISP) 333,2 [(M+N)+].

Example M63

tert-Butyl ether (RS)-[5-dimethylamino-2-(3-{3-[2-methyl-4-(tetrahydropyran-2-intoximeter)-2H-pyrazole-3-yl]phenyl}-3-oxopropylidene)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) and the pet-butyl ether (RS)-3-{3-[2-methyl-4-(tetrahydropyran-2-intoximeter)-2H-pyrazole-3-yl]phenyl}-3-oxopropanoic acid (example C) according to the standard method M The connection was received in the form of a solid light red (576 mg).

MS (ISN) 658 [(M-N)-].

Example M64

tert-Butyl ester {4-chloro-5-dimethylamino-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) and tert-butyl ester 3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionic acid [CAS-No. 335255-88-4] according to the standard method M Compound was obtained in the form of a solid light-yellow color (427 mg).

MS (ISN) 497 [(M-N)-] 499 [(M+2-N)-].

Example M65

tert-Butyl ether {5-dimethylamino-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) and tert-butyl ester 3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionic acid [CAS-No. 335255-88-4]according to the standard method M Compound was obtained in the form of a solid light red (502 mg).

MS (ISN) 531 [(M-N)-].

Example M66

tert-Butyl ether {2-[3-(3-tianfeng)-3-oxopropionate]-5-dimethylamino-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-b is delovogo ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (320 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example L1) (275 mg, 1.2 mmole) according to the standard method M Compound was obtained as a viscous oil red (196 mg).

MS (ISN) 489,1 [(M-N)-].

Example M

tert-Butyl ether (RS)-[5-(cyclopropanemethylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(cyclopropanemethylamine)-4-triptoreline]carbamino acid (example J18) (719 mg, 2.0 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (803 mg, 2.0 mmole) according to the standard method M Compound was obtained as an amorphous substances in yellow (985 mg).

MS (ISP) 687 [(M+N)+].

Example M

tert-Butyl ether [2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-(cyclopropanemethylamine)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(cyclopropanemethylamine)-4-triptoreline]carbamino acid (example J18) (180 mg, 0.5 mmole) and tert-butyl ester 3-(2-lepirudin-4-yl)-3-oxopropanoic acid (example K3) (123 mg, 0.5 mmole) according to the standard method M Soy is inania received in the form of an amorphous yellow substance (206 mg).

MS (ISP) 532 [(M+N)+].

Example M

tert-Butyl ether (RS)-{5-dimethylamino-2-[3-oxo-3-(3-{2-[2-(tetrahydropyran-2-yloxy)ethyl]-2H-pyrazole-3-yl}phenyl)propionamido]-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (639 mg, 2.0 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-(3-{2-[2-(tetrahydropyran-2-yloxy)ethyl]-2H-pyrazole-3-yl}phenyl)propionic acid (example C) (829 mg, 2.0 mmole) according to the standard method M Connection received the form of amorphous material, pink color (272 mg).

MS (ISN) 658 [(M-N)-].

Example M70

tert-Butyl ether [2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-(cyclopropylamino)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(cyclopropylamino)-4-triptoreline]carbamino acid (example J19) (259 mg, 0.75 mmole) and tert-butyl ester 3-(2-lepirudin-4-yl)-3-oxopropanoic acid (example K3) (192 mg, 0,78 mmole) according to the standard method M Compound was obtained in a solid yellow color (228 mg).

MS (ISN) 516,2 [(M-N)-]; tPL114-116°C.

Example M

tert-Butyl ether {2-dimethylamino-2'-fluoro-5-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]bifen the l-4-yl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (5-amino-2-dimethylamino-2'-forbiden-4-yl)carbamino acid (example J20) (691 mg, 2.0 mmole) and 2,2-dimethyl-6-(3-[1,2,3]triazole-1-ylphenyl)-[1,3]dioxin-4-it (example L4) (543 g, 2.0 mmole) according to the standard method M Compound was obtained in a solid yellow color (820 mg).

TPL125-135 mA°C.

Example M72

tert-Butyl ether (RS)-{5-dimethylamino-2-[3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,2,3]triazole-1-yl}phenyl)propionamido]-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylethylamine-4-triptoreline)carbamino acid (example J6) and tert-butyl methyl ether (RS)-3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,2,3]triazole-1-yl}phenyl)propionic acid (example C) according to the standard method M Compound was obtained in the form of oil light red (527 mg).

MS (ISP) 577 [(M+N)+].

Example M73

tert-Butyl ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)pyrazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) and ethyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-and oxymethyl)pyrazole-1-yl]phenyl}propionic acid (example C) according to the standard method M The compound was obtained as brown oil (179 mg).

MS (ISP) 646 [(M+N)+].

Example M74

tert-Butyl ether {5-dimethylamino-2-[3-oxo-3-(3-[1,2 .3]triazole-1-ylphenyl)propionamido]-4-triptoreline) carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (639 mg, 2.0 mmole) and 2,2-dimethyl-6-(3-[1,2,3]triazole-1-ylphenyl)-[1,3]dioxin-4-it (example L4) (543 mg, 2.0 mmole) according to the standard method M Compound was obtained in a solid red color (915 mg).

MS (ISP) 533,3 [(M+N)+]; tPL79-81°C.

Example M75

tert-Butyl ether [2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-(2,2,2-triptoreline)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(2,2,2-triptoreline)-4-triptoreline]carbamino acid (example J21) and tert-butyl ester 3-(2-lepirudin-4-yl)-3-oxopropanoic acid (example K3) according to the standard method M Compound was obtained in the form of a solid light brown color (262 mg).

MS (ISN) 545,0 [(M-N)-]; tPL158°C (decomp.).

Example m

tert-Butyl ether {2-[3-(3-tianfeng)-3-oxopropionate]-4-dimethylamino-5-were}carbamino acid

Specified in the title of soy is inania was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-were)carbamino acid (example J22) (300 mg, 1.0 mmol) and tert-butyl ester 3-(3-tianfeng)-3-oxopropanoic acid (example K2) (245 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance light brown color (250 mg, 57%).

MS (ISP) 437,4 [(M+N)+].

Example M

tert-Butyl ether (RS)-[5-dimethylamino-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylethylamine-4-were)carbamino acid (example J22) (265 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (402 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance yellow color (420 mg, 71%).

MS (ISP) 593,5 [(M+N)+].

Example M

tert-Butyl ether {5-cyan-2-[3-(3-tianfeng)-3-oxopropionate]-4-dimethylaminophenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-cyan-5-dimethylaminophenyl)carbamino acid (example J23) (276 mg, 1.0 mmol) and tert-butyl ester 3-(3-tianfeng)-3-oxopropanoic acid (example K2) (245 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance of korichnevogo the color (290 mg, 65%).

MS (ISP) 448,3 [(M+N)+].

An example of an m-79

tert-Butyl ether [2-[3-(3-tianfeng)-3-oxopropionate]-5-methyl-4-(methylpropylamine)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-methyl-5-(methylpropylamine)phenyl]carbamino acid (example J24) (293 mg, 1.0 mmol) and tert-butyl ester 3-(3-tianfeng)-3-oxopropanoic acid (example K2) (245 mg, 1.0 mmol) according to the standard method M Compound was obtained in the form of butter, light brown (170 mg, 37%).

MS (ISN) 463,3 [(M-N)-].

Example M80

tert-Butyl ether (RS)-[4-methyl-5-(methylpropylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-methyl-5-(methylpropylamine)phenyl]carbamino acid (example J24) (293 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (402 mg, 1.0 mmol) according to the standard method M Compound was obtained in the form foamy substance in yellow (350 mg, 56%).

MS (ISP) 621,2 [(M+N)+].

Example m

tert-Butyl ether (RS)-[5-(ethylmethylamino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]the carbs the OIC acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(ethylmethylamino)-4-were]carbamino acid (example J25) (279 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (402 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substances in yellow (400 mg, 66%).

MC (ISP) 607,1 [(M+N)+].

Example m

tert-Butyl ether (RS)-[4-cyan-5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-cyan-5-dimethylaminophenyl)carbamino acid (example J23) (276 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (402 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance light brown (360 mg, 59%).

MC (ISN) 602,1 [(M-N)-].

Example m

tert-Butyl ether (RS)-[4-chloro-5-(isopropylethylene)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl} propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(isopropyl is ethylamino)phenyl]carbamino acid (example J26) (300 mg, 0.96 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (383 mg, 0.96 mmole) according to the standard method M Compound was obtained in the form of oil is light yellow in color (530 mg, 86%).

MC (ISN) 639,2 [(M-H)-].

Example m

tert-Butyl ester [4-methyl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-5-(methylpropylamine)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-methyl-5-(methylpropylamine)phenyl]carbamino acid (example J24) (293 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance of light-yellow color (340 mg, 65%).

MC (ISN) 519,3 [(M-H)-].

Example m

tert-Butyl ester (4-cyan-5-dimethylamino-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-cyan-5-dimethylaminophenyl)carbamino acid (example J23) (276 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance light is on-brown color (320 mg, 64%).

MC (ISP) 504,3 [(M+N)+].

Example M

tert-Butyl ester (5-(ethylmethylamino)-4-methyl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(ethylmethylamino)-4-were]carbamino acid (example J25) (279 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance brown (390 mg, 77%).

MC (ISN) 505,3 [(M-H)-].

Example M

tert-Butyl ester (5-dimethylamino-4-methyl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-were)carbamino acid (example J22) (265 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance brown (330 mg, 67%).

MS (ISN) 491,3 [(M-H)-].

Example M

tert-Butyl ether (RS)-[4-chloro-5-(isobutylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(isobutylamino)phenyl]carbamino acid (example J27) (328 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (401 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance, light brown (330 mg, 50%).

MS (ISP) 655,1 [(M+N)+].

Example M

tert-Butyl ester (4-chloro-5-(isobutylamino)-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(isobutylamino)phenyl]carbamino acid (example J27) (328 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance light yellow (360 mg, 65%).

MS (ISP) 555,1 [(M+N)+].

Example M90

tert-Butyl ether (RS)-[4-cyan-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-5-pyrrolidin-1-ylphenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-cyan-5-pyrrolidin-1-ylphenyl)carbamino acid (example J28) (302 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (401 mg, 1.0 IMO the b) according to the standard method M The compound was obtained as foamy substance light orange color (380 mg, 60%).

MS (ISP) 630,1 [(M+N)+].

Example M

tert-Butyl ester (4-cyan-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-5-pyrrolidin-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-cyan-5-pyrrolidin-1-ylphenyl)carbamino acid (example J28) (302 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance in a light brown colour (420 mg, 79%).

MS (ISP) 530,2 [(M+N)+].

Example M

tert-Butyl ether (RS)-[4-cyan-5-(methylpropylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-cyan-5-(methylpropylamine)phenyl]carbamino acid (example J29) (304 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (401 mg, 1.0 mmol) according to the standard method M Compound was obtained in the form foamy substance light red (440 mg, 70%).

MC (ISP) 630,1 [(M+H)+].

Example M

tert-Butyl E. the Il [4-cyan-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropylidene)-5-(methylpropylamine)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-cyan-5-(methylpropylamine)phenyl]carbamino acid (example J29) (304 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance, light brown (370 mg, 70%).

MS (ISP) 532,3[(M+N)+].

Example M

tert-Butyl ester (4-cyan-5-diethylamino-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-cyan-5-diethylaminophenyl)carbamino acid (example J30) (304 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance, light brown (360 mg, 68%).

MS (ISP) 530,2 [(M+N)+].

Example M

tert-Butyl ester (4-cyan-5-(isopropylethylene)-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-cyan-5-(isopropylethylene)phenyl]carbamino acid (example J31) (304 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-is)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance, light brown (380 mg, 71%).

MS (ISN) 530,2[(M-N)-].

Example M

tert-Butyl ether (RS)-[4-cyan-5-(isopropylethylene)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-cyan-5-(isopropylethylene)phenyl]carbamino acid (example J31) (304 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (401 mg, 1.0 mmol) according to the standard method M Compound was obtained in the form foamy substance in yellow (460 mg, 73%).

MC (ISN) 630,1 [(M-N)-].

Example M

tert-Butyl ester (4-cyan-5-(isobutylamino)-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-cyan-5-(isobutylamino)phenyl]carbamino acid (example J32) (318 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance, light brown (400 mg, 73%).

MS (IN) TO 544.3 [(M-N) -].

Example M98

tert-Butyl ether (RS)-[4-cyan-5-(isobutylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-cyan-5-(isobutylamino)phenyl]carbamino acid (example J32) (318 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (401 mg, 1.0 mmol) according to the standard method M Compound was obtained in the form foamy substance in yellow (470 mg, 73%).

MC (ISN) 644,2 [(M-H)-].

Example m

tert-Butyl ester (4-cyan-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-5-piperidine-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-cyan-5-piperidine-1-ylphenyl)carbamino acid (example J33) (316 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance in a light brown colour (420 mg, 77%).

MS (ISP) 544,2 [(M+N)+].

Example M100

tert-Butyl ester (4-chloro-5-isobutylamino-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

is shown in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-isobutylamino)carbamino acid (example J34) (314 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained in the form of not quite white foamy substance (340 mg, 63%).

MS (ISP) 542,2 [(M+N)+].

Example M101

tert-Butyl ether (RS)-[4-chloro-5-isobutylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-isobutylamino)carbamino acid (example J34) (314 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (401 mg, 1.0 mmol) according to the standard method M Compound was obtained as red oil (180 mg, 28%).

MS (ISN) 640,2 [(M-H)-].

Example M102

tert-Butyl ether (RS)-[5-(methylpropylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(methylpropylamine)-4-triptoreline]carbamino acid (example J35) (380 mg, 1.09 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (mg, 1.09 mmole) according to the standard method M Compound was obtained as foamy substance in red (150 mg, 20%).

MS (ISN) 675,4 [(M-N)-].

Example M103

tert-Butyl ether [2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-5-(methylpropylamine)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(methylpropylamine)-4-triptoreline]carbamino acid (example J35) (360 mg, the 1.04 mmole) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (312 mg, the 1.04 mmole) according to the standard method M Compound was obtained as foamy substance light red (270 mg, 45%).

MS (ISN) 573,2 [(M-N)-].

Example M104

tert-Butyl ether (RS)-[5-(isobutylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isobutylamino)-4-triptoreline]carbamino acid (example J36) (370 mg, of 1.02 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (411 mg, of 1.02 mmole) according to the standard method M Compound was obtained as foamy substance light-coric is avago color (520 mg, 74%).

MS (ISN) 687,2 [(M-N)-].

Example M105

tert-Butyl ester (5-(isobutylamino)-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isobutylamino)-4-triptoreline]carbamino acid (example J36) (360 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (302 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance, light brown (430 mg, 73%).

MS (ISN) 587,3 [(M-N)-].

Example M106

tert-Butyl ether (RS)-[5-(isopropylethylene)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isopropylethylene)-4-triptoreline]carbamino acid (example J37) (340 mg, and 0.98 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (393 mg, and 0.98 mmole) according to the standard method M Compound was obtained as foamy substances pale yellow (510 mg, 77%).

MS (ISN) 673,3 [(M-N)-].

Example M107

tert-Butyl ester (5-(isopropylethylene is)-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isopropylethylene)-4-triptoreline]carbamino acid (example J37) (350 mg, 1,01 mmole) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (304 mg, 1,01 mmole) according to the standard method M Compound was obtained as foamy substance, light brown (380 mg, 66%).

MS (ISN) 573,2 [(M-N)-].

Example M108

tert-Butyl ether (RS)-[5-(isobutylamino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isobutylamino)-4-were]carbamino acid (example J38) (307 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (401 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substances pale yellow (330 mg, 52%).

MC (ISP) 635,2 [(M+H)+].

Example M109

tert-Butyl ester (5-(isobutylamino)-4-methyl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isobutylamino)-4-were]carb is inovas acid (example J38) (307 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance light yellow (330 mg, 62%).

MC (ISP) 535,4 [(M+H)+].

Example M110

tert-Butyl ether (RS)-[4-methyl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-5-pyrrolidin-1-ylphenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-methyl-5-pyrrolidin-1-ylphenyl)carbamino acid (example J39) (292 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (401 mg, 1.0 mmol) according to the standard method M Connection received the form of a foamy substance of light-yellow color (410 mg,66%).

MS (ISP) 619,3 [(M+N)+].

Example M111

tert-Butyl ester (4-methyl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropylidene)-5-pyrrolidin-1-ylphenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-methyl-5-pyrrolidin-1-ylphenyl)carbamino acid (example J39) (291 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Connect the ie received in the form of a foamy substance, light brown (330 mg, 64%).

MC (ISN) 517,3 [(M-H)-].

Example M112

tert-Butyl ester (4-chloro-5-isopropylamino-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-isopropylaminomethyl)carbamino acid (example J40) (300 mg, 1.0 mmol) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (301 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance, light brown (169 mg, 32%).

MS (ISN) 525,2 [(M-H)-].

Example M113

tert-Butyl ether (RS)-[4-chloro-5-isopropylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-isopropylaminomethyl)carbamino acid (example J40) (300 mg, 1.0 mmol) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionic acid (example K5) (401 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance light yellow (375 mg, 60%).

MC (ISN) 625,1 [(M-N)-].

Example M114

tert-Butyl ether (RS)-[4-chloro-5-(methylpropylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,4]triazole-1-the l]phenyl} propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(methylpropylamine)phenyl]carbamino acid (example J8) (1.0 g, 3,19 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,4]triazole-1-yl]phenyl}propionic acid (example K24) (1.28 g, 3,19 mmole) according to the standard method M Compound was obtained in the form foamy substance in yellow (1.48 g).

MS (ISP) 641,3 [(M+N)+].

Example M115

tert-Butyl ether (RS)-[4-chloro-5-(isobutylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,4]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(isobutylamino)phenyl]carbamino acid (example J24) (1.0 g, was 3.05 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,4]triazole-1-yl]phenyl}propionic acid (example K24) (1.22 g, of 3.05 mmole) according to the standard method M Compound was obtained in the form foamy substance, light brown (620 mg, 31%).

MS (ISP) 655,1 [(M+N)+].

Example M116

tert-Butyl ether (RS)-[5-(isobutylamino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,4]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(and what butylmethylamine)-4-were]carbamino acid (example J38) (1.0 g, 3.25 mmole) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,4]triazole-1-yl]phenyl}propionic acid (example K24) (1.31 g, 3.25 mmole) according to the standard method M Compound was obtained as foamy substance of light-yellow color (970 mg,47%).

MS (ISP) 635,2 [(M+N)+].

Example M117

tert-Butyl ether {5-(methylpropylamine)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(methylpropylamine)-4-triptoreline]carbamino acid (example J35) (347 mg, 1.0 mmol) and tert-butyl ester 3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionic acid (example C) (287 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance of light-yellow color (320 mg, 57%).

MS (ISP) 561,4 [(M+N)+].

Example M118

tert-Butyl ether {5-(methylpropylamine)-2-[3-oxo-3-(3-[1,2 .3]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(methylpropylamine)-4-triptoreline]carbamino acid (example J35) (347 mg, 1.0 mmol) and tert-butyl ester 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example C) (287 mg, 1.0 mmol) according to the standard method M Connection p which were given in the form of butter, light brown (340 mg, 61%).

MS (ISP) 561,3 [(M+N)+].

Example M

tert-Butyl ether {5-(isobutylamino)-2-[3-oxo-3-(3-pyrazole-1-ylphenyl)propionamido]-4-triptoreline} carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isobutylamino)-4-triptoreline]carbamino acid (example J40) (361 mg, 1.0 mmol) and tert-butyl ester 3-oxo-3-(3-pyrazole-1-ylphenyl)propionic acid (example C) (286 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance, light brown (500 mg, 87%).

MS (ISP) 574,2 [(M+N)+].

Example M120

tert-Butyl ether [2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-(isopropylethylene)-4-triptoreline]carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isopropylethylene)-4-triptoreline]carbamino acid (example J37) (500 mg, 1.44 mmole) and tert-butyl ester 3-(2-lepirudin-4-yl)-3-oxopropanoic acid (example K3) (355 mg, 1.44 mmole) according to the standard method M Compound was obtained in the form of oil light orange color (670 mg, 90%).

MC (ISN) 518,1 [(M-N)-].

Example M121

tert-Butyl ester {4-chloro-5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid

Specified in the title is connected to the e was obtained from tert-butyl ether [2-amino-4-chloro-5-(isobutylamino)phenyl]carbamino acid (example J27) (500 mg, of 1.53 mmole) and tert-butyl ester 3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionic acid (example C) (438 mg, 1,53 mmole) according to the standard method M Compound was obtained as foamy substance light orange (700 mg, 85%).

MS (ISN) 539,2 [(M-H)-].

Example M122

tert-Butyl ether {5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]-4-triptoreline)carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isobutylamino)-4-triptoreline]carbamino acid (example J36) (361 mg, 1.0 mmol) and tert-butyl ester 3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionic acid (example C) (287 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance light red (490 mg, 85%).

MS (ISP) 575,2 [(M+N)+].

Example M123

tert-Butyl ester {4-chloro-5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(isobutylamino)phenyl]carbamino acid (example J27) (328 mg, 1.0 mmol) and tert-butyl ester 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example C) (287 mg, 1.0 mmol) according to the standard method M Compound was obtained as orange oil (250 is g, 46%).

MS (ISN) 539,2 [(M-N)-].

Example M124

tert-Butyl ether {5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isobutylamino)-4-triptoreline]carbamino acid (example J41) (460 mg, of 1.27 mmole) and tert-butyl ester 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example C) (364 mg, of 1.27 mmole) according to the standard method M Compound was obtained in the form of butter, light brown (480 mg, 69%).

MC (ISN) 573,1 [(M-N)-].

Example M125

tert-Butyl ether {2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-isobutylamino-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isobutylamino)-4-triptoreline]carbamino acid (example J41) (347 mg, 1.0 mmol) and tert-butyl ester 3-(3-imidazol-1-ylphenyl)-3-oxopropanoic acid (example C) (286 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance of light-yellow color (430 mg, 77%).

MS (ISN) 558,2 [(M-N)-].

Example M126

tert-Butyl ester {4-chloro-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-isobutylamino}carbamino acid

Specified in the title compound was obtained from the t is et-butyl ether (2-amino-4-chloro-5-isobutylamino]carbamino acid (example J34) (313 mg, 1.0 mmol) and tert-butyl ester 3-(3-imidazol-1-ylphenyl)-3-oxopropanoic acid (example C) (286 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance light yellow (330 mg, 63%).

MS (ISN) 524,1 [(M-N)-].

Example M127

tert-Butyl ester {4-chloro-5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]phenyl)carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(isobutylamino)phenyl]carbamino acid (example J34) (313 mg, 1.0 mmol) and tert-butyl ester 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example C) (287 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance pale brown (220 mg, 42%).

MS (ISN) 525,1 [(M-N)-].

Example M

tert-Butyl ether {5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isobutylamino)-4-triptoreline]carbamino acid (example J41) (347 mg, 1.0 mmol) and tert-butyl ester 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example C) (287 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance of light-yellow color (340 mg,60%).

MS (ISN) 559,2 [(M-N)-].

Example M129

tert-Butyl ester {4-chloro-5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(isobutylamino)phenyl]carbamino acid (example J34) (313 mg, 1.0 mmol) and tert-butyl ester 3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionic acid (example C) (287 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance of light-yellow color (390 mg, 74%).

MC (ISN) 525,1 [(M-N)-].

Example M130

tert-Butyl ether {5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(isobutylamino)-4-triptoreline]carbamino acid (example J41) (347 mg, 1.0 mmol) and tert-butyl ester 3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionic acid (example C) (287 mg, 1.0 mmol) according to the standard method M Compound was obtained as foamy substance of light-yellow color (430 mg, 77%).

MS (ISP) 559,2 [(M+N)+].

The standard technique N

Getting 4-aryl-1,3-dihydrobenzo[b][1,4]diazepin-2-ones

The solution or suspension of tert-butyl methyl ether {2-[3-aryl-3-oxopropionate]phenyl}carbamino acid (1.0 mmol)in dichloromethane (5 ml) [if necessary, may be added anisole or 1,3-dimethoxybenzene (5-15 mmol)] was treated triperoxonane acid (0.5 to 5.0 ml) at 0° C and stirring was continued at 23°until, while according to TLC were observed full of the educt. Processing according to method a). The solvent was removed in vacuo, the residue was treated with a small amount of diethyl ether, resulting in the residue crystallized. The solid was stirred with saturated sodium bicarbonate solution or 1 M sodium carbonate solution, filtered, washed with water and diethyl ether or mixtures of diethyl ether/tetrahydrofuran/methanol and dried, has been specified in the title compound, which if necessary, may be purified by crystallization from 1,4-dioxane or by column chromatography on silica gel using as eluent cyclohexane/ethyl acetate or ethyl acetate/ethanol.

Processing according to method b). The reaction mixture was diluted with dichloromethane or ethyl acetate, washed with saturated sodium bicarbonate solution or 1 M sodium carbonate solution, with brine and dried over magnesium sulfate or sodium sulfate. After removal of solvent in vacuo received substance that you RUB with diethyl ether or mixtures of diethyl ether/tetrahydrofuran/methanol to obtain the title compound, which if necessary, may be purified by crystallization from 14-dioxane or by column chromatography on silica gel using as eluent cyclohexane/ethyl acetate or ethyl acetate/ethanol.

Example 1

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

Specified in the title compound was obtained from tert-butyl ester {4-chloro-2-[3-(3-tianfeng)-3-oxopropionate]-5-dimethylaminophenyl}carbamino acid (example M1) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (85 mg).

MS (ISP) 339 [(M+N)+] 341 [(M+2+N)+]; tPL>250°C.

Example 2

8-Chloro-7-dimethylamino-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ester {4-chloro-5-dimethylamino-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid (example M2) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solid light yellow (87 mg).

MC (ISP) 381(M+H)+] 383 [(M+2+N)+]; tPL222-225°C.

Example 3

8-Chloro-7-dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example MOH) when clicks the development triperoxonane acid in dichloromethane according to the standard method N. The connection was received in the form of a solid beige color (60 mg).

MS (ISP) 411 [(M+N)+] 413 [(M+2+N)+]; tPL210-214°C.

Example 4

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

Specified in the title compound was obtained from tert-butyl ether {2-[3-(3-tianfeng)-3-oxopropionate]-5-dimethylamino-4-phenylethylene}carbamino acid (example M4) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid orange (65 mg).

MS (ISP) 405 [(M+N)+]; tPL215-216°C.

Example 5

7-Dimethylamino-8-phenylethynyl-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether {5-dimethylamino-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]-4-phenylethylene}carbamino acid (example M5) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid orange (76 mg).

MS (ISP) 447 [(M+N)+]; tPL185-186°C.

Example 6

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

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-dimethylamino-2-{3-[3-(3-METI is isoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example M6) when processing triperoxonane acid in dichloromethane according to the standard method N. The connection was received in the form of solid light yellow (68 mg).

MS (EI) 394 (M+and 396 [(M+2)+]; tPL212-215°C.

Example 7

8-(2,3-Differenl)-7-dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[2-dimethylamino-2',3'-debtor-5-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)biphenyl-4-yl]carbamino acid (example M7) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (26 mg).

MS (ISP) 489 [(M+N)+].

Example 8

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

Specified in the title compound was obtained from tert-butyl ether {2-dimethylamino-2',3'-debtor-5-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]biphenyl-4-yl}carbamino acid (example M8) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (47 mg).

MS (ISP) 459 [(M+N)+]; tPL197-199°C.

Example 9

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

Specified in the title compound was obtained istrat-butyl ester {5-[3-(3-tianfeng)-3-oxopropionate]-2-dimethylamino-2',3'-diferuloyl-4-yl}carbamino acid (example M9) when processing triperoxonane acid in dichloromethane according to the standard method N. The connection was received in the form of solid light yellow (75 mg).

MS (ISP) 417 [(M+N)+]; tPL228-229°C.

Example 10

8-Chloro-7-dimethylamino-4-[2-(3-methylisoxazol-5-yl)pyridin-4-yl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-dimethylamino-2-{3-[2-(3-methylisoxazol-5-yl)pyridin-4-yl]-3-oxopropionate}-phenyl)carbamino acid (example M10) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (111 mg).

MS (ISP) 396 [(M+N)+] 398 [(M+N+2)+]; tPL>250°C.

Example 11

8-Chloro-7-[(2-methoxyethyl)methylamino]-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-[(2-methoxyethyl)methylamino]-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example M11) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (115 mg).

MS (EI) 438 (M+) and 440 [(M+2)+]; tPL182°C.

Example 12

8-Chloro-7-[(2-methoxyethyl)methylamino]-4-[2-(3-methylisoxazol-5-yl)pyridin-4-yl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in sahlawi the compound was obtained from tert-butyl ether (4-chloro-5-[(2-methoxyethyl)methylamino]-2-{3-[2-(3-methylisoxazol-5-yl)pyridin-4-yl]-3-oxopropionate}phenyl)carbamino acid (example M12) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (106 mg).

MC (ISP) 440(M+H)+] 442 [(M+N+2)+]; tPL213°C.

Example 13

8-Chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-[(2-methoxyethyl)methylamino]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-[(2-methoxyethyl)methylamino]-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M13) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid beige color (50 mg).

MS (ISP) 455 [(M+N)+] 457 [(M+N+2)+]; tPL185°C.

Example 14

8-Chloro-7-[(2-methoxyethyl)methylamino]-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ester {4-chloro-5-[(2-methoxyethyl)methylamino]-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid (example M14) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (69 mg).

MS (ISP) 425 [(M+N)+] 427 [(M+N+2)+]; tPL156°C.

Example 15

4-(7-Chloro-8-dimethylamino-4-oxo-45-dihydro-3H-benzo[b][1,4]diazepin-2-yl)pyridine-2-carbonitrile

Specified in the title compound was obtained from tert-butyl ester {4-chloro-2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-dimethylaminophenyl}carbamino acid (example M15) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (50 mg).

MS (ISP) 340 [(M+N)+] 342 [(M+2+N)+]; tPL216°C.

Example 16

8-Chloro-7-dimethylamino-4-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-dimethylamino-2-{3-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example M16) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid (67 mg).

MS (ISP) 394 [(M+N)+] 396 [(M+2+N)+]; tPL225°C.

Example 17

7-Dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b|[1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid (example M17) when processing triperoxonane acid in dichloromethane under a hundred is a standard method N. The connection was received in the form of not-quite-white solid (62 mg).

MS (ISP) 489 [(M+N)+]; tPL210°C.

Example 18

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

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid (example M18) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid (28 mg).

MS (ISP) 429 [(M+N)+]; tPL223°C.

Example 19

8-Chloro-7-dimethylamino-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 3-(7-chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)thiobenzamide {obtained from 3-(7-chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile (example 1) as follows: to the solution of hexamethyldisilazane (0,55 ml, 2.6 mmole) in 1,3-dimethyl-2-imidazolidinone (2.6 ml) was added at 20°With sodium methylate (0,13 g, 2.5 mmole). The mixture was stirred 15 minutes and the resulting blue solution was then added to a solution of 3-(7-chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile (example 1) (0.34 g, 1.0 mmol) in 1,3-dim the Teal-2-imidazolidinone (2 ml). The mixture was stirred 3 hours at 20°and then poured into water. The precipitate was isolated by filtration and triturated with acetone, was obtained 3-(7-chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)thiobenzamide (0.35 g) as a solid yellow color, tPL234°C (decomp.), MS (ISP) 373,2 [(M+N)+]} (0.71 g, 1.9 mmole), 1,3-dichloro-2-propanone (0.36 g, to 2.85 mmole) and sodium bicarbonate (0.24 g, to 2.85 mmole) in 1,4-dioxane (15 ml), all were heated for 48 hours at 60°C. a Clear solution was evaporated in vacuum. To a solution of the residue in 1,4-dioxane (5 ml) was added 2 N. potassium hydroxide (3.8 ml) and the mixture was stirred for 1 hour at 20°C. was Added water (100 ml) and the mixture was stirred for 0.5 hours. The precipitate was filtered and was led from dichloromethane, got mentioned in the title compound (0,69 g) as a solid pale yellow color.

MS (ISP) 427,2 [(M+N)+]; tPL134°C (decomp.).

Example 20

8-Chloro-7-dimethylamino-4-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-dimethylamino-2-{3-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example M19) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solid substances is and beige (34 mg).

MS (ISP) 438 [(M+N)+] 440 [(M+2+N)+]; tPL145-160°C.

Example 21

8-Chloro-7-dimethylamino-4-[3-(3-methoxymethylethoxy-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-dimethylamino-2-{3-[3-(3-methoxymethylethoxy-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example M20) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (157 mg).

MS (ISP) 425 [(M+N)+] 427 [(M+2+N)+]; tPL191°C.

Example 22

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

Specified in the title compound was obtained from tert-butyl ether {2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-dimethylamino-4-triptoreline}carbamino acid (example M21) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (158 mg).

MS (ISP) 374 [(M+N)+]; tPL248°C.

Example 23

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

Specified in the title compound was obtained from tert-butyl ether [2'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate what about]-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid (example M22) when processing triperoxonane acid in dichloromethane according to the standard method N. The compound was obtained in a solid brown color (50 mg).

MS (EI) 494 (M+); tPL208-210°C.

Example 24

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

Specified in the title compound was obtained from tert-butyl ether [2'-fluoro-5-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid (example M23) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solid light yellow (21 mg).

MS (EI) 509 (M+); tPL218-220°C.

Example 25

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

Specified in the title compound was obtained from tert-butyl ether [2'-fluoro-5-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid (example M24) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid orange (45 mg).

MS (EI) 495 (M+).

Example 26

8-(2-Forfinal)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(2,2,2-triptoreline)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS-[2'-fluoro-5-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamido)-2-(2,2,2-triptoreline)biphenyl-4-yl]carbamino acid (example M25) when processing triperoxonane acid in dichloromethane according to the standard the method N. Compound was obtained in the form of not-quite-white solid (10 mg).

MS (ISP) 526 [(M+N)+]; tPL232-234°C.

Example 27

8-Chloro-7-dimethylamino-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J2) (170 mg) and tert-butyl methyl ether (RS)-3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)oxazol-2-yl]phenyl}propionic acid (example C) (270 mg) according to the standard procedure M. the Obtained compound was subjected to unprotect and then cyclization when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solid light yellow (110 mg).

MS (ISP) 411,2 [(M+N)+]; tPL193-195°C.

Example 28

8-Chloro-7-(ethylmethylamino)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-(ethylmethylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M26) (0.5 g, 0.8 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not quite white solid substances is a (60 mg).

MS (ISP) 425,4 [(M+N)+]; tPL206°C (decomp.).

Example 29

8-Chloro-7-(methylpropylamine)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-(methylpropylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M27) (0,41 g of 0.64 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid pale yellow color (110 mg).

MS (ISP) RUR 439,3 [(M+N)+]; tPL178°C (decomp.).

Example 30

8-Chloro-7-(diethylamino)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-(diethylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example covered by M28) (0,53 g, 0,827 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid (210 mg).

MS (ISP) RUR 439,3 [(M+N)+]; tPL208°C (decomp.).

Example 31

8-Chloro-7-dimethylamino-4-[3-(3-hydroxymethylimidazole-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title with the unity was obtained from tert-butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}propionamide)phenyl]carbamino acid (example M29) (81 mg, of 0.13 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (38 mg).

MS (ISP) 411 [(M+N)+] 413 [(M+2+N)+]; tPL132°C.

Example 32

8-Chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-pyrrolidin-1-yl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-5-pyrrolidin-1-ylphenyl]carbamino acid (example M30) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (58 mg).

MS (ISP) 437 [(M+N)+] 439 [(M+2+N)+]; tPL193-197°C.

Example 33

7-Dimethylamino-4-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-2-{3-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid (example M31) (78 mg, 0, 14 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid (48 mg).

MS (ISP) 428 [(M+N)+]; tPL225°C.

Prima is 34

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

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(cyclopropylamino)phenyl]carbamino acid (example J11) (150 mg, 0.5 mmole) and tert-butyl ester 3-(2-lepirudin-4-yl)-3-oxopropanoic acid (example K3) (150 mg, and 0.61 mmole) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (69 mg).

MS (ISN) 340 [(M-N)-] 366 [(M+2-N)-]; tPL199-201°C.

Example 35

8-Chloro-7-dimethylamino-4-[3-(4-hydroxymethyl-3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-{3-[3-methyl-4-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}-3-oxopropionate)phenyl]carbamino acid (example M32) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (60 mg).

MS (ISP) 425 [(M+N)+] 427 [(M+2+N)+]; tPL232-233°C.

Example 36

8-Chloro-7-(cyclopropylamino)-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-d is hydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(cyclopropylamino)phenyl]carbamino acid (example J11) (156 mg, 0.5 mmole) and tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example K4) (170 mg, of 0.56 mmole) according to the standard procedure M. the Obtained compound was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. the Connection was received in a solid yellow (49 mg).

MS (ISP) 421,3 [(M+N)+] 423 [(M+2+N)+]; tPL195-197°C.

Example 37

8-Chloro-7-(cyclopropylamino)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-(cyclopropylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example m) (200 mg, 0,313 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow (54 mg).

MS (ISP) 437,3 [(M+N)+] 439 [(M+2+N)+].

Example 38

7-Dimethylamino-4-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title with the Association was obtained from tert-butyl ether (5-dimethylamino-2-{3-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid (example M) (126 mg, 0,214 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solid light yellow (23 mg).

MS (ISP) 472 [(M+N)+]; tPL200°C.

Example 39

8-Chloro-7-dimethylamino-4-[3-(5-hydroxymethyl-2-methyl-2H-pyrazole-3-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-{3-[2-methyl-5-(tetrahydropyran-2-intoximeter)-2H-pyrazole-3-yl]phenyl}-3-oxopropionate)phenyl]carbamino acid (example M35) (278 mg, of 0.44 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (129 mg).

MS (ISP) 424 [(M+N)+] 426 [(M+2+N)+]; tPL184°C.

Example 40

4-(4-Oxo-8-pyrrolidin-1-yl-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)pyridine-2-carbonitrile

Specified in the title compound was obtained from tert-butyl ether {2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-pyrrolidin-1-yl-4-triptoreline}carbamino acid (example m) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid orange (65 mg).

MS (ISP) 400,4 [(M+H)+]; tPL188°C (decomp.).

When is EP 41

4-[3-(5-Hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-pyrrolidin-1-yl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-5-pyrrolidin-1-yl-4-triptoreline]carbamino acid (example M) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solid light yellow (33 mg).

MS (ISP) 471,2 [(M+N)+]; tPL134°C.

Example 42

7-Dimethylamino-8-fluoro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-dimethylamino-4-fluoro-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M38) (375 mg, 0,63 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (115 mg).

MS (ISP) 395 [(M+N)+]; tPL75°C.

Example 43

7-Dimethylamino-4-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-8-fluoro-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-2-{3-[3-(5-dimethylaminomethyl the l-[1,2,3]triazole-1-yl)phenyl]-3-oxopropionate}-4-forfinal)carbamino acid (example m) (170 mg, of 0.32 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (34 mg).

MS (ISP) 422 [(M+N)+]; tPL181°C.

Example 44

7-Dimethylamino-8-fluoro-4-[3-(3-hydroxymethylimidazole-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-dimethylamino-4-fluoro-2-(3-oxo-3-{3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}propionamide)phenyl]carbamino acid (example M40) (314 mg, of 0.53 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (95 mg).

MS (ISP) 395 [(M+N)+]; tPL187°C.

Example 45

8-Chloro-7-dimethylamino-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-7-dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 3) (123 mg, 0.3 mmole) by treatment with thionyl chloride (0,044 ml, 0.6 mmole) in dichloromethane (2 ml) at a temperature of 23°C to boiling point and boiling under reflux for 15 minutes, then evaporated dry. Technical chloride was dissolved in dimethylformamide (2 ml) and stirred with catalic the ical quantity of sodium iodide and pyrrolidine (0,248 ml, 3.0 mmole) at 23°until then, until TLC indicated full conversion of the chloride. The reaction mixture was mixed with ethyl acetate, washed with water and with brine, dried over sodium sulfate. After removal of solvent in vacuo remained semi-hard yellow substance, which was purified by column chromatography on silica gel. The connection was received in the form of a solid yellow (101 mg).

MS (ISP) 464 [(M+N)+] 466 [(M+2+N)+]; tPL180-182°C.

Example 46

7-Dimethylamino-4-[3-(3-hydroxymethylimidazole-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[3-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}propionamide)-4-triptoreline]carbamino acid (example M41) (680 mg, 1.05 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (294 mg).

MS (ISP) 455 [(M+N)+]; tPL219°C.

Example 47

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

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-4-fluoro-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino the acid (example M42) (233 mg, to 0.47 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained as a solid substance, yellowish-brown (59 mg).

MS (ISP) 379 [(M+N)+]; tPL124°C.

Example 48

4-[3-(5-Azetidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-8-chloro-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-7-dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 3) (123 mg, 0.3 mmole) by treatment with thionyl chloride (3 EQ.) and trimethylaluminum (10 equiv.) as described in example 45. The connection was received in the form of a solid yellow (17 mg).

MS (ISP) 450 [(M+N)+]; tPL153°C.

Example 49

8-Chloro-7-dimethylamino-4-[3-(5-hydroxymethylimidazole-3-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionamide)phenyl]carbamino acid (example M) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (113 mg).

MS (ISP) 411,3 [(M+N)+] 413 [(M+2+N)+]; tPL211°C (decomp.).

Example 50

8-Chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-yl)phenyl]-7-piperidine-1-yl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-5-piperidine-1-ylphenyl]carbamino acid (example M44) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solid light yellow (99 mg).

MS (ISP) 451,3 [(M+N)+] 453 [(M+2+N)+]; tPL246°C (decomp.).

Example 51

7-Dimethylamino-4-[3-(5-hydroxymethylimidazole-3-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionamide)-4-triptoreline]carbamino acid (example M45) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (103 mg).

MS (ISP) 445,3 [(M+N)+]; tPL211°C (decomp.).

Example 52

8-Chloro-7-dimethylamino-4-(3-pyrazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ester {4-chloro-(5-dimethylamino-2-[3-oxo-3-(3-pyrazole-1-ylphenyl)propionamido]phenyl}carbamino acid (example M46) when processing triperoxonane of Kolotov dichloromethane according to the standard method N. The compound was obtained in a solid yellow color (75 mg).

MS (ISP) 380 [(M+N)+] 382 [(M+2+N)+]; tPL231-234°C.

Example 53

7-Dimethylamino-4-[3-(3-pyrrolidin-1-ilmestymisesta-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 7-dimethylamino-4-[3-(3-hydroxymethylimidazole-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 46) (111 mg, 0.25 mmole) by treatment with thionyl chloride (3 EQ.) and pyrrolidine (10 equiv.) as described in example 45. The connection was received in the form of a solid yellow (28 mg).

MS (ISP) 498 [(M+N)+]; tPL160°C.

Example 54

7-Dimethylamino-4-[3-(3-morpholine-4-ilmestymisesta-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 7-dimethylamino-4-[3-(3-hydroxymethylimidazole-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example M46) (53 mg, 0, 12 mmole) by treatment with thionyl chloride (3 EQ.) and morpholine (10 equiv.) as described in example 45. The compound was obtained in a solid yellow color (33 mg).

MS (ISP) 514 [(M+N)+]; tPL165°C.

Example 55

7-Dimethylamino-4-[3-(3-dimethylaminomethylphenol-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 7-dimethylamino-4-[3-3-hydroxymethylimidazole-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 46) (53 mg, 0, 12 mmole) by treatment with thionyl chloride (3 EQ.) and 40%aqueous solution of dimethylamine (10 equiv.) as described in example 45. The connection was received in the form of solid light yellow (21 mg).

MS (ISP) 472 [(M+N)+]; tPL160°C.

Example 56

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

Specified in the title compound was obtained from tert-butyl ether {2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-4-fluoro-5-pyrrolidin-1-ylphenyl}carbamino acid (example m) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid orange (54 mg).

MS (ISP) 350 [(M+N)+]; tPL278-279°C.

Example 57

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

Specified in the title compound was obtained from tert-butyl ether (4-fluoro-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-5-pyrrolidin-1-ylphenyl)carbamino acid (example M48) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solids brown (86 mg).

MS (ISP) 405 [(M+N)+]; tPL236°C.

Example 58

8-Fluoro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-pyrrolidin-1-yl-1,3-dihydrobenzo[][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-fluoro-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-5-pyrrolidin-1-ylphenyl]carbamino acid (example M49) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid orange (72 mg).

MS (ISP) 421 [(M+N)+]; tPL184-185°C.

Example 59

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

Specified in the title compound was obtained from tert-butyl ether {5-azetidin-1-yl-4-chloro-2-[3-(2-lepirudin-4-yl)-3-oxopropionate]phenyl}carbamino acid (example M50) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid orange (66 mg).

MS (ISP) 352 [(M+N)+] 354 [(M+2+N)+]; tPL276°C.

Example 60

4-[3-(5-Hydroxymethylimidazole-3-yl)phenyl]-7-pyrrolidin-1-yl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionamide)-5-pyrrolidin-1-yl-4-triptoreline]carbamino acid (example M51) when processing triperoxonane acid in dichloro ethane according to the standard method N. The compound was obtained in a solid yellow color (224 mg).

MS (ISP) 471,2 [(M+N)+]; tPL206-208°C.

Example 61

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

Specified in the title compound was obtained from tert-butyl ether {5-azetidin-1-yl-2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-4-triptoreline}carbamino acid (example M52) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid orange (51 mg).

MS (ISN) 384,2 [(M-N)-]; tPL241°C.

Example 62

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

Specified in the title compound was obtained from tert-butyl ether (5 azetidin-1-yl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid (example M53) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (94 mg).

MS (ISP) 441,3 [(M+N)+]; tPL239°C (decomp.).

Example 63

7 Azetidin-1-yl-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl EF is RA (RS)-[5-azetidin-1-yl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid (example M54) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (182 mg).

MS (ISP) 457,4 [(M+N)+]; tPL202°C (decomp.).

Example 64

7-Dimethylamino-4-(3-pyrazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether {5-dimethylamino-2-[3-oxo-3-(3-pyrazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid (example M55) (438 mg, of 0.82 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (238 mg).

MS (ISP) 414 [(M+N)+]; tPL176°C.

Example 65

7-Dimethylamino-4-(3-[1,2,4]triazole-4-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether {5-dimethylamino-2-[3-oxo-3-(3-[1,2,4]triazole-4-ylphenyl)propionamido]-4-triptoreline}carbamino acid (example M56) (280 mg, 0,526 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (121 mg).

MS (ISP) of 415.3 [(M+N)+]; tPL247-250°C.

Example 66

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

Specified in the title compound was obtained from the pet-butyl ester {5-dimethylamino-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-4-triptoreline}carbamino acid (example m) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (132 mg).

MC (ISP) 414 [(M+N)+]; tPL203-205°C.

Example 67

8-Chloro-7-dimethylamino-4-[3-(4-hydroxymethylimidazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)pyrazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M58) (642 mg, 1.05 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (365 mg).

MS (ISP) 410 [(M+N)+]; tPL211°C.

Example 68

7-Dimethylamino-4-[3-(4-hydroxymethylimidazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)pyrazole-1-yl]-phenyl}propionamide)-4-triptoreline]carbamino acid (example M58) (590 mg, of 0.91 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (299 mg).

MS (ISP) 444 [(M+N)+]; tPL175°C.

Example 69

7-Dimethylamino-4-[3-(4-hydroxymethyl-3-methylisoxazol-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydr the benzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-dimethylamino-2-(3-{3-[3-methyl-4-(tetrahydropyran-2-intoximeter)isoxazol-5-yl]phenyl}-3-oxopropylidene)-4-triptoreline]carbamino acid (example M60) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (64 mg).

MS (ISP) 459 [(M+N)+]; tPL207-208°C.

Example 70

7-Dimethylamino-4-[3-(4-hydroxymethylimidazole-3-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[4-(tetrahydropyran-2-intoximeter)isoxazol-3-yl]phenyl}propionamide)-4-triptoreline]carbamino acid (example M61) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow (50 mg).

MS (ISP) 445 [(M+N)+]; tPL217-219°C.

Example 71

7-Dimethylamino-4-[3-(2-methylsulfonylamino-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-2-{3-[3-(2-methylsulfonylamino-1-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid (example M62) (mg, 0,78 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (253 mg).

MS (ISP) 460 [(M+N)+]; tPL192°C.

Example 72

7-Dimethylamino-4-[3-(4-hydroxymethyl-2-methyl-2H-pyrazole-3-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-dimethylamino-2-(3-{3-[2-methyl-4-(tetrahydropyran-2-intoximeter)-2H-pyrazole-3-yl]phenyl}-3-oxopropylidene)-4-triptoreline]carbamino acid (example M63) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (272 mg).

MS (ISP) 458 [(M+N)+]; tPL243-244°C.

Example 73

8-Chloro-7-dimethylamino-4-(3-[1,2,4]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ester {4-chloro-5-dimethylamino-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid (example M64) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (316 mg).

MS (ISP) 381 [(M+N)+] 383 [(M+2+N)+]; tPL239-241°C.

Example 74

7-Dimethylamino-4-(3-[1,2,4]triazole-1-fenil)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether {5-dimethylamino-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid (example M65) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (269 mg).

MS (ISP) 415 [(M+N)+]; tPL228-230°C.

Example 75

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

Specified in the title compound was obtained from tert-butyl ether {2-[3-(3-tianfeng)-3-oxopropionate]-5-dimethylamino-4-triptoreline}carbamino acid (example M66) (180 mg, 1.0 mmol) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (41 mg).

MS (ISN) 371 [(M-N)-]; tPL224-227°C.

Example 76

7-Dimethylamino-4-(3-{5-[(2,2,2-triptoreline)methyl]-[1,2,3]triazole-1-yl}-phenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 7-dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 17) (133 mg, 0.3 mmole) by treatment with thionyl chloride (3 EQ.) and 2,2,2-triptoreline (10 equiv.) as described in example 45. The connection was received is in the form of solid light yellow (19 mg).

MS (ISP) 526 [(M+N)+]; tPL168-170°C.

Example 77

7-(Cyclopropanemethylamine)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-(cyclopropanemethylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid (example M) (939 mg, of 1.37 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (544 mg).

MS (ISN) 483 [(M-N)-]; tPL212°C.

Example 78

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

Specified in the title compound was obtained from tert-butyl ether [2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-(cyclopropanemethylamine)-4-triptoreline]carbamino acid (example M) (173 mg, of 0.33 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (81 mg).

MS (ISN) 412 [(M-N)-]; tPL155°C.

Example 79

4-[3-(4-Cyclopropanemethanol-1-yl)phenyl]-7-dimethylamino-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-on the Sabbath.

Specified in the title compound was obtained from 7-dimethylamino-4-[3-(4-hydroxymethylimidazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 68) (133 mg, 0.3 mmole) by treatment with thionyl chloride (3 EQ.) and cyclopropylamine (10 equiv.) as described in example 45. The connection was received in the form of a solid yellow (45 mg).

MS (ISP) 483 [(M+N)+]; tPL135°C.

Example 80

4-[3-(5-Cyclopropylmethyl-[1,2,3]triazole-1-yl)phenyl]-7-(cyclopropanemethylamine)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 7-(cyclopropanemethylamine)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 78) (145 mg, 0.3 mmole) by treatment with thionyl chloride (3 EQ.) and cyclopropylamine (10 equiv.) as described in example 45. The compound was obtained in a solid yellow color (97 mg).

MS (ISP) 524 [(M+N)+]; tPL35-46°C.

Example 81

7-Dimethylamino-4-{3-[2-(2-hydroxyethyl)-2H-pyrazole-3-yl]phenyl}-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-{5-dimethylamino-2-[3-oxo-3-(3-{2-[2-(tetrahydropyran-2-yloxy)ethyl]-2H-pyrazole-3-yl}phenyl)propionamido]-4-triptoreline}carbamino acid (example B) (237 mg, of 0.36 mmole) when processing triperoxonane acid is the same in dichloromethane according to the standard method N. The connection was received in the form of not-quite-white solid (48 mg).

MS (ISP) 458 [(M+N)+]; tPL138°C.

Example 82

4-[3-(5-Cyclopropylmethyl-[1,2,3]triazole-1-yl)phenyl]-7-dimethylamino-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 7-dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 17) (444 mg, 1.0 mmol) by treatment with thionyl chloride (3 EQ.) and cyclopropylamine (10 equiv.) as described in example 45. The connection was received in the form of a solid yellow (248 mg).

TPL145-148°C.

Example 83

4-[8-(Cyclopropylamino)-4-oxo-7-trifluoromethyl-4.5-dihydro-3H-benzo[b][1.4]diazepin-2-yl]pyridine-2-carbonitrile

Specified in the title compound was obtained from tert-butyl ether [2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-(cyclopropylamino)-4-triptoreline]carbamino acid (example M70) (215 mg, at 0.42 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (87 mg).

MS (ISP) 400,4 [(M+N)+]; tPL200-205°C.

Example 84

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

Specified in the title compound was obtained from tert-butyl EPE is {2-dimethylamino-2'-fluoro-5-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]biphenyl-4-yl}carbamino acid (example M70) (810 mg, a 1.45 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (61 mg).

MS (ISP) 400,4 [(M+N)+]; tPL225-230°C.

Example 85

7-Dimethylamino-4-{3-[5-(2-hydroxyethyl)-[1,2,3]triazole-1-yl]phenyl}-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-{5-dimethylamino-2-[3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,2,3]triazole-1-yl}phenyl)propionamido]-4-triptoreline}carbamino acid (example M72) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (179 mg).

MS (ISP) 459 [(M+N)+]; tPL172-175°C.

Example 86

7-Dimethylamino-4-[3-(5-hydroxymethyluracil-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)pyrazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid (example M73) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solid light yellow (109 mg).

MS (ISP) 444 [(M+N)+]; tPL228-229° C.

Example 87

7-Dimethylamino-4-(3-[1,2,3]triazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether {5-dimethylamino-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid (example M74) (905 mg, 1.7 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (566 mg).

MS (ISN) 413,2 [(M-N)-]; tPL210-212°C.

Example 88

4-[4-Oxo-8-(2,2,2-triptoreline)-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile

Specified in the title compound was obtained from tert-butyl ether [2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-(2,2,2-triptoreline)-4-triptoreline]carbamino acid (example M75) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow (100 mg).

MS (EI) 428,2 (M+); tPL252-255°C.

Example 89

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

Specified in the title compound was obtained from tert-butyl ether {2-[3-(3-tianfeng)-3-oxopropionate]-4-dimethylamino-5-were}carbamino acid (example m) (0.24 g, 0.55 mmole) if arr is the development triperoxonane acid in dichloromethane according to the standard method N. The connection was received in the form of a solid pale yellow color (114 mg, 59%).

MS (ISP) 319,3 [(M+N)+]; tPL257°C.

Example 90

7-Dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-dimethylamino-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M) (0,42 g of 0.71 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid pale yellow color (200 mg, 72%).

MS (ISP) 391,3 [(M+N)+]; tPL190°C.

Example 91

2-(3-Tianfeng)-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Specified in the title compound was obtained from tert-butyl ether {5-cyan-2-[3-(3-tianfeng)-3-oxopropionate]-4-dimethylaminophenyl}carbamino acid (example M) (0.28 g, to 0.63 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (36 mg, 59%).

MS (ISN) 328,3 [(M-N)-]; tPL251°C.

Example 92

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

Specified in the title compound was obtained from the pet-butyl ether [2-[3-(3-tianfeng)-3-oxopropionate]-5-methyl-4-(methylpropylamine)phenyl]carbamino acid (example m-79) (0.17 g, 0.37 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (74 mg, 58%).

MS (ISP) 347,4 [(M+N)+]; tPL195°C.

Example 93

4-[3-(5-Hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-methyl-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-methyl-5-(methylpropylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M80) (0,42 g of 0.71 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid pale yellow color (200 mg, 72%).

MS (ISP) 419,4[(M+N)+]; tPL186°C.

Example 94

7-(Ethylmethylamino)-4-[3-(5-hydroxymethyl-[1,2 .3]triazole-1-yl)phenyl]-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-(ethylmethylamino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example m) (0.39 g, of 0.64 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid (159 mg, 61%).

MS (ISP) to 405.5 [(M+N)+ ]; tPL207°C.

Example 95

8-Dimethylamino-2-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-cyan-5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example m) (0.35 g, of 0.58 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (149 mg, 64%).

MS (ISP) 402,5 [(M+N)+]; tPL234°C.

Example 96

8-Chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-(isopropylethylene)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example m) (0,53 g, or 0.83 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid (120 mg, 33%).

MS (ISP) 439,5 [(M+N)+]; tPL207°C.

Example 97

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

Specified in the title compound was obtained from tert-BU is silt ester [4-methyl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-5-(methylpropylamine)phenyl]carbamino acid (example m) (0.33 g, to 0.63 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (163 mg, 64%).

MS (ISP) 403,4 [(M+N)+]; tPL194°C.

Example 98

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

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-dimethylamino-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-phenyl)carbamino acid (example m) (0.31 g, of 0.62 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (171 mg, 72%).

MS (ISP) 386,3 [(M+N)+]; tPL248°C.

Example 99

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

Specified in the title compound was obtained from tert-butyl ether (5-(ethylmethylamino)-4-methyl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-phenyl)carbamino acid (example M) (0,38 g, 0.75 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (160 mg, 55%).

MS (ISP) to 389.5 [(M+N)+]; tPL198°C.

Example 100

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

Specified in the title compound was obtained from tert-butyl ether (5-dimethylamino-4-methyl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example M) (0.32 g, 0.65 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (140 mg, 57%).

MS (ISP) 375,4 [(M+N)+]; tPL204°C.

Example 101

8-Chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-(isobutylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M) (0.32 g, of 0.49 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid (107 mg, 48%).

MS (ISP) 453,4 [(M+N)+]; tPL201°C.

Example 102

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

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-(isobutylamino)-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example M) (0.35 g, to 0.63 mmole) when processing three is terukuni acid in dichloromethane according to the standard method N. The connection was received in the form of a solid light-yellow color (114 mg, 41%).

MS (ISP) 437,4 [(M+N)+]; tPL194°C.

Example 103

2-[3-(5-Hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-4-oxo-8-pyrrolidin-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-cyan-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-5-pyrrolidin-1-ylphenyl]carbamino acid (example M90) (0,37 g of 0.59 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (140 mg, 56%).

MS (ISP) 428,5 [(M+N)+]; tPL241°C.

Example 104

2-[3-(3-Methylisoxazol-5-yl)phenyl]-4-oxo-8-pyrrolidin-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Was obtained from tert-butyl ether (4-cyan-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-5-pyrrolidin-1-ylphenyl)carbamino acid (example M) (0,41 g, 0.77 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (90 mg, 28%).

MS (ISP) 412,3 [(M+N)+]; tPL267°C.

Example 105

2-[3-(5-Hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-(methylpropylamine)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Indicated the data in the title compound was obtained from tert-butyl ether (RS)-[4-cyan-5-(methylpropylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M) (0,43 g, 0.68 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (100 mg, 34%).

MS (ISP) 430,5 [(M+N)+]; tPL221°C.

Example 106

2-[3-(3-Methylisoxazol-5-yl)phenyl]-8-(methylpropylamine)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Specified in the title compound was obtained from tert-butyl ether [4-cyan-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-5-(methylpropylamine)phenyl]carbamino acid (example M) (0.36 g, 0.68 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (94 mg, 34%).

MS (ISP) 414,4 [(M+N)+]; tPL133°C.

Example 107

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

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-diethylamino-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example M) (0.35 g, of 0.66 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (209 mg, 77%).

MS (ISP) 414,4 [(M+N)+]; tPL191°C.

Example 108

8-(Isopropylethylene-2-[3-(3-metalis xazal-5-yl)phenyl]-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-(isopropylethylene)-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example M) (0,37 g 0,70 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (219 mg, 76%).

MS (ISP) 414,4 [(M+N)+]; tPL197°C.

Example 109

2-[3-(5-Hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-(isopropylethylene)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-cyan-5-(isopropylethylene)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M) (0.45 g, of 0.71 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (236 mg, 77%).

MS (ISP) 430,5 [(M+N)+]; tPL206°C.

Example 110

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

Specified in the title compound was obtained from tert-butyl ether (4-cyan-5-(isobutylamino)-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example M) (0.39 g, 0,Mola) when processing triperoxonane acid in dichloromethane according to the standard method N. The compound was obtained in a solid yellow color (230 mg, 75%).

MS (ISP) 428,5 [(M+N)+]; tPL170°C.

Example 111

2-[3-(5-Hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-(isobutylamino)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-cyan-5-(isobutylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M98) (0,46 g of 0.71 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (180 mg, 57%).

MS (ISP) 444,4 [(M+H)+]; tPL199°C.

Example 112

2-[3-(3-Methylisoxazol-5-yl)phenyl]-4-oxo-8-piperidine-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Specified in the title compound was obtained from tert-butyl ether (4-cyan-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-5-piperidine-1-yl-phenyl)carbamino acid (example m) (0,41 g, 0.75 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (226 mg, 70%).

MS (ISP) 426,4 [(M+N)+]; tPL246°C.

Example 113

8-Chloro-7-isobutylamino-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he/p>

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-isobutylamino)-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example M100) (0.34 g, to 0.63 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (216 mg, 81%).

MS (ISP) 423,3 [(M+N)+]; tPL249°C.

Example 114

8-Chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-isobutylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-isobutylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M101) (0, 17 g of 0.27 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (41 mg, 35%).

MS (ISP) 439,4 [(M+N)+]; tPL214°C.

Example 115

4-[3-(5-Hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(methylpropylamine)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-(methylpropylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid (example M10) (0.15 g, 0.22 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid (31 mg, 30%).

MS (ISP) 473,2 [(M+N)+]; tPL230°C.

Example 116

4-[3-(3-Methylisoxazol-5-yl)phenyl]-7-(methylpropylamine)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-5-(methylpropylamine)-4-triptoreline]carbamino acid (example M103) (0.26 g, 0.45 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (127 mg, 61%).

MS (ISP) 457,4 [(M+N)+]; tPL193°C.

Example 117

4-[3-(5-Hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-(isobutylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid (example M) (0.51 g, of 0.74 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid (169 mg, 47%).

MS (ISP) 487,3 [(M+is) +]; tPL230°C.

Example 118

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

Specified in the title compound was obtained from tert-butyl ether (5 isobutylamino)-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropylidene)-4-triptoreline)carbamino acid (example M105) (0,42 g of 0.71 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (161 mg, 48%).

MS (ISP) 471,2 [(M+N)+]; tPL195°C.

Example 119

4-[3-(5-Hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-(isopropylethylene)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)-4-triptoreline]carbamino acid (example m) (0.50 g, of 0.74 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid (156 mg, 45%).

MS (ISP) 473,3 [(M+N)+]; tPL234°C.

Example 120

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

Specified in the title compound recip is of tert-butyl methyl ether (5-(isopropylethylene)-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-4-triptoreline)carbamino acid (example M107) (0,37 g, of 0.64 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (74 mg, 25%).

MS (ISP) 457,4 [(M+N)+]; tPL199°C.

Example 121

8-Chloro-7-(methylpropylamine)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-7-(methylpropylamine)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 29) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by pyrrolidino in dimethylformamide according to the method described in example 45. The compound was obtained as foamy substance in yellow (63 mg, 26%).

MS (ISP) 492,3 [(M+N)+].

Example 122

4-[3-(5-Azetidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-8-chloro-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-7-(methylpropylamine)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 29) (118 mg, of 0.27 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by trimethylaluminum in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light is altago color (65 mg, 50%).

MS (ISP) 478,3 [(M+N)+]; tPL169°C.

Example 123

8-Chloro-4-[3-(5-diethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-7-(methylpropylamine)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 29) (219 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by diethylamino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (123 mg, 50%).

MS (ISP) 494,3 [(M+N)+]; tPL151°C.

Example 124

8-Chloro-4-(3-{5-[(isopropylethylene)methyl]-[1,2,3]triazole-1-yl}phenyl)-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-7-(methylpropylamine)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 29) (219 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isopropylacrylamide in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (129 mg, 52%).

MS (ISP) 494,3 [(M+N)+]; tPL148°C.

Example 125

8-Chloro-7-(isopropylethylene)-4-[3-(5-pyrrole the Jn-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 96) (219 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by pyrrolidino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (157 mg, 64%).

MS (ISP) 492,3 [(M+N)+]; tPL172°C.

Example 126

8-Chloro-7-(isobutylamino)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 101) (226 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by pyrrolidino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (163 mg, 64%).

MS (ISP) 506,3 [(M+N)+]; tPL190°C.

Example 127

8-Chloro-4-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylamino the but)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 99) (219 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light brown color (143 mg, 61%).

MS (ISP) 566,3 [(M+N)+]; tPL225°C.

Example 128

8-Chloro-4-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 101) (226 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light brown color (134 mg, 56%).

MS (ISP) 480,5 [(M+N)+]; tPL199°C.

Example 129

4-[3-(5-Azetidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-8-chloro-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 99) (219 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride is demetilenimida in dimethylformamide according to the method, described in example 45. The connection was received in the form of a solid light brown color (102 mg, 43%).

MS (ISP) 478,3 [(M+N)+]; tPL177°C.

Example 130

4-[3-(5-Azetidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-8-chloro-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 101) (220 mg, of 0.49 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by trimethylaluminum in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light brown color (125 mg, 52%).

MS (ISP) 492,3 [(M+H)+]; tPL191°C.

Example 131

8-Chloro-4-[3-(5-methylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-7-(methylpropylamine)-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 29) (230 mg, 0.52 in mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with methylamine in dimethylformamide according to the method described in example 45. The connection was received in the form of solid light yellow (122 mg, 52%).

MS (ISP) 452,4 (M+N) +]; tPL185°C.

Example 132

4-[3-(5-Hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[5-(isobutylamino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M108) (0.33 g, of 0.52 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid pale brown (188 mg, 79%).

MS (ISN) 431,4 [(M-N)-]; tPL198°C.

Example 133

4-[3-(5-Hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-methyl-7-pyrrolidin-1-yl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-methyl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}-propionamide)-5-pyrrolidin-1-ylphenyl]carbamino acid (example M110) (0,41 g of 0.66 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (239 mg, 86%).

MS (ISP) 417,3 [(M+N)+]; tPL202°C.

Example 134

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

Specified in the title of a connection is Uchali from tert-butyl ether (5-(isobutylamino)-4-methyl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxo-propionamide}phenyl)carbamino acid (example M) (0.33 g, of 0.62 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid pale brown (136 mg, 53%).

MS (ISP) 417,3 [(M+N)+]; tPL187°C.

Example 135

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

Specified in the title compound was obtained from tert-butyl ether (4-methyl-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}-5-pyrrolidin-1-yl-phenyl)carbamino acid (example M111) (0.33 g, of 0.64 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid (223 mg, 87%).

MS (ISP) is 401.5 [(M+N)+]; tPL211°C.

Example 136

4-[3-(5-Dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 117) (300 mg, of 0.62 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-brown (110 mg, 35).

MS (ISP) 514,3 [(M+N)+]; tPL182°C.

Example 137

8-(Isobutylamino)-4-oxo-2-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Specified in the title compound was obtained from 2-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-(isobutylamino)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile (example 111) (200 mg, 0.45 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by pyrrolidino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (140 mg, 63%).

MS (ISP) 497,3 [(M+N)+]; tPL174°C.

Example 138

7-(Isobutylamino)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 117) (300 mg, of 0.62 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by pyrrolidino in dimethylformamide according to the method described in example 45. The compound was obtained as foamy substance light orange (80 mg, 24%).

MS (ISP) to 540.5 [(M+N)+].

Example 139

7-(Isobutylamino)--methyl-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 132) (200 mg, and 0.46 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by pyrrolidino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow (50 mg, 22%).

MS (ISP) 486,4 [(M+N)+]; tPL177°C.

Example 140

8-(Isobutylamino)-2-(3-{5-[(isobutylamino)methyl]-[1,2,3]triazole-1-yl}phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile

Specified in the title compound was obtained from 2-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-8-(isobutylamino)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile (example 111) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isobutylamino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow (100 mg, 39%).

MS (ISP) 513,4 [(M+N)+]; tPL169°C.

Example 141

7-(Isobutylamino)-4-(3-{5-[(isopropylethylene)methyl]-[1,2,3]triazole-1-yl}phenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydro is simetal-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 117) (260 mg, of 0.53 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isopropylacrylamide in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light brown color (70 mg, 24%).

MS (ISP) USD 542.3 [(M+N)+]; tPL157°C.

Example 142

8-Chloro-4-[3-(5-cyclopentylmethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 96) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by cyclopentylamine in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (170 mg, 67%).

MS (ISP) 506,3 [(M+N)+]; tPL174°C.

Example 143

4-(3-{5-[(Cyclopropanemethylamine]-[1,2,3]triazole-1-yl)phenyl)-7-(isobutylamino)-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 132) (250 mg, of 0.58 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment with the corresponding chloride by cyclopropanemethylamine in dimethylformamide according to the method, described in example 45. The connection was received in the form of a solid light-yellow (50 mg, 18%).

MS (ISP) 486,4 [(M+N)+]; tPL184°C.

Example 144

8-Chloro-7-(isobutylamino)-4-[3-(5-piperidine-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 101) (220 mg, of 0.49 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with piperidine in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light brown color (250 mg, 99%).

MS (ISP) 520,3 [(M+N)+]; tPL169°C.

Example 145

8-Chloro-4-{3-[5-(isopropylaminomethyl)-[1,2,3]triazole-1-yl]phenyl}-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 96) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by isopropylamino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (160 mg, 67%).

MS (SP) 480,3 [(M+N) +]; tPL208°C.

Example 146

8-Chloro-7-(isopropylethylene)-4-[3-(5-{[(2-methoxyethyl)methylamino]methyl}-[1,2,3]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 96) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride N-(2-methoxyethyl)methylamine in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (120 mg, 47%).

MS (ISP) 510,4 [(M+N)+]; tPL119°C.

Example 147

8-Chloro-4-(3-{5-[(cyclopropylamino)methyl]-[1,2,3]triazole-1-yl}phenyl)-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 96) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by aminomethylpropanol in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light brown color (150 mg, 61%).

MS (ISP) 592,2 [(M+N)+]; tPL151°C.

Example 148

8-Chloro-7-(isopro is ylmethylamino)-4-(3-{5-[(isopropylethylene)methyl]-[1,2,3]triazole-1-yl}phenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 96) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isopropylacrylamide in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (120 mg, 49%).

MS (ISP) 494,3 [(M+N)+]; tPL180°C.

Example 149

8-Chloro-4-(3-{5-[(isobutylamino)methyl]-[1,2,3]triazole-1-yl}phenyl)-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 96) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isobutylamino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (190 mg, 75%).

MS (ISP) 508,4 [(M+N)+]; tPL182°C.

Example 150

4-[3-(5-Dimethylaminomethyl-[1,2,3]triazole-1-yl]phenyl]-7-(isopropylethylene)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,3]triazole-yl)phenyl]-7-(isopropylethylene)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 119) (200 mg, at 0.42 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in dimethylformamide according to the method described in example 45. The connection was received in the form of not-quite-white solid (80 mg, 38%).

MS (ISP) 500,4 [(M+N)+]; tPL197°C.

Example 151

7-(Isopropylethylene)-4-[3-(5-pyrrolidin-1-ylmethyl}-[1,2,3]triazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 119) (200 mg, at 0.42 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by pyrrolidino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light brown color (140 mg, 63%).

MS (ISP) 526,2 [(M+N)+]; tPL175°C.

Example 152

7-(Isopropylethylene)-4-(3-{5-[(isopropylethylene)methyl]-[1,2,3]triazole-1-yl}phenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 119) (220 mg, of 0.47 mmole) in reaction with thionyl chloride in dichloromethane and subsequent the treatment of the corresponding chloride with N-isopropylacrylamide in dimethylformamide according to the method, described in example 45. The connection was received in the form of solid light yellow (110 mg, 45%).

MS (ISP) 528,4 [(M+N)+]; tPL182°C.

Example 153

4-(3-{5-[(Cyclopropylamino)methyl]-[1,2,3]triazole-1-yl}phenyl)-7-(isopropylethylene)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 119) (210 mg, of 0.44 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by aminomethylpropanol in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-brown (110 mg, 47%).

MS (ISP) 526,2 [(M+N)+]; tPL152°C.

Example 154

8-Chloro-4-[3-(5-cyclopropylmethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 96) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by cyclopropylamino in dimethylformamide according to the method described in example 45. The connection was received in the form of Targovishte light yellow (40 mg, 17%).

MS (ISP) 478,4 [(M+N)+]; tPL144°C.

Example 155

4-{3-[5-(Isopropylaminomethyl)-[1,2,3]triazole-1-yl]phenyl}-7-(isopropylethylene)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 119) (236 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by isopropylamino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow (100 mg, 39%).

MS (ISP) 514,4 [(M+N)+]; tPL191°C.

Example 156

8-Chloro-4-{3-[5-(isobutylamino)-[1,2,3]triazole-1-yl]phenyl}-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 96) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by isobutylamino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (160 mg, 65%).

MS (ISP) 494,4 [(M+N)+]; tPL182°C.

Example 157

4-[3-(5-Cyclopropyl nametil-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isopropylethylene)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 119) (236 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by cyclopropylamino in dimethylformamide according to the method described in example 45. The connection was received in the form of solid light yellow (70 mg, 27%).

MS (ISP) 512,4 [(M+N)+]; tPL178°C.

Example 158

7-(Isobutylamino)-8-methyl-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,4]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,4]triazole-1-yl)phenyl]-7-(isobutylamino)-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 132) (180 mg, at 0.42 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by pyrrolidino in dimethylformamide according to the method described in example 45. The connection was received in the form of not-quite-white solid (106 mg, 52%).

MS (ISP) 486,5 [(M+N)+]; tPL164°C.

Example 159

4-[3-(5-Cyclopropylmethyl-[1,2,4]triazole-1-yl)phenyl]-7-(isobutylamino)-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 4-[3-(5-hydroxymethyl-[1,2,4]triazole-1-yl)phenyl]-7-(isobutyl is ethylamino)-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (primer) (180 mg, at 0.42 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by cyclopropylamino in dimethylformamide according to the method described in example 45. The connection was received in the form of solid light yellow (108 mg, 55%).

MS (ISP) 472,4 [(M+N)+]; tPL114°C.

Example 160

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

Specified in the title compound was obtained from tert-butyl ether (4-chloro-5-isopropylamino-2-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropylidene)-phenyl)carbamino acid (example M112) (0.16 g, 0.31 in mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid pale brown (120 mg, 93%).

MS (ISP) 409,4 [(M+N)+]; tPL225°C.

Example 161

8-Chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazole-1-yl)phenyl]-7-isopropylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-isopropylamino-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,3]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M113) (0,37 g, 0.60 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solid substances is light yellow (209 mg, 82%).

MS (ISP) 425,4 [(M+N)+]; tPL250°C.

Example 162

8-Chloro-7-(methylpropylamine)-4-[3-(5-hydroxymethyl-[1,2,4]triazole-1-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-(methylpropylamine)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,4]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M114) (1.47 g, to 2.29 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid pale yellow color (1.0 g, 99%).

MS (ISP) 439,5 [(M+N)+]; tPL192°C.

Example 163

8-Chloro-4-[3-(5-hydroxymethyl-[1,2,4]triazole-1-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (RS)-[4-chloro-5-(isobutylamino)-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,4]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M115) (0,61 g of 0.93 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light brown color (290 mg, 69%).

MS (ISP) 453,5 [(M+N)+]; tPL195°C.

Example 164

8-Chloro-7-(methylpropylamine)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,4]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he/p>

Specified in the title compound was obtained from 8-chloro-7-(methylpropylamine)-4-[3-(5-hydroxymethyl-[1,2,4]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 162) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by pyrrolidino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (114 mg, 46%).

MS (ISP) 492,3 [(M+N)+]; tPL183°C.

Example 165

8-Chloro-7-(isobutylamino)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,4]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,4]triazole-1-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 163) (200 mg, of 0.44 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by pyrrolidino in dimethylformamide according to the method described in example 45. The connection was received in the form of solid light yellow (99 mg, 44%).

MS (ISP) 506,4 [(M+N)+]; tPL164°C.

Example 166

8-Chloro-4-[3-(5-dimethylaminomethyl-[1,2,4]triazole-1-yl}phenyl]-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-7-(methylpropylamine)-4-[3-(5-hydroxymethyl-[1,2,4]triazole-1-yl)phenyl]-1,3-dihyd is ebenso[b][1,4]diazepin-2-it (example 162) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in dimethylformamide according to the method described in example 45. The connection was received in the form of solid light yellow (93 mg, 54%).

MS (ISP) 466,4 [(M+N)+]; tPL170°C.

Example 167

8-Chloro-4-[3-(5-cyclopropylmethyl-[1,2,4]triazole-1-yl)phenyl]-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from 8-chloro-7-(methylpropylamine)-4-[3-(5-hydroxymethyl-[1,2,4]triazole-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 162) (220 mg, of 0.50 mmole) in reaction with thionyl chloride in dichloromethane and subsequent treatment of the corresponding chloride by cyclopropylamino in dimethylformamide according to the method described in example 45. The connection was received in the form of a solid light-yellow color (95 mg, 40%).

MS (ISP) 478,4 [(M+N)+]; tPL123°C.

Example 168

4-[3-(5-Hydroxymethyl-[1,2,4]triazole-1-yl)phenyl]-7-(isobutylamino)-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

The compound was obtained from tert-butyl ether (RS)-[5-(isobutylamino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,2,4]triazole-1-yl]phenyl}propionamide)phenyl]carbamino acid (example M116) (0.96 g and 1.51 mmole) when processing triperoxonane acid in dichloromethane according to andartes method N. The connection was received in the form of a solid pale brown (480 mg, 73%).

MS (ISP) 433,6 [(M+N)+]; tPL191°C.

Example 169

7-(Methylpropylamine)-4-(3-[1,2,4]triazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether {5-(methylpropylamine)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid (example M117) (0.31 g, 0.55 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (192 mg, 78%).

MS (ISP) 443,4 [(M+N)+]; tPL185°C.

Example 170

7-(Methylpropylamine)-4-(3-[1,2,3]triazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether {5-(methylpropylamine)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid (example M118) (0.33 g, a 0.59 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solid light yellow (115 mg, 44%).

MS (ISP) 443,4 [(M+N)+]; tPL147°C.

Example 171

7-(Isobutylamino)-4-(3-pyrazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in C is glavie compound was obtained from tert-butyl ether {5-(isobutylamino)-2-[3-oxo-3-(3-pyrazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid (example M119) (0,49 g, of 0.85 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (324 mg, 83%).

MS (ISN) 454,4 [(M-N)-]; tPL182°C.

Example 172

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

Specified in the title compound was obtained from tert-butyl ether [2-[3-(2-lepirudin-4-yl)-3-oxopropionate]-5-(isopropylethylene)-4-triptoreline]carbamino acid (example M) (0,67 g of 1.29 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (210 mg, 41%).

MS (ISN) 400,3 [(M-N)-]; tPL189°C.

Example 173

8-Chloro-7-(isobutylamino)-4-(3-[1,2,4]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ester {4-chloro-5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid (example M121) (0,76 g of 1.41 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light orange color (530 mg, 89%).

MS (ISP) 423,4 [(M+N)+]; tPL213°C.

Example 174

7-(Isobutylphenyl the Mino)-4-(3-[1,2,4]triazole-1-ylphenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

The compound was obtained from tert-butyl ether {5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid (example M) (0.50 g, 0.87 for mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light brown color (350 mg, 88%).

MS (ISP) at the rate of 457.5 [(M+N)+]; tPL198°C.

Example 175

8-Chloro-7-(isobutylamino)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ester {4-chloro-5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid (example M) (0.17 g, 0.31 in mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow (100 mg, 75%).

MS (ISP) 423,5 [(M+N)+]; tPL85°C.

Example 176

7-(Isobutylamino)-4-(3-[1,2,3]triazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether {5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid (example M124) (0,44 g, 0.77 mmole) in processing triperoxonane acid in dichloromethane according to the mill is artney method N. The connection was received in the form of a solid light brown color (170 mg, 49%).

MS (ISP) at the rate of 457.5 [(M+N)+]; tPL202°C.

Example 177

4-(3-Imidazol-1-ylphenyl)-7-isobutylamino-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether {2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-isobutylamino-4-triptoreline}carbamino acid (example M) (0,43 g, 0.77 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (260 mg, 76%).

MS (ISP) 442,4 [(M+N)+]; tPL221°C.

Example 178

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

Specified in the title compound was obtained from tert-butyl ester {4-chloro-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-isobutylamino}carbamino acid (example M) (0.33 g, was 0.63 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (240 mg, 94%).

MS (ISP) 408,4 [(M+N)+]; tPL212°C.

Example 179

8-Chloro-7-(isobutylamino)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether 4-chloro-5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid (example M) (0,22 g, at 0.42 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of solid light yellow (90 mg, 53%).

MS (ISN) 407,3 [(M-N)-]; tPL249°C.

Example 180

7-(Isobutylamino)-4-(3-[1,2,3]triazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether {5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid (example M) (0.34 g, and 0.61 mmole) when processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light brown color (150 mg, 56%).

MS (ISP) 443,4 [(M+N)+]; tPL212°C.

Example 181

8-Chloro-7-(isobutylamino)-4-(3-[1,2,4]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ester {4-chloro-5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid (example M) (0.39 g, of 0.74 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light orange color (270 mg, 89%).

MS (ISN) 407,3 [(M-N)-]; tPL222°C.

Example 182

7-(Isobutylamino)-4-(3-[1,2,4]triazole-1-Ilf the Nile)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether {5-(isobutylamino)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]-4-triptoreline}carbamino acid (example M130) (0,43 g, 0.77 mmole) in processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light brown color (270 mg, 61%).

MS (ISN) 441,3 [(M-N)-]; tPL191°C.

Example 183

8-Chloro-7-(ethylmethylamino)-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(ethylmethylamino)phenyl]carbamino acid (0.15 g) (example J7) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]propionic acid (0,23 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method of Connection N. got in a solid yellow color (0.14 g).

MS (ISN) 439,2 [(M-N)-]; tPL136-137°C.

Primer

8-Chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(methylpropylamine)the dryer is l]carbamino acid (0.16 g) (example J8) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]propionic acid (0,23 g) (example C) according to the standard method M The resulting material was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (0.10 g).

MS (ISN) 453,2 [(M-N)-]; tPL211-213°C.

Example 185

8-Chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(isopropylethylene)phenyl]carbamino acid (0.17 g) (example J26) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]propionic acid (example C) (0,23 g) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method of Connection N. got in a solid light brown color (0.05 g).

MS (ISP) to 455.2 [(M+N)+]; tPL193-195°C.

Example 186

8-Chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(isobutylamino)phenyl]carbamino acid (0,23 g) (example J27) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]prop is about acid (0.32 g) (example C) according to the standard method M The resulting material was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (0.06 g).

MS (ISP) 469,1 [(M+N)+]; tPL135-136°C.

Example 187

8-Chloro-7-(ethylmethylamino)-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(ethylmethylamino)phenyl]carbamino acid (0.15 g) (example J7) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)oxazol-2-yl]phenyl]propionic acid (0,22 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method of Connection N. got in a solid yellow color (0.10 g).

MS (ISN) 423,1 [(M-N)-]; tPL165-166°C.

Example 188

8-Chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(methylpropylamine)phenyl]carbamino acid (0.16 g) (example J8) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)oxazol-2-yl]phenyl]propionic acid (0,22 g) (if the EP C) according to the standard method M The resulting material was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (0.10 g).

MS (ISN) 437,2 [(M-N)-]; tPL166-167°C.

Example 189

8-Chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(isopropylethylene)phenyl]carbamino acid (0.17 g) (example J26) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)oxazol-2-yl]phenyl]propionic acid (0,22 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method of Connection N. got in a solid yellow color (0.05 g).

MS (ISP) RUR 439,3 [(M+N)+]; tPL143-145°C.

Example 190

8-Chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(isobutylamino)phenyl]carbamino acid (0,23 g) (example J27) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)oxazol-2-yl]phenyl]propionic what Islami (0.31 g) (example C) according to the standard method M The resulting material was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (0, 18 g).

MS (ISP) 453,3 [(M+N)+]; tPL166-167°C.

Example 191

8-Chloro-7-dimethylamino-4-[3-(4-methylaminomethyl-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

a) 8-Chloro-4-[3-(4-chloromethylthiazole-2-yl)phenyl]-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A mixture of 8-chloro-7-dimethylamino-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it (0,38 g) (example 19) and thionyl chloride (0, 1 ml) in dichloromethane was heated for 2 hours at 40°C. the Heterogeneous mixture was evaporated in vacuo and the residue triturated with ethyl acetate, has been specified in the title compound (0,44 g) as a solid light brown color, MS (ISP) 445,1 [(M+N)+].

b) 8-Chloro-7-dimethylamino-4-[3-(4-methylaminomethyl-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A mixture of 8-chloro-4-[3-(4-chloromethylthiazole-2-yl)phenyl]-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-she (89 mg) and iodotope potassium (3 mg) in 8 M solution of methylamine in ethanol (1 ml) was stirred for 20 hours at 20°C. was Added water (25 ml) and was installed in a mixture rn by adding 2 N. sodium hydroxide. The precipitate was collected by filtration and was purified by chromatography on silicagel is, using as elution solvent is methyl alcohol. The product was stirred with 20%aqueous methanol (10 ml) and the solid was isolated by filtration, has been specified in the title compound (49 mg) as yellow powder.

MS (ISP) 440,2 [(M+N)+]; tPL129-130°C.

Example 192

8-Chloro-7-dimethylamino-4-[3-(4-(morpholine-4-ilmatieteen-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A mixture of 8-chloro-4-[3-(4-chloromethylthiazole-2-yl)phenyl]-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-she (89 mg) (example a), research (0.17 ml) and iodotope potassium (3 mg) in ethanol (0.5 ml) was stirred 3 hours at 60°C. To the cooled solution was added water (25 ml) and the precipitate was collected by filtration, purified by chromatography on silica gel, using as eluent ethyl acetate/acetone (1:1). The product was stirred with 20%aqueous methanol (20 ml). Installed in a mixture rn by adding 1 N. sodium hydroxide and the solid is then isolated by filtering, has been specified in the title compound (55 mg) as yellow powder.

MS (ISP) 496,2 [(M+N)+]; tPL138-143°C.

Example 193

8-Chloro-7-dimethylamino-4-[3-(2-hydroxyethylthio-4-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

a) 4-(3-Bromoacetyl]-8-chloro-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A solution of tert-butyl ester 3-oxo-3-[3-(2-bromo-11-dimethoxymethyl)phenyl]propionic acid (2,34 g) (example C) and tert-butyl methyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J2) (1,57 g) in toluene (16 ml) was heated for 5 hours at 100° C. the Solvent is evaporated in vacuum and the technical product was purified using chromatography on silica gel, using as eluent dichloromethane/ethyl acetate (1:20). The solution of purified substances (2.4 g) in dichloromethane/triperoxonane acid (1:1, 30 ml) was stirred at 20°C for 15 minutes and then was evaporated. The oily residue was dissolved in ethyl acetate and the solution washed with 1 N. hydrochloric acid and with brine, dried and evaporated. The residue was led from ethyl acetate/diethyl ether, there was obtained 4-(3-bromoacetyl)-8-chloro-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-he is a solid light brown color.

b) 8-Chloro-7-dimethylamino-4-[3-(2-hydroxyethylthio-4-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A mixture of 4-(3-bromoacetyl)-8-chloro-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-it (0,22 g) and 2-(tert-BUTYLCARBAMATE)thioacetamide (0.11 g) in ethanol (3 ml) was heated at 80°C for 0.5 hour. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saline solution, dried and evaporated. The residue was stirred in a mixture of methanol (8 ml) and 1.5 N. potassium hydroxide (8 ml) at 20°C for 20 minutes. Was added water (30 ml) and precipitated precipitated product was collected by filtration, has been specified in the title compound (0.9 g) as yellow powder.

The (ISP) 427,3 [(M+N) +]; tPL176-178°C.

Example 194

4-[3-(2-Aminothiazol-4-yl)phenyl]-8-chloro-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A mixture of 4-(3-bromoacetyl)-8-chloro-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-it (0.73 g) (example a) and thiourea (0,13 g) in tetrahydrofuran (10 ml) was heated for 15 minutes at 60°C. the Mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saline. The organic layer was dried and evaporated and the residue was stirred with dichloromethane, got mentioned in the title compound (0.14 g) as a solid yellow color.

MS (ISN) 410,2 [(M-N)-]; tPL247-248°C.

Example 195

8-Chloro-7-dimethylamino-4-[3-(2-ethylaminomethyl-4-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A mixture of 4-(3-bromoacetyl)-8-chloro-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-she (130 mg) (example a) and N-ethylthiophene (31 mg) in tetrahydrofuran (3 ml) was heated for 15 minutes at 60°C. the Mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saline. The organic layer was dried and evaporated, and the residue was purified by chromatography on silica gel, using as eluent ethyl acetate/hexane (1:1). The purified product was washed with diethyl ether, was obtained is listed in the title compound (24 mg) as a solid yellow color.

MS (ISP) 440,3 [M+N) +]; tPL122-123°C.

Example 196

N-{4-[3-(7-Chloro-8-dimethylamino-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)phenyl]thiazol-2-yl}guanidine

A mixture of 4-(3-bromoacetyl)-8-chloro-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-she (130 mg) (example a) and N-imigination (35 mg) in tetrahydrofuran (3 ml) was heated for 1 hour at 60°C. the Mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saline. The organic layer was dried and evaporated, and the residue was purified by chromatography on silica gel, using as eluent ethyl acetate/methanol (20:1). The purified product was led from acetone, has been specified in the title compound (22 mg) as a solid yellow color.

MS (ISP) 454,2 [(M+N)+]; tPL221°C (decomp.).

Example 197

8-Chloro-7-dimethylamino-4-{3-[2-(pyridine-4-ylamino)thiazol-4-yl]phenyl}-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A mixture of 4-(3-bromoacetyl)-8-chloro-7-dimethylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-she (130 mg) (example a) and 1-(4-pyridyl)-2-thiourea (46 mg) in tetrahydrofuran (3 ml) was heated for 45 minutes at 60°C. the Mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saline. The organic layer was dried and evaporated, and the residue triturated with diethyl ether, was obtained is listed in the title compound (55 mg) in the form of solid substances is STW yellow color.

MS (ISP) 489,2 [(M+N)+]; tPL231-234°C.

Example 198

8-Chloro-4-[3-(2-methoxazole-4-yl)phenyl]-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-chloro-5-(methylpropylamine)phenyl]carbamino acid (0.16 g) (example J8) and tert-butyl ester 3-oxo-3-[3-(2-methoxazole-4-yl]phenyl]propionic acid (0.17 g) (example K29) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (0.07 g).

MS (ISP) 423,2 [(M+N)+]; tPL163-164°C.

Example 199

4-[3-(4-Hydroxymethylimidazole-2-yl)phenyl]-8-methyl-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-methyl-5-(methylpropylamine)phenyl]carbamino acid (0.21 g) (example J24) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]propionic acid (example C) (0.31 g) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method of Connection N. got in a solid yellow t the ETA (0.09 g).

MS (ISP) 435,3 [(M+N)+]; tPL222-224°C.

Example 200

4-[3-(4-Hydroxymethylimidazole-2-yl)phenyl]-8-methyl-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-4-methyl-5-(methylpropylamine)phenyl]carbamino acid (0.21 g) (example J24) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)oxazol-2-yl]phenyl]propionic acid (example C) (0.31 g) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method of Connection N. got in a solid yellow color (0.16 g).

MS (ISP) 419,3 [(M+N)+]; tPL200-202°C.

Example 201

7-Dimethylamino-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0.16 g) (example J6) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]propionic acid (example C) (0,23 g) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. the floor Connection is made in a solid yellow color (0.12 g).

MS (ISP) 461,2 [(M+N)+]; tPL198-199°C.

Example 202

7-Dimethylamino-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0.16 g) (example J6) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)oxazol-2-yl]phenyl]propionic acid (0,22 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form solid yellow (0.11 g).

MS (ISP) 445,0 [(M+H)+]; tPL197-198°C.

Example 203

4-[3-(4-Hydroxymethylimidazole-2-yl)phenyl]-7-(methylpropylamine)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(methylpropylamine)-4-triptoreline]carbamino acid (0.71 g) (example J35) and tert-butyl ester 3-oxo-3-[3-[4-(tetrahydropyran-2-intoximeter)thiazol-2-yl]phenyl]propionic acid (example C) (0,23 g) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method n With the unity was received in the form of a solid yellow (0.06 g).

MS (ISP) 489,2 [(M+N)+]; tPL177-180°C.

Example 204

7-Dimethylamino-4-[3-(5-hydroxymethyl-[1,3,4]thiadiazole-2-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0.16 g) (example J6) and tert-butyl ester 3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]thiadiazole-2-yl]phenyl}propionic acid (0,23 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. The connection was received in the form of not-quite-white solid (0.06 g).

MS (ISP) 462,1 [(M+N)+]; tPL242-246°C.

Example 205

7-Dimethylamino-4-{3-[5-(2-hydroxyethyl)-[1,3,4]thiadiazole-2-yl]phenyl}-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0.16 g) (example J6) and tert-butyl ester 3-oxo-3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]thiadiazole-2-yl}phenyl)propionic acid (0.24 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to article Hartnoll method N. The connection was received in the form of not-quite-white solid (0.06 g).

MS (ISN) 474,2 [(M-N)-]; tPL234-237°C.

Example 206

7-Dimethylamino-4-[3-(5-hydroxymethyl-[1,3,4]oxadiazol-2-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (1.44 g) (example J6) and tert-butyl ester 3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]oxadiazol-2-yl]phenyl}propionic acid (2.17 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. The connection was received in the form of not-quite-white solid (0.88 g).

MS (ISP) 463,2 [(M+NH4)+].

Example 207

7-Dimethylamino-4-{3-[5-(2-hydroxyethyl)-[1,3,4]oxadiazol-2-yl]phenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0.16 g) (example J6) and tert-butyl ester 3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]oxadiazol-2-yl}phenyl)propionic acid (0,23 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization with the development of triperoxonane acid in dichloromethane according to the standard method N. The connection was received in the form of not-quite-white solid (0.88 g).

MS (ISP) 460,2 [(M+N)+]; tPL237°C (decomp.).

Example 208

7-Dimethylamino-4-(3-oxazol-4-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (96 mg) (example J6) and tert-butyl ester 3-(3-oxazol-4-ylphenyl)-3-oxopropanoic acid (103 mg) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid yellow (50 mg).

MS (ISP) 415,2 [(M+N)+]; tPL218-219°C.

Example 209

7-Dimethylamino-4-(3-thiazol-4-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (96 mg) (example J6) and tert-butyl ester 3-oxo-3-(3-thiazol-4-ylphenyl)propionic acid (109 mg) (example K35) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of owls who eat white solid (61 mg).

MS (ISP) 431,2 [(M+N)+]; tPL200°C (decomp.).

Example 210

7-Dimethylamino-4-[3-(2-methoxazole-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0.16 g) (example J6) and tert-butyl ester 3-[3-(2-methoxazole-4-yl)phenyl]-3-oxopropanoic acid (0.18 g) (example K29) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (0.04 g).

MS (ISP) 429,3 [(M+N)+]; tPL192-193°C.

Example 211

7-Dimethylamino-4-[3-(5-methoxazole-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0.16 g) (example J6) and tert-butyl ester 3-[3-(5-methoxazole-4-yl)phenyl]-3-oxopropanoic acid (0.18 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (0,13 g).

MS (SP) 429,3 [(M+H) +]; tPL238-239°C.

Example 212

7-Dimethylamino-4-[3-(2-methyl-5-preprocessor-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (80 mg) (example J6) and tert-butyl ester 3-[3-(2-methyl-5-preprocessor-4-yl)phenyl]-3-oxopropanoic acid (103 mg) (example kastrofylakas k37) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid pale yellow (20 mg).

MS (ISP) 471,2 [(M+N)+]; tPL211-212°C.

Example 213

7-Dimethylamino-4-[3-(5-methylthiazole-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0.16 g) (example J6) and tert-butyl ester 3-[3-(5-methylthiazole-4-yl)phenyl]-3-oxopropanoic acid (0,19 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (0.06 g).

MS (IS) 445,2 [(M+N) +]; tPL214-215°C.

Example 214

7-Dimethylamino-4-[3-(2,5-dimethylthiazol-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (48 mg) (example J6) and tert-butyl ester 3-[3-(2,5-dimethylthiazol-4-yl)phenyl]-3-oxopropanoic acid (50 mg) (example KZ 9) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (38 mg).

MS (ISP) 459,2 [(M+N)+]; tPL208-209°C.

Example 215

7-Dimethylamino-4-[3-(2-hydroxyethylthio-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

a) 4-(3-Bromoacetyl)-7-dimethylamino-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A solution of tert-butyl methyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (example J6) (0.32 g) and tert-butyl ester 3-oxo-3-[3-(2-bromo-1,1-dimethoxymethyl)phenyl]propionic acid (0,43 g) (example C) in toluene (3 ml) was heated for 2 hours at 100°C. the Solvent is evaporated in vacuum and the technical product was purified using chromatography on silica gel, using as eluent ethyl acetate/hexane (1:3). Restorational substances (0,57 g) in dichloromethane/triperoxonane acid (1:1, 7 ml) was stirred at 20°C for 15 minutes and then was evaporated. The oily residue was dissolved in ethyl acetate and the solution washed with 1 N. hydrochloric acid and with brine, dried and evaporated, received technical 4-(3-bromoacetyl)-7-dimethylamino-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he (0,22 g) as a solid light brown color.

b) 7-Dimethylamino-4-[3-(2-hydroxyethylthio-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A mixture of 4-(3-bromoacetyl)-7-dimethylamino-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (0.40 g) and 2-(tert-BUTYLCARBAMATE)thioacetamide (0.21 g) in ethanol (5 ml) was heated at 80°C for 0.5 hour. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saline solution, dried and evaporated. The residue was stirred in a mixture of methanol (5 ml) and 1.5 N. potassium hydroxide (5 ml) at 20°C for 20 minutes. Was added water and the precipitated precipitated product was collected by filtration and was purified by chromatography on silica gel, using as eluent ethyl acetate has been specified in the title compound (0.01 g) as a solid yellow color.

MC (ISP) 461,1 [(M+N)+].

Example 216

7-Dimethylamino-4-[3-(2-hydroxymethyl-5-methylthiazole-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0.16 g) (example J6) and tert-butyl ester 3-oxo-3-{3-[5-methyl-2-(tetrahydropyran-2-intoximeter)thiazol-4-yl]phenyl}propionic acid (0.26 g) (example 40) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of a solid light-yellow color (0.11 g).

MS (ISP) 475,2 [(M+N)+]; tPL190-193°C.

Example 217

7-Dimethylamino-4-[3-(2-hydroxymethyl-5-propertiesa-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (79 mg) (example J6) and tert-butyl ester 3-oxo-3-{3-[5-propyl-2-(tetrahydropyran-2-intoximeter)thiazol-4-yl]phenyl}propionic acid (138 mg) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. The connection was received in the form of a solid yellow (45 mg).

MS (ISP) 503,2 [(M+N)+]; tPL112-114°C.

Example 218

7-Dimethylamino-4-[3-(5-hydroxymethyl-2-methylthiazole-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0.16 g) (example J6) and tert-BU is silt ester 3-oxo-3-{3-[2-methyl-5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]phenyl}propionic acid (0.26 g) (example C) according to the standard method M The resulting material was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (0.11 g).

MS (ISN) 473,0 [(M-N)-]; tPL226-227 of the°C.

Example 219

7-Dimethylamino-4-[3-(5-hydroxymethylimidazole-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0.16 g) (example J6) and tert-butyl ester 3-oxo-3-{[5-(tetrahydropyran-2-intoximeter)thiazol-4-yl]phenyl}propionic acid (0.25 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not quite white solid (0.08 g).

MS (ISN) 459,3 [(M-N)-].

Example 220

4-(3-{5-[(Cyclopropylamino)methyl]thiazol-4-yl}phenyl)-7-dimethylamino-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A mixture of 7-dimethylamino-4-[3-(5-hydroxymethylimidazole-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 219) (65 mg) and thionyl chloride (0,015 ml) in dichloromethane (0.3 ml) was stirred for 1 hour at 20°C. the Heterogeneous mixture was evaporated in vacuum and the residue with what was spencervale in ethanol (0.5 ml). Were added aminomethylpropanol (0,12 ml) and modesty potassium (3 mg) and the mixture was stirred at 80°C for 5 hours. The mixture was evaporated in vacuum and the residue was purified by chromatography on silica gel, using as eluent ethyl acetate/methanol (50:1). The resulting product was stirred with 20%aqueous methanol (10 ml), was established pH 11 by adding 1 N. sodium hydroxide and the solid was isolated by filtration, has been specified in the title compound (44 mg) as not quite white solid.

MS (ISP) 514,3 [(M+N)+]; tPL157-158°C.

Example 221

7-Dimethylamino-4-[3-(2-isopropyl-1H-imidazol-4-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-5-dimethylamino-4-triptoreline)carbamino acid (0,13 g) (example J6) and tert-butyl ester 3-[3-(2-isopropyl-3H-imidazol-4-yl)phenyl]-3-oxopropanoic acid (0.20 g) (example K44) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in the form of not-quite-white solid substances (0.10 g).

MS (ISP) 456,4 [(M+H)+]; tPL150°C (decomp.).

Example 222

4-[3-(5-Hydroxymethyl-[1,3,4]thiadiazole-2-yl)phenyl]-7-(methyl is propylamino)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether [2-amino-5-(methylpropylamine)-4-triptoreline]carbamino acid (0.17 g) (example J35) and tert-butyl ester 3-oxo-3-{3-[5-(tetrahydropyran-2-intoximeter)-[1,3,4]thiadiazole-2-yl]phenyl}propionic acid (0,23 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard the method N. Compound was obtained in the form of a solid yellow (0.02 g).

MS (ISP) 490,2 [(M+N)+]; tPL193-194°C.

Example 223

8-Chloro-7-dimethylamino-4-{3-[5-(2-hydroxyethyl)-[1,3,4]thiadiazole-2-yl]phenyl}-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Specified in the title compound was obtained from tert-butyl ether (2-amino-4-chloro-5-dimethylaminophenyl)carbamino acid (example J1) (0.15 g) and technical tert-butyl ester 3-oxo-3-(3-{5-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3,4]thiadiazole-2-yl}phenyl)propionic acid (0.24 g) (example C) according to the standard procedure M. the Obtained substance was subjected to unprotect and cyclization during processing triperoxonane acid in dichloromethane according to the standard method N. Compound was obtained in a solid yellow color (0.10 g).

MS (ISN) 440,2 [(M-N)-]; tPL198-200°C.

Example I

Tablets of the following composition are produced by a common way:
mg tablet
The active ingredient100
Powdered lactose95
White corn starch35
Polyvinylpyrrolidone8
Natrocarbonatite10
Magnesium stearate2
Weight pills250

Example II

Tablets of the following composition are produced by a common way:
mg tablet
The active ingredient200
Powdered lactose100
White corn starch64
Polyvinylpyrrolidone12
Natrocarbonatite20
Magnesium stearate4
Weight pills400

Example III

Capsules of the following composition is produced:
mg/capsule
The active ingredient50
Crystalline lactose60
Microcrystalline cellulose34
Talc5
Magnesium stearate1
Mass content capsules150

Mixed together until a homogeneous state of the active ingredient with particles of a suitable size, crystalline lactose and microcrystalline cellulose, sieved and then mixed into talc and magnesium stearate. The final mixture to fill hard gelatin capsules of suitable size.

1. Derivative dihydrobenzo[b][1,4]diazepin-2-it General formula

where X is a simple bond or etendering group;

where in the case when X is a simple bond,

R1means langroup, halogen, lower alkyl, (C3-C6)cycloalkyl, (ness.)alkoxy, fluorine(ness.)alkoxy, fluorine(ness.)alkyl or means pyrrol-1-yl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of fluorine, chlorine, langroup,-(CH2)1-4-hydroxyl group, fluorine(ness.)of alkyl, lower alkyl, -(CH2)n-(ness.)alkoxyl, -(CH )n-C(O)OR", -(CH2)1-4-R NR'r", hydroxy(ness.)alkoxyl and -(CH2)n-CONR'R", or means phenyl, unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, lower alkyl, fluorine(ness.)of alkyl, (ness.)alkoxyl, fluorine(ness.)alkoxyl and langroup;

in the case when X is etendering group,

R1means phenyl, unsubstituted or substituted by 1-3 substituents selected from the group consisting of halogen, lower alkyl, fluorine(ness.)of alkyl, (C3-C6)cycloalkyl, (ness.)alkoxyl and fluorine(ness.)alkoxyl;

R2means R NR'r", fluorine(ness.)alkoxy or 3-oxopiperidin-1-yl, pyrrolidin-1-yl or piperidine-1-yl ring which is optionally substituted by R";

R' represents hydrogen, lower alkyl, (C3-C6)cycloalkyl, fluorine(ness.)alkyl or 2-(ness.)alkoxy(ness.)alkyl;

R indicates hydrogen, lower alkyl, (C3-C6)cycloalkyl, fluorine(ness.)alkyl, 2-(ness.)alkoxy(ness.)alkyl, -(CH2)2-4di(ness.)alkylamino, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(ness.)alkyl;

Y represents-CH= or =N-;

R3means halogen, lower alkyl, fluorine(ness.)alkyl, (ness.)alkoxyl, langroup, -(CH2)n-C(O)OR", -(C 2)n-C(O)NR'r R" means or optionally substituted 5-membered aromatic heterocycle which may be substituted with halogen, fluorine(ness.)the alkyl, fluorine(ness.)alkoxyl, langroup, -(CH2)n-R NR'r", -(CH2)n-C(O)OR", -(CH2)n-C(O)NR'r R", -(CH2)n-SO2NR'r R", -(CH2)n-C(NH2)=NR", hydroxyl, (ness.)alkoxyl, (ness.)alkylthiophene or lower alkyl, which is optionally substituted by fluorine, hydroxyl, (ness.)alkoxyl, langroup or carbamoyloximes;

n means 0, 1, 2, 3 or 4;

and their pharmaceutically acceptable additive salt.

2. Compounds according to claim 1, where X means a simple link.

3. Compounds according to claim 2, where R1means trifluoromethyl.

4. Compounds according to claim 3, where R3means langroup.

5. Compounds according to claim 4, selected from the group consisting of 4-(4-oxo-8-pyrrolidin-1-yl-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)pyridine-2-carbonitrile,

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

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

4-[4-oxo-8-(2,2,2-triptoreline)-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile and

4-[8-(isopropyl is ethylamino)-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile.

6. Compounds according to claim 3, where R3means optionally substituted 5-membered aromatic heterocycle which may be substituted with halogen, fluorine(ness.)the alkyl, fluorine(ness.)alkoxyl, langroup, -(CH2)n-R NR'r", -(CH2)n-C(O)OR", -(CH2)n-C(O)NR'r R", -(CH2)n-SO2NR'r R", -(CH2)n-C(NH2)=NR", hydroxyl, (ness.)alkoxyl, (ness.)alkylthiophene or lower alkyl, which is optionally substituted by fluorine, hydroxyl, (ness.)alkoxyl, langroup or carbamoyloximes.

7. Compounds according to claim 6, selected from the group consisting of

7-dimethylamino-4-[3-(3-methylisoxazol-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-dimethylamino-4-[3-(2-methyl-2H-pyrazole-3-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-dimethylamino-4-(3-imidazol-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

4-[3-(3-methylisoxazol-5-yl)phenyl]-7-(methylpropylamine)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isobutylamino)-4-[3-(3-methylisoxazol-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isopropylethylene)-4-[3-(3-methylisoxazol-5-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isobutylamino)-4-(3-{5-[(isopropylethylene)methyl]-[1,2,3]triazole-1-yl}-enyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isopropylethylene)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(methylpropylamine)-4-(3-[1,2,3]triazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isobutylamino)-4-(3-[1,2,3]triazole-1-ylphenyl)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

4-(3-imidazol-1-ylphenyl)-7-isobutylamino-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-dimethylamino-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-dimethylamino-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(methylpropylamine)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-she

4-[3-(5-hydroxymethyl-[1,3,4]thiadiazole-2-yl)phenyl]-7-(methylpropylamine)-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it.

8. Compounds according to claim 2, where R1means chlorine.

9. Connection of claim 8, selected from the group consisting of

8-chloro-7-isobutylamino-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(methylpropylamine)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(isopropylethylene)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-the l)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(isobutylamino)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)-phenyl]-1,3-dihydrobenzo[b] [1,4]diazepin-2-it,

8-chloro-4-[3-(5-dimethylaminomethyl-[1,2,3]triazole-1-yl)phenyl]-7-(isobutylphenyl-amino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

4-[3-(5-azetidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-8-chloro-7-(isopropylphenyl-amino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

4-[3-(5-azetidin-1-ylmethyl-[1,2,3]triazole-1-yl)phenyl]-8-chloro-7-(isobutylphenyl-amino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(isobutylamino)-4-[3-(5-piperidine-1-ylmethyl-[1,2,3]triazole-1-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(isopropylethylene)-4-(3-{5-[(isopropylethylene)methyl]-[1,2,3]triazole-1-yl}phenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-(3-{5-[(isobutylamino)methyl]-[1,2,3]triazole-1-yl}phenyl)-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-isopropylamino-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(isobutylamino)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-(3-imidazol-1-ylphenyl)-7-isobutylamino-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(ethylmethylamino)-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(metalpro is ylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-7-(ethylmethylamino)-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(methylpropylamine)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isopropylethylene)-1,3-dihydrobenzo[b][1,4]diazepin-2-she

8-chloro-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-7-(isobutylamino)-1,3-dihydrobenzo[b][1,4]diazepin-2-it.

10. Compounds according to claim 2, where R1means langroup.

11. Connection of claim 10, selected from the group consisting of

8 diethylamino-2-[3-(3-methylisoxazol-5-yl)phenyl]-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile and

2-[3-(3-methylisoxazol-5-yl)phenyl]-4-oxo-8-piperidine-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile.

12. Compounds according to claim 1, where R3means optionally substituted 5-membered aromatic heterocycle which may be substituted with halogen, fluoro-(ness.)the alkyl, fluorine(ness.)alkoxyl, langroup, -(CH2)n-R NR'r", -(CH2)n-C(O)OR", -(CH2)n-C(O)NR'r R", -(CH2)n-SO2NR'r R", -(CH2) n-C(NH2)=NR", hydroxyl, (ness.)alkoxyl, (ness.)alkylthiophene or lower alkyl, which is optionally substituted by fluorine, hydroxyl, (ness.)alkoxyl, langroup or carbamoyloximes.

13. The connection section 12, where R3means optionally substituted 5-membered aromatic heterocycle selected from the group consisting of thiazolyl, oxazolyl, isoxazolyl, imidazolyl 2N-pyrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]thiadiazolyl and [1,3,4]oxadiazolyl.

14. Connection 13, which is selected from the group consisting of

7-dimethylamino-8-phenylethynyl-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

8-(2-forfinal)-4-(3-[1,2,3]triazole-1-ylphenyl)-7-(2,2,2-triptoreline)-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(ethylmethylamino)-8-methyl-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-dimethylamino-8-methyl-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isobutylamino)-8-methyl-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-it,

7-(isobutylamino)-8-methyl-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazole-1-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-she

4-(3-{5-[(cyclopropylamino)methyl]-[1,2,3]triazole-1-yl}phenyl)-7-(isobutyl-methylamino)-8-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it.

1. The compound according to any one of claims 1 to 14 for use in the treatment or prevention of diseases.

16. The drug, which is the receptor antagonist mGlu group II, containing one or more compounds according to any one of claims 1 to 14 and a pharmaceutically acceptable fillers.

17. Drug in article 16, for the treatment or prevention of acute and/or chronic neurological disorders, including psychosis, schizophrenia, Alzheimer's disease, disorders of cognitive abilities and impaired memory.



 

Same patents:

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 a derivative of 1,2,4-thiadiazole, substituted in the 5-position of General formula I, in which X Is N; R1- C1-6alkyl; R2is hydrogen, R3, R4and R5each independently selected from hydrogen; trifloromethyl;is Ar2, Ar2CH2or Het2; AG2is phenyl; Het2is a monocyclic heterocycle selected from thiadiazolyl, pyridinyl, pyrimidinyl or pyrazinyl, their N-oxide forms, the pharmaceutically acceptable acid additive salts and stereochemical isomeric forms

The invention relates to new heterocyclic compounds of the formula (I), where R1represents a group of formula (II), R is 2,4-dioxothiazolidine-5-ylmethylene group and others, And represents C1-6alkylenes group, A represents an oxygen atom, R4represents a substituted phenyl or pyridyl which may have a Deputy, R6represents a hydrogen atom or a C1-6alkyl group, D represents an oxygen atom or sulfur, E is a CH group or a nitrogen atom, or their pharmacologically acceptable salts

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivative

The invention relates to novel potassium salts derived biphenylmethane - mono - or dicale 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazoline-2-ilidene] aminocarbonyl] -1-cyclopentanecarboxylate having anti-hypertensive activity

The invention relates to a derivative of a simple ester, application and intermediate compounds used for their production

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to derivatives of piperazine and piperidine of the formula (I): wherein ---Z represents =C or -N; Q means benzyl or 2-, 3- or 4-pyridylmethyl that can be substituted with one or more substitutes taken among group comprising halogen atom, cyano-group, (C1-C3)-alkoxy-group, CF3, OCF3, SCF3, (C1-C4)-alkyl, (C1-C3)-alkylsulfonyl and their salts, and to a method for their preparing also. It has been found that these compounds elicit valuable pharmacological properties owing to combination of (partial) agonism with respect to members of dopamine receptors subtype and affinity with respect to corresponding serotonin and/or noradrenergic receptors and can be useful in preparing compositions used in treatment of fear and/or depression or Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 3 ex

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

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

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

Up!