Tri-substituted amine compounds and their application as inhibitors of cholesterol ester transfer protein (cetp)

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

 

The technical field to which the invention relates

The present invention relates to compounds having activity of inhibiting protein transfer cholesterolemia ether (SETR), increase HDL cholesterol and reduce LDL cholesterol, due to which the specified connection can be used for the prevention and/or treatment arteriosclerotic diseases, hyperlipemia or dyslipidemia.

The level of technology

Through the implementation of a number of epidemiological surveys, hypercholesterolemia, due, in particular, high levels of serum cholesterol of low density lipoprotein (LDL), is a risk factor arteriosclerotic diseases. To prevent coronary artery disease use drugs are able to reduce the level of LDL cholesterol, such as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase, whose effectiveness has been demonstrated in many large-scale clinical trials. However, the preventive effect of the medicines in relation to ischemic heart disease are limited to some extent and is not sufficiently satisfactory.

As a result of execution of a number of epidemiological surveys and large-scale liniceski tests recently installed, that low serum cholesterol is high density lipoprotein (HDL) is a strong risk factor arteriosclerotic diseases. It is known that HDL has a different antiarteriosclerotic action, so at this time attention is drawn to the ability of drugs to increase the level of HDL cholesterol as a means for prevention or treatment arteriosclerotic diseases. However, there is no drug that can satisfactorily be used to achieve this goal. Fibrates and inhibitors of HMG-CoA-reductase have low activity levels to increase HDL cholesterol; derivatives of nicotinic acid can significantly increase the level of HDL cholesterol, but there are serious problems with portability. There is therefore a need for good portable tool that is able to significantly increase the level of HDL cholesterol and, thus, prevent or delay the development of atherosclerosis.

It is known that the mechanism of regulation of the catabolism of different lipoproteins involves many proteins. Among these proteins, particular attention is drawn to protein transfer cholesterolemia ether (SETR). SETR is a protein that transfers cholesterolemia ester (CE) and triglyceride between lipopro the ins and mediates the transfer of CE from HDL to LDL or lipoprotein very low density (VLDL). Thus, the activity SETR has a great influence on the composition of lipids in the lipoprotein particles. For example, it is known that the introduction of the active neutralizing monoclonal antibodies against SETR rabbits or hamsters increases the level of HDL or reduces the level of LDL cholesterol. In addition, the reduction or suppression activity SETR in humans due to genetic mutation causes an increase in levels of HDL cholesterol and lowering levels of LDL cholesterol in the blood. On the other hand, it is known that transgenic mice and rats, which caused the expression of SER, are characterized by low HDL cholesterol and elevated levels of LDL cholesterol. Thus, it is believed that SETR largely regulates the content of lipids in serum and affects the changes in lipid profile in serum by reducing levels of HDL cholesterol and enhance levels of LDL cholesterol. Therefore, it is recognized that a high level of activity SETR should cause arteriosclerosis.

In fact, the activity SETR varies depending on species. It is known that arteriosclerotic defeat easily occur under the influence of cholesterol in animals with high activity SETR, such as rabbits, whereas such lesions are practically absent in animals with low activity SETR, such as rats. Chrome is also it is established that continuous suppression of activity SETR by introduction of antisense oligodeoxynucleotide causes an increase in levels of HDL in the blood and decrease arteriosclerotic lesions in rabbits receiving food with high cholesterol content.

The above discoveries show that the activity SETR negatively affect cholesterol NDL and the suppression of activity SETR reduces the risk for arteriosclerotic diseases. Therefore, we can assume that compounds capable of inhibiting activity SETR, can block the transfer of cholesterol from HDL to LDL or VLDL and, thus, to increase the level of HDL cholesterol, prevent the occurrence of arteriosclerosis by reducing the level of LDL cholesterol, stimulate the occurrence of arteriosclerosis. Such compounds can serve as a useful prophylactic or therapeutic agent against arteriosclerotic diseases, hyperlipemia or dyslipemia and to provide effective medical treatment.

Examples of compounds having the activity of inhibiting SETR are derived tetrahydroquinoline. Cm. international PCT publication WO00/17164, international PCT publication WO00/17165 and international PCT publication WO00/17166.

However, these compounds have the op is edelenyi disadvantages. In particular, they do not dissolve in water and are not well absorbed in vivo, with a sufficient level of these compounds in the blood that are necessary for the emergence of therapeutic effect, can not be achieved even with the introduction of a generic drug for oral administration. Cm. WO03/63868.

There is a need for a new connection, which will eliminate the above disadvantages, therefore, we carried out a comprehensive study on the connection type dibenzylamine and the like. Cm. international PCT publication WO05/100298, international PCT publication WO04/020393, international PCT publication WO06/056854 and the patent application of Japan JP 2003-221376 A.

The invention

The present invention relates to compounds having excellent activity of inhibiting SETR, which are suitable for the prophylaxis and/or treatment arteriosclerotic diseases, hyperlipemia or dyslipidemia.

The authors of the present invention have performed extensive research to achieve the above objectives and discovered that compounds having the activity of inhibiting SETR, improve cholesterol NDL and reduce the level of LDL cholesterol, which formed the basis of the present invention.

The best ways of carrying out the invention

The present invention relates to ergonomic design is sought following variants of implementation, includes the following objects:

1. The compound of General formula (1):

where Y denotes a methylene group optionally substituted by substituent(s)selected from alkyl groups and the carbonyl group or a simple bond;

And means (i) a group selected from optionally substituted alkenylphenol group, halogen atom, carbonyl group, hydroxyl group, ceanography, nitro, carboxyl group, sulfopropyl, optionally substituted alkyl groups, optionally substituted cycloalkyl group, optionally substituted alkenylphenol group, optionally substituted CNS group, optionally substituted cycloalkene group, optionally substituted alkoxycarbonyl group, optionally substituted carbamoyl group, optionally substituted carbimazole group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted amino, optionally substituted sulfamoyl group, optionally substituted alkanoyloxy group, optionally substituted gamecycledelay group, actigraphy, substituted optionally substituted gamecycledelay group, carbonyl group, a substituted neobyazatel is substituted gamecycledelay group, optionally substituted heterocyclic group, actigraphy, substituted by optionally substituted heterocyclic group, and a carbonyl group substituted by optionally substituted heterocyclic group;

(ii) homocyclic group, optionally substituted by 1-5 substituents independently selected from the groups listed in paragraph (i); or

(iii) heterocyclic group optionally substituted by 1-5 substituents independently selected from the groups listed in paragraph (i);

In means a phenyl group optionally substituted by 1-4 substituents, independently selected from the following groups: optionally substituted Alchemilla group, halogen atom, hydroxyl group, cyano, a nitro-group, a carboxyl group, alphagraph, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted Alchemilla group, optionally substituted CNS group, optionally substituted cycloalkenyl group, optionally substituted alkoxycarbonyl group, optionally substituted carnemolla group, optionally substituted carbamazepina group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl gr is the PAP optionally substituted amino group, optionally substituted Altamarena group, optionally substituted alcoolica group, optionally substituted homozygocity group, oxygraph, substituted optionally substituted gamecycledelay group, a carbonyl group substituted by optionally substituted gamecycledelay group, optionally substituted heterocyclic group, oxygraph, substituted by optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group, and Allenova group; and specified Allenova group may contain 1-3 heteroatoms independently selected from oxygen atoms, sulfur and nitrogen, and may optionally have one or more substituents;

R1means a hydrogen atom or optionally substituted alkyl group; and the alkyl group may be further optionally substituted by substituent(s)selected from optionally substituted gamecycledelay group and optionally substituted heterocyclic group;

R2means a group selected from optionally substituted alkenylphenol group, halogen atom, carbonyl group, hydroxyl group, ceanography, nitro, carboxyl group, sulfopropyl, optionally substituted alkyl group, obazatelno substituted cycloalkyl group, optionally substituted alkenylphenol group, optionally substituted CNS group, optionally substituted cycloalkene group, optionally substituted alkoxycarbonyl group, optionally substituted carbamoyl group, optionally substituted carbimazole group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted amino, optionally substituted sulfamoyl group, optionally substituted alkanoyloxy group, optionally substituted gamecycledelay group, carbonyl group, substituted by an optionally substituted gamecycledelay group, a carbonyl group substituted by optionally substituted gamecycledelay group, optionally substituted heterocyclic group, a carbonyl group, substituted by an optionally substituted heterocyclic group, and carbonyl group, optionally substituted substituted heterocyclic group.

or its pharmaceutically acceptable derivative.

2. The connection of the above variant of the invention 1, in which homozygocity group is cycloalkyl group, phenyl group or naftilos group;

heterocyclic group is a t Niley, furillo, pyrrolidino, pyrrolidine, oxazolidine, thiazolidine, pyrazolidine, imidazolidine, imidazolinones, isoxazolidine, isothiazolines, oxadiazolidine, furazolidine, thiadiazolidine, triazoline, triazinyl, thiazolidinones, tetrazolyl, peredelnoj, imidazopyridines, pyrimidinyl, thiomorpholine, morpholinyl, triazinyl, pyrrolidinyl, piperidino, perenlei, tetrahydropyranyloxy, tipirneni, oxalidales, chiudinelli, piperazinilnom, triazinyl, oxothiazolidine, pyridazinyl, personalni, benzoperylene, benzothiazoline, benzoxazolyl, tetrachlorethylene, triazolopyridazines, benzimidazolyl, chinoline, isohynolines, dihydroisoquinoline, indolenines, phthalazinone, chineselovelinks, khinoksalinona, indolizinyl, dihydroindole, indolines, chinoiseries, naphthyridinone, perenlei, pteridinyl, dibenzofuranes, benzofuranyl, carbazolyl, greenley, phenanthridinone, romanillos, benzoxazinones, feninine, phenothiazinyl, phenoxazines, hexahydroazepin, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, DIOXOLANYL, oxiranyl, dihydropyrimidines, oxazolidines, dihydrooxazolo is, dihydropyrazolo, imidazopyridines, dihydropyrimidines, tetrahydroquinolines, benzothiazoles, dihydrooxazolo, oxadiazoline, dihydrooxazolo or tetrahydroquinoline group;

Deputy(s) for optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted alkenylphenol group, optionally substituted CNS group, optionally substituted cycloalkene group, optionally substituted alkoxycarbonyl group, optionally substituted carbamoyl group, optionally substituted carbimazole group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted amino, optionally substituted sulfamoyl group, optionally substituted alkanoyloxy group, optionally substituted gamecycledelay group, carbonyl group, substituted by an optionally substituted gamecycledelay group, a carbonyl group substituted by optionally substituted gamecycledelay group, optionally substituted heterocyclic group, carbonyl group, substituted by an optionally substituted heterocyclic group, a carbonyl group, a substituted optional is entrusted substituted heterocyclic group, optionally substituted phenyl group, optionally substituted alkylsulfonate, optionally substituted alkenylphenol group or optionally substituted alkalinous groups are 1-5 groups independently selected from the following groups:

halogen atom; cyano; hydroxyl group; nitro-group; carboxyl group; oxoprop; tocograph; alphagraph; cycloalkyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkoxycarbonyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; carnemolla group; mono - or dialkylanilines group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono- or dialkylamino, phenyl group or morpholinyl group; an alkyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinylcarbonyl; alcoolica group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; CNS group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkanoyloxy, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkylsulfonyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkylsulfonyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkylsulfonyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group Il is morpholinyl group; mono - or dialkylaminoalkyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; amino group; mono - or dialkylamino, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; mono - or dialkylaminoalkyl, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; mono - or dialkylamide, optionally substituted a hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; homozygocity group selected from cycloalkyl groups, phenyl groups and naftilos group; oxygraph, substituted above gamecycledelay group; a carbonyl group substituted by the above gamecycledelay group; heterocyclic group selected from thienyl, furillo, pyrrolidino, pyrrolidine, oxazolidine, thiazolidine, ratlines, imidazolidine, imidazolinones, isoxazolidine, isothiazolines, oxadiazolidine, furazolidine, thiadiazolidine, triazoline, triazinyl, thiazolidinones, tetrazolyl, peredelnoj, imidazopyridines, pyrimidinyl, thiomorpholine, morpholinyl, triazinyl, pyrrolidinyl, piperidino, perenlei, tetrahydropyranyloxy, tipirneni, oxalidales, chiudinelli, piperazinilnom, triazinyl, oxothiazolidine, pyridazinyl, personalni, benzoperylene, benzothiazoline, benzoxazolyl, tetrachlorethylene, triazolopyridazines, benzimidazolyl, chinoline, isohynolines, dihydroisoquinoline, indolenines, phthalazinone, chineselovelinks, khinoksalinona, indolizinyl, dihydroindole, indolines, chinoiseries, naphthyridinone, perenlei, pteridinyl, dibenzofuranes, benzofuranyl, carbazolyl, greenley, phenanthridinone, romanillos, benzoxazinones, feninine, phenothiazinyl, phenoxazines, hexahydroazepin, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, DIOXOLANYL, oxiranyl, dihydropyrimidines, oxazolidines, dihydrooxazolo, dihydropyrazolo, imidazopyridines, dihydropyrimidines, tetrahydroindole Inoi, benzodiazelines, dihydrooxazolo, oxadiazoline, dihydrooxazolo and tetrahydroquinolines group; oxygraph, above substituted heterocyclic group; a carbonyl group substituted by the above-mentioned heterocyclic group; and a group of the formula:

where each X1and X3independent means of CH2, NH, O, S, SO or SO2; each X2and X5independent means of CH2, O, S, SO or SO2; X4indicates NH, O, S, SO or SO2; each X6and X7independently denotes O or S; X8means S or SO; and each n, o, p, q and r independently denotes an integer from 1 to 4, and, in addition, each of the above groups may be optionally substituted by 1-3 substituents selected from the following groups: halogen atom, carboxyl group, hydroxyl group, cyano, oxoprop, tocograph, alkyl group, hydroxyalkyl group, alkoxycarbonyl group, carboxialkilnuyu group, morpholinylcarbonyl group, fenilalanina group, alcoolica group, hydroxyalkenals group, alkoxyalkanols group, CNS group, fenilalanina group, alkoxycarbonyl group, benzyloxycarbonyl group, mono - or dialkylamino, mono - or dialkylanilines group, mono - or dia is killalpaninna group, alkylsulfonyl group and tetrataenia group;

or its pharmaceutically acceptable derivative.

3. The connection of the above variant of the invention 2, in which a represents a group of the formula:

-And1-And2,

where a1means phenyl, naftalina, pyrimidinyl, pyridazinyl, pyridyloxy, triazolyl, tetrazolyl, oxadiazolyl, dihydropyrimidines, personilnya, thiazolidine, oxazolidine, dihydrooxazolo, imidazolidinyl, parasailing or dihydropyrimidine group;

And2means carboxyl group; a cyano; a nitro-group; alkyl group optionally substituted by a group selected from a hydroxyl group, ceanography, carboxyl group, alkoxycarbonyl group, CNS group, generalkonsulat group, hydroxyalkoxy group, carboxylcontaining group, alkylsulfonyl group, alkylsulfonyl group, alkylsulfonyl group, amino group, mono - or dialkylamino, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl group, oxiranyl group, dialkylanilines group, pyrrolidinyl group, optionally substituted carboxyl group, piperidino group optionally substituted by amoxilina group, piperazinilnom group, optionally substituted alkyl group, and morpholinyl group; alkenylphenol group optionally substituted by carboxyl group; CNS group, optionally substituted by a group selected from a hydroxyl group, ceanography, carboxyl group, alkoxycarbonyl group, CNS group, generalkonsulat group, hydroxyalkoxy group, carboxylcontaining group, alkylsulfonyl group, alkylsulfonyl group, alkylsulfonyl group, amino group, mono - or dialkylamino, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl group, oxiranyl group, dialkylanilines group, pyrrolidinyl group, optionally substituted carboxyl group, piperidino group, optionally substituted carboxyl group, piperazinilnom group, optionally substituted alkyl group, and morpholinyl group; alkoxycarbonyl group; hydroxycarbamoyl group; alkylsulfonyl group; alkylsulfonyl group optionally substituted by carboxyl group; a mono - or dialkylamino, optionally substituted hydroxyl group, a carboxyl group, CNS group or mono - or dialkylamino; morpho is enelow group, optionally substituted by carboxyl group, alkyl group, carboxialkilnuyu group or alkoxycarbonyl group; optionally oxidized thiomorpholine group; piperazinilnom group optionally substituted by a group selected from alkyl groups, alkanoyloxy group and hydroxyalkanoates group; pyrrolidinyl group optionally substituted by carboxyl group, alkyl group, carboxialkilnuyu group or alkoxycarbonyl group; piperidino group optionally substituted by carboxyl group, alkyl group, carboxialkilnuyu group or alkoxycarbonyl group; tetrazolyl group, optionally substituted by alkyl group, hydroxyalkyl group, carboxialkilnuyu group or morpholinomethyl group; oxodegradable group; pyrimidinyl group or tetrahydropyranyl group;

R1means a group of the formula:

-R11-R12,

where R11means alkylenes group;

R12means the substituent(s)selected from phenyl, peredelnoj, pyrimidinyl, pyridazinyl, furillo, thienyl, triazoline, tetrazolyl, oxadiazolyl, dihydropyrimidines, personalni, thiazolidine, oxazolidine, imidazolidine, dihydrooxazolo, dihydropyrazine the school and pyrazolidine group;

moreover specified(e) the Deputy(s) can be optionally substituted by 1-4 substituents, independently selected from halogen atom, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono - or dialkylanilines groups, alkyl groups, CNS group, hydroxyl group, nitro group, ceanography, amino, mono - or dialkylamino, alkanoyloxy group, alkylsulfonyl group, tetrazolyl group and dihydrooxazolo group; and, in addition, each specified alkyl group, CNS group, mono - or dialkylamino, mono - or dialkylanilines group, alcoolica group and alkylsulfonyl group can be optionally substituted by 1-5 substituents independently selected from halogen atom, hydroxyl group, CNS group, amino group, morpholinyl group, piperidino group, pyrrolidinyl group, piperazinilnom group, alkylpiperidines group and alkanolamines group;

R2means halogen atom;

hydroxyl group;

the cyano;

the nitro-group;

carboxyl group;

alphagroup;

cycloalkyl group optionally substituted by carboxyl group or alkoxycarbonyl group;

alkyl group optionally substituted by a group selected from the volume of halogen, ceanography, hydroxyl group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, mono - or dialkylanilines group, CNS group (specified CNS group can be optionally substituted phenyl group, a carboxyl group or a hydroxyl group), alkanoyloxy group, alkanoyloxy, alkylsulfanyl group, alkylsulfonyl group, alkylsulfonyl group, amino group, mono - or dialkylamino, optionally substituted carboxyl group or CNS group, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl group, oxiranyl group, DIOXOLANYL group, optionally substituted alkyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl group or a carboxyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl group or carboxialkilnuyu group, piperidino group, optionally substituted alkoxycarbonyl group or a carboxyl group, piperidino group, optionally substituted alkoxycarbonyl group or carboxialkilnuyu group, piperazinilnom group, optionally substituted alkyl group, hexahydroazepin gr is PPI, morpholinyl group and piperidinomethyl, optionally substituted alkyl group;

alkenylphenol group optionally substituted by a group selected from ceanography, hydroxyl group, carboxyl group, benzyloxycarbonyloxy group and tetrazolyl group;

alkenylacyl, optionally substituted by carboxyl group;

CNS group, optionally substituted by a group selected from a halogen atom, ceanography, hydroxyl group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono - or dialkylanilines group (specified mono - or dialkylanilines group can be optionally substituted carboxyl group, alkoxycarbonyl group or a hydroxyl group), CNS group (specified CNS group may be optionally substituted by carboxyl group, formyl group or hydroxy group), alkanoyloxy, alkylsulfanyl group, alkylsulfonyl group, alkylsulfonyl group, aminosulfonyl group, amino group, mono - or dialkylamino, optionally substituted carboxyl group or CNS group, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl groups is th, cycloalkyl group, optionally substituted carboxymethyl group, oxiranyl group, phenyl group, optionally substituted CNS group or a carboxyl group, morpholinyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl group or a carboxyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl group or carboxialkilnuyu group, pyrrolidinyl group, optionally substituted by exography, piperidino group, optionally substituted alkoxycarbonyl group or a carboxyl group, piperidino group, optionally substituted alkoxycarbonyl group or carboxialkilnuyu group, piperazinilnom group, optionally substituted alkyl group, hexahydroazepin group, pyrimidinyl group, peredelnoj group, DIOXOLANYL group, optionally substituted alkyl group, oxadiazolyl group, optionally substituted by exography, oxadiazolyl group, optionally substituted by exography, pyrrolidinylcarbonyl group, optionally substituted carboxyl group, piperidinomethyl, optionally substituted alkyl group, and morpholinylcarbonyl group;

alkoxycarbonyl group, optional what about a substituted phenyl group;

karbamoilnuyu group;

mono - or dialkylamino group optionally substituted by a group selected from carboxyl group, morpholinyl group and CNS group;

hydroxycarbamoyl group;

alkylsulfanyl group optionally substituted by a group selected from hydroxyl group, carboxyl group and mono - or dialkylanilines group;

alkylsulfonyl group;

alkylsulfonyl group optionally substituted by a group selected from hydroxyl group, carboxyl group, alkoxycarbonyl group and mono - or dialkylanilines group;

the amino group;

mono - or dialkylamino, optionally substituted by a group selected from hydrogen atom, ceanography, hydroxyl group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, carbamoyl group, mono - or dialkylanilines group (specified mono - or dialkylanilines group can be optionally substituted carboxyl group, alkoxycarbonyl group or a hydroxyl group), CNS group (specified CNS group may be optionally substituted by carboxyl group, formyl group or hydroxy group), alkanoyloxy, alkylsulfanyl group, alkylsulfonyl group, and killalpaninna group, aminosulfonyl group, amino group, mono - or dialkylamino, optionally substituted carboxyl group or CNS group, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl group, cycloalkyl group, optionally substituted carboxymethyl group, oxiranyl group, phenyl group, optionally substituted CNS group or a carboxyl group, morpholinyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl group or a carboxyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl or carboxialkilnuyu group, pyrrolidinyl group, substituted exography, piperidino group, optionally substituted alkoxycarbonyl group or a carboxyl group, piperidino group, optional substituted alkoxycarbonyl group or carboxialkilnuyu group, piperazinilnom group, optionally substituted alkyl group, hexahydroazepin group, pyrimidinyl group, peredelnoj group, DIOXOLANYL group, optionally substituted alkyl group, oxadiazolyl group, optionally substituted by exography, oxadiazolyl group, optional samisen the th exography, pyrrolidinylcarbonyl group, optionally substituted carboxyl group, piperidinomethyl, optionally substituted alkyl group, and morpholinylcarbonyl group;

alkanolamines, optionally substituted by a group selected from a hydroxyl group, CNS group, carboxyl group and amino group;

mono - or dialkylanilines, optionally substituted CNS group;

morpholinylcarbonyl;

sulfamoyl group;

mono - or dialkylaminoalkyl group;

alkanoyloxy group optionally substituted by a group selected from hydroxyl group, carboxyl group, alkoxycarbonyl group, CNS group, mono - or dialkylamino and morpholinyl group; or

cyclic group selected from cycloalkyl, phenyl, naftilos, thienyl, furillo, pyrrolidino, pyrrolidine, oxazolidine, thiazolidine, pyrazolidine, imidazolidine, imidazolinones, isoxazolidine, isothiazolines, oxadiazolidine, furazolidine, thiadiazolidine, triazoline, triazinyl, thiazolidinones, tetrazolyl, peredelnoj, imidazopyridines, pyrimidinyl, thiomorpholine, morpholinyl, triazinyl, pyrrolidinyl, piperidino, perenlei, tetrahydropyranyloxy, t is Opernring, oxaziridine, chiudinelli, piperazinilnom, triazinyl, oxothiazolidine, pyridazinyl, personalni, benzoperylene, benzothiazoline, benzoxazolyl, tetrachlorethylene, triazolopyridazines, benzimidazolyl, chinoline, isohynolines, dihydroisoquinoline, indolenines, phthalazinone, chineselovelinks, khinoksalinona, indolizinyl, dihydroindole, indolines, chinoiseries, naphthyridinone, perenlei, pteridinyl, dibenzofuranes, benzofuranyl, carbazolyl, greenley, phenanthridinone, romanillos, benzoxazinones, feninine, phenothiazinyl, phenoxazines, hexahydroazepin, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, DIOXOLANYL, oxiranyl, dihydropyrimidines, oxazolidines, dihydrooxazolo, dihydropyrazolo, imidazopyridines, dihydropyrimidines, tetrahydroquinolines, benzodiazelines, dihydrooxazolo, oxadiazoline, dihydrooxazolo and tetrahydroquinolines group;

moreover, the specified cyclic group may be optionally substituted by the following groups: halogen atom, alkoxyalkyl group, an alkyl group, optionally substituted by 1-5 halogen atoms, mono - or dialkylaminoalkyl group, mono - or d is acylaminoalkyl group, carboxyl group, hydroxyl group, cyano, oxoprop, alkyl group, hydroxyalkyl group, alkoxycarbonyl group, carboxialkilnuyu group, morpholinylcarbonyl group, fenilalanina group, alcoolica group, hydroxyalkenals group, alkoxyalkanols group, CNS group, fenilalanina group, alkoxycarbonyl group, benzyloxycarbonyl group, mono - or dialkylamino, mono - or dialkylanilines group, mono - or dialkylaminoalkyl group, alkylsulfonyl group and tetrataenia group;

moreover, the above substituents may be further substituted by substituents selected from the following groups:

halogen atom, alkoxyalkyl group, an alkyl group, optionally substituted by 1-5 halogen atoms, mono - or dialkylaminoalkyl group, mono - or dialkylaminoalkyl group, carboxyl group, hydroxyl group, cyano, oxoprop, alkyl group, hydroxyalkyl group, alkoxycarbonyl group, carboxialkilnuyu group, morpholinylcarbonyl group, fenilalanina group, alcoolica group, hydroxyalkenals group, alkoxyalkanols group, CNS group, fenilalanina group, alkoxycarbonyl group, benzyloxycarbonyl group, mono - and who and dialkylamino, mono - or dialkylanilines group, mono - or dialkylaminoalkyl group, alkylsulfonyl group and tetrataenia group;

or its pharmaceutically acceptable derivative.

4. The connection of the above variant of the invention 1, in which Y denotes a methylene group optionally substituted by substituent(s)selected from alkyl groups and the carbonyl group or a simple bond;

A represents a group of the formula:

-And1-And2;

where a1means heterocyclic group or homocyclic group;

And2means optionally substituted homocyclic group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, neobyazatelno substituted alkylsulfonyl group optionally substituted alkyl group, a nitrogroup, hydroxyl group, cyano, optionally substituted alkenylphenol group, optionally substituted heterocyclic group, substituted CNS group, halogen atom, amino group, substituted by 1-2 substituents, or a hydrogen atom;

In means a phenyl group optionally substituted by 1-4 substituents, independently selected from ceanography, halogen atom, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl the school group, optionally substituted alkylsulfonyl group, amino group, substituted by 1-2 substituents, hydroxyl group, optionally substituted heterocyclic group, optionally substituted cycloalkene group, carboxyl group, optionally substituted cycloalkyl group, optionally substituted carbamoyl group, optionally substituted alkyl groups and optionally substituted CNS group;

R1means a hydrogen atom, alkyl group, substituted heterocyclic group, or alkyl group, substituted gamecycledelay group; and specified heterocyclic group, homozygocity group or alkyl group may further have substituent(s);

R2means optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, cyano, optionally substituted alkenylphenol group, amino group, optionally substituted by 1-2 substituents, halogen atom, optionally substituted CNS group, optionally substituted carbamoyl group, oxygraph, optionally substituted by optionally substituted heterocyclic group, hydroxyl group, optionally substituted heterocyclic group, not necessarily for sennou homocyclic group, oxoprop, optionally substituted optionally substituted gamecycledelay group, neobyazatelno substituted alkyl group, or a nitro-group;

provided that when Y represents a methylene group and a2means a halogen atom, a hydrogen atom, a nitro-group, hydroxyl group or cyano, then R2is not optionally substituted alkyl group, optionally substituted alkenylphenol group, optionally substituted CNS group or amino group, optionally substituted by 1-2 substituents;

or its pharmaceutically acceptable derivative.

5. The connection of the above variant of the invention 4, in which Y denotes a methylene group optionally substituted by substituent(s)selected from alkyl groups and the carbonyl group;

And1means heterocyclic group;

And2means optionally substituted heterocyclic group, optionally substituted alkyl group, substituted CNS group, halogen atom, amino group, optionally substituted by 1-2 substituents, or a hydrogen atom;

In means a phenyl group optionally substituted by 1-4 groups independently selected from ceanography, halogen atom, hydroxyl group, optionally substituted cycloalkyl group, not necessarily samewe the Noah cycloalkene group, optionally substituted piperidine group, cycloalkyl group, cycloalkene group, optionally substituted alkyl groups and optionally substituted CNS group;

R1means a hydrogen atom or alkyl group, substituted phenyl group which is substituted by 1-2 groups independently selected from CNS group, optionally substituted by 1-3 halogen atoms, alkyl groups, optionally substituted by 1 to 3 halogen atoms, and cyanopropyl;

R2means amino group, optionally substituted by 1-2 substituents, halogen atom, optionally substituted CNS group, optionally substituted carbamoyl group, oxygraph, substituted by optionally substituted heterocyclic group, hydroxyl group, optionally substituted heterocyclic group, optionally substituted homocyclic group, oxygraph, substituted optionally substituted gamecycledelay group, hydroxyalkyl group, or a nitro-group;

or its pharmaceutically acceptable derivative.

6. The connection of the above variant of the invention 5 in which homozygocity group is cycloalkyl group, phenyl group or naftilos group;

heterocyclic group is thienyl, furillo, pyrrolidino,pyrrolidine, oxazolidines, thiazolidines, pyrazolidine, imidazolidine, imidazolinones, isoxazolidine, isothiazolines, oxadiazolidine, furazolidine, thiadiazolidine, triazoline, triazinyl, thiazolidinones, tetrazolyl, peredelnoj, imidazopyridines, pyrimidinyl, thiomorpholine, morpholinyl, triazinyl, pyrrolidinyl, piperidino, perenlei, tetrahydropyranyloxy, tipirneni, oxalidales, chiudinelli, piperazinilnom, triazinyl, oxothiazolidine, pyridazinyl, personalni, benzoperylene, benzothiazoline, benzoxazolyl, tetrachlorethylene, triazolopyridazines, benzimidazolyl, chinoline, isohynolines, dihydroisoquinoline, indolenines, phthalazinone, chineselovelinks, khinoksalinona, indolizinyl, dihydroindole, indolines, chinoiseries, naphthyridinone, parinello, pteridinyl, dibenzofuranes, benzofuranyl, carbazolyl, greenley, phenanthridinone, romanillos, benzoxazinones, feninine, phenothiazinyl, phenoxazines, hexahydroazepin, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, DIOXOLANYL, oxiranyl, dihydropyrimidines, oxazolidines, dihydrooxazolo, dihydropyrazolo, imidazopyridine is Oh, dihydropyridines, tetrahydroquinolines, benzothiazoles, dihydrooxazolo, oxadiazoline, dihydrooxazolo or tetrahydroquinoline group;

Deputy(s) for optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted alkenylphenol group, optionally substituted CNS group, optionally substituted cycloalkene group, optionally substituted alkoxycarbonyl group, optionally substituted carbamoyl group, optionally substituted carbimazole group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted amino, optionally substituted sulfamoyl group, optionally substituted alkanoyloxy group, optionally substituted gamecycledelay group, carbonyl group, substituted by an optionally substituted gamecycledelay group, a carbonyl group substituted by optionally substituted gamecycledelay group, optionally substituted heterocyclic group, carbonyl group, substituted by an optionally substituted heterocyclic group, a carbonyl group substituted by optionally substituted heterocyclic group is, optionally substituted phenyl group, optionally substituted alkylsulfonate, optionally substituted alkenylphenol group or optionally substituted alkalinous groups include 1-5 groups, nuovissimo selected from the following groups:

halogen atom; cyano; hydroxyl group; nitro-group; carboxyl group; oxoprop; tocograph; alphagraph; cycloalkyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkoxycarbonyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; carnemolla group; mono - or dialkylanilines group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono- or dialkylamino, phenyl group or morpholinyl group; an alkyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; al is anjilina group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; CNS group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkanoyloxy, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkylsulfonyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkylsulfonyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; alkylsulfonyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group is Oh; mono - or dialkylaminoalkyl group, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; amino group; mono - or dialkylamino, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; mono - or dialkylaminoalkyl, optionally substituted hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; mono - or dialkylamide, optionally substituted a hydroxyl group, a halogen atom, a carboxyl group, alkoxycarbonyl group, mono - or dialkylamino, phenyl group or morpholinyl group; homozygocity group selected from cycloalkyl groups, phenyl groups and naftilos group; oxygraph, substituted above gamecycledelay group; a carbonyl group substituted by the above gamecycledelay group; heterocyclic group selected from thienyl, furillo, pyrrolidino, pyrrolidine, oxazolidine, thiazolidine, ratlines, imidazolidine, imidazolinones, isoxazolidine, isothiazolines, oxadiazolidine, furazolidine, thiadiazolidine, triazoline, triazinyl, thiazolidinones, tetrazolyl, peredelnoj, imidazopyridines, pyrimidinyl, thiomorpholine, morpholinyl, triazinyl, pyrrolidinyl, piperidino, perenlei, tetrahydropyranyloxy, tipirneni, oxalidales, chiudinelli, piperazinilnom, triazinyl, oxothiazolidine, pyridazinyl, personalni, benzoperylene, benzothiazoline, benzoxazolyl, tetrachlorethylene, triazolopyridazines, benzimidazolyl, chinoline, isohynolines, dihydroisoquinoline, indolenines, phthalazinone, chineselovelinks, khinoksalinona, indolizinyl, dihydroindole, indolines, chinoiseries, naphthyridinone, perenlei, pteridinyl, dibenzofuranes, benzofuranyl, carbazolyl, greenley, phenanthridinone, romanillos, benzoxazinones, feninine, phenothiazinyl, phenoxazines, hexahydroazepin, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, DIOXOLANYL, oxiranyl, dihydropyrimidines, oxazolidines, dihydrooxazolo, dihydropyrazolo, imidazopyridines, dihydropyrimidines, tetrahydroindole Inoi, benzodiazelines, dihydrooxazolo, oxadiazoline, dihydrooxazolo and tetrahydroquinolines group; oxygraph, above substituted heterocyclic group; a carbonyl group substituted by the above-mentioned heterocyclic group; and a group of the formula:

where each X1and X3independent means of CH2, NH, O, S, SO or SO2; each X2and X5independent means of CH2, O, S, SO or SO2; X4indicates NH, O, S, SO or SO2; each X6and X7independently denotes O or S; X8means S or SO; and each n, o, p, q and r independently denotes an integer from 1 to 4, and, in addition, each of the above groups may be optionally substituted by 1-3 substituents selected from the following groups: halogen atom, carboxyl group, hydroxyl group, cyano, oxoprop, tocograph, alkyl group, hydroxyalkyl group, alkoxycarbonyl group, carboxialkilnuyu group, morpholinylcarbonyl group, fenilalanina group, alcoolica group, hydroxyalkenals group, alkoxyalkanols group, CNS group, fenilalanina group, alkoxycarbonyl group, benzyloxycarbonyl group, mono - or dialkylamino, mono - or dialkylanilines group, mono - or dia is killalpaninna group, alkylsulfonyl group and tetrataenia group;

or its pharmaceutically acceptable derivative.

7. The connection of the above variant embodiment of the invention 6 in which And1means pyrimidinyl group or pyridyloxy group;

And2means (a) a heterocyclic group selected from piperidino group and morpholinyl groups, respectively optionally substituted by substituent(s)selected from a carboxyl group, carboxialkilnuyu groups and alkyl groups;

(b) CNS group substituted by a group selected from carboxyl group, hydroxyl group, CNS group and cyanopropyl;

(C) a halogen atom;

(d) amino group, optionally substituted with 1-2 substituents independently selected from carboxialkilnuyu group, hydroxyalkyl group, alkyl group, alkoxyalkyl group and aminoalkyl group, optionally substituted with 1-2 alkyl groups;

(e) a hydrogen atom;

In means a phenyl group optionally substituted by 1-4 groups independently selected from halogen atom, hydroxyl group, alkyl group, optionally substituted by 1 to 3 halogen atoms, and CNS group, optionally substituted by 1 to 3 halogen atoms;

R1means a hydrogen atom or a benzyl group substituted by 1-3 groups is AMI, independently selected from the CNS group, optionally substituted by 1-3 halogen atoms, alkyl groups, optionally substituted by 1 to 3 halogen atoms, and cyanopropyl;

R2means (a) an amino group, optionally substituted with 1-2 groups independently selected from alkyl groups, alkoxyalkyl group, cycloalkylation group, alkoxycarbonyl group, alkylcarboxylic group, alkylcarboxylic group, carboxialkilnuyu group, cycloalkylation group, substituted carboxialkilnuyu group, hydroxyalkyl group, carboxylcontaining group, carboxymethyloxysuccinic group, carboxyethylgermanium group, phenylalaline group, alkoxycarbonyl group, alkoxycarbonyl groups, alkyl groups, substituted piperidine group, piperidylamine group, substituted carboxialkilnuyu group, and alkyl groups substituted by phenyl, which is optionally substituted with 1-2 alkyl group (this alkyl group may be optionally substituted with 1-3 atoms halogen);

moreover, the specified alkyl group or CNS group may be further optionally substituted by 1-5 groups independently selected from the following groups:

halogen atom, cyano, hydroxyl group, carboxyl group, aldoxycarb the ilen group, tetrataenia group, carnemolla group, mono - or dialkylanilines group (specified mono - or dialkylanilines group can be optionally substituted carboxyl group, alkoxycarbonyl group or a hydroxyl group), CNS group (specified CNS group may be optionally substituted by carboxyl group, formyl group or hydroxy group), alkanoyloxy, alkylsulfanyl group, alkylsulfonyl group, alkylsulfonyl group, aminosulfonyl group, amino group, mono - or dialkylamino, optionally substituted carboxyl group or CNS group, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl group, cycloalkyl group, optional substituted carboxymethyl group, oxiranyl group, phenyl group, optionally substituted CNS group or a carboxyl group, morpholinyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl group or a carboxyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl group or carboxialkilnuyu group, pyrrolidinyl group, optionally substituted by exography, piperideine group is a, optionally substituted alkoxycarbonyl group or a carboxyl group, piperideine group, optionally substituted alkoxycarbonyl group or carboxialkilnuyu group, piperazinilnom group, optionally substituted alkyl group, hexahydroazepin group, pyrimidinyl group, Peregrina group, DIOXOLANYL group, optionally substituted alkyl group, oxadiazolyl group, optionally substituted by exography, oxadiazolyl group, optionally substituted by exography, pyrrolidinylcarbonyl group, optionally substituted carboxyl group, piperidinyloxy, optionally substituted alkyl group, and morpholinylcarbonyl group;

(b) a halogen atom;

(C) CNS group, optionally substituted by a group selected from carboxyl group, cycloalkyl group and CNS group;

moreover, the specified cycloalkyl group or CNS group may be optionally substituted by 1-5 groups independently selected from the following groups:

halogen atom, cyano, hydroxyl group, carboxyl group, alkoxycarbonyl group, tetrataenia group, carnemolla group, mono - or dialkylanilines group (specified mono - or dialkylanilines group may be the optionally substituted carboxyl group, alkoxycarbonyl group or a hydroxyl group), CNS group (specified CNS group may be optionally substituted by carboxyl group, formyl group or hydroxy group), alkanoyloxy, alkylsulfanyl group, alkylsulfonyl group, alkylsulfonyl group, aminosulfonyl group, amino group, mono - or dialkylamino, optionally substituted carboxyl group or CNS group, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl group, cycloalkyl group, optionally substituted carboxymethyl group, oxiranyl group, phenyl group, optionally substituted CNS group or a carboxyl group, morpholinyl group, pyrrolidinyl group, optional substituted alkoxycarbonyl group or a carboxyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl group or carboxialkilnuyu group, piperideine group, optionally substituted by exography, piperideine group, optionally substituted alkoxycarbonyl group or a carboxyl group, piperideine group, optionally substituted alkoxycarbonyl group or carboxialkilnuyu GRU is sing, piperazinilnom group, optionally substituted alkyl group, hexahydroazepin group, pyrimidinyl group, Peregrina group, DIOXOLANYL group, optionally substituted alkyl group, oxadiazolyl group, optionally substituted by exography, oxadiazolyl group, optionally substituted by exography, pyrrolidinylcarbonyl group, optionally substituted carboxyl group, piperidinyloxy, optionally substituted alkyl group, and morpholinylcarbonyl group;

(d) karbamoilnuyu group, optionally substituted with 1-2 substituents independently selected from alkyl groups and carboxialkilnuyu group;

moreover, the mentioned alkyl group may be optionally substituted by 1-5 groups independently selected from the following groups:

halogen atom, cyano, hydroxyl group, carboxyl group, alkoxycarbonyl group, tetrataenia group, carnemolla group, mono - or dialkylanilines group (specified mono - or dialkylanilines group may be substituted by carboxyl, alkoxycarbonyl or a hydroxyl group), CNS group (specified CNS group may be substituted by carboxyl, formyl or hydroxy group), alkanoyloxy, alkylsulfanyl group,alkylsulfonyl group, alkylsulfonyl group, aminosulfonyl group, amino group, mono - or dialkylamino, optionally substituted carboxyl, or CNS group, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl group, cycloalkyl group, optionally substituted carboxymethyl group, oxiranyl group, phenyl group, optionally substituted CNS or carboxyl group, morpholinyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl or a carboxyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl or carboxialkilnuyu group, pyrrolidinyl group, substituted exography, piperideine group, optionally substituted alkoxycarbonyl or a carboxyl group, piperideine group, optionally substituted alkoxycarbonylmethyl or carboxialkilnuyu group, piperazinilnom group, optionally substituted alkyl group, hexahydroazepin group, pyrimidinyl group, Peregrina group, DIOXOLANYL group, optionally substituted alkyl group, oxadiazolyl group, optionally substituted by exography, oxadiazolyl group, optionally substituted, oxoprop is, pyrrolidinylcarbonyl group, optionally substituted carboxyl group, piperidinyloxy, optionally substituted alkyl group, and morpholinylcarbonyl group;

(e) a hydroxyl group;

(f) oxygraph substituted heterocyclic group selected from pyrimidinyl group and tetrahydropyranyl group;

(g) a heterocyclic group selected from morpholinyl, pyrimidinyl, piperidine, piperazinilnom, personalni, tetrazolyl, thienyl, furillo, dihydroisoquinoline, peredelnoj and pyrrolidino groups, each of which is optionally substituted by 1-3 substituents, independently selected from pyrimidinyl group, alkyl group, halogen atom, ceanography, mono - or dialkylamino, CNS group, phenyl group, carboxyl group, carbamoyl group and carboxialkilnuyu group;

moreover, the specified CNS group or alkyl group may be optionally substituted by 1-5 groups independently selected from the following groups:

halogen atom, cyano, hydroxyl group, carboxyl group, alkoxycarbonyl group, tetrataenia group, carnemolla group, mono - or dialkylanilines group (specified mono - or dialkylanilines group can be optionally substituted carboxy who enoy group, alkoxycarbonyl group or a hydroxyl group), CNS group (specified CNS group may be optionally substituted by carboxyl group, formyl group or hydroxy group), alkanoyloxy, alkylsulfanyl group, alkylsulfonyl group, alkylsulfonyl group, aminosulfonyl group, amino group, mono - or dialkylamino, optionally substituted carboxyl group or CNS group, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl group, cycloalkyl group, optionally substituted carboxymethyl group, oxiranyl group, phenyl group, optionally substituted CNS group or a carboxyl group, morpholinyl group, pyrrolidinyl group, optional substituted alkoxycarbonyl group or a carboxyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl group or carboxialkilnuyu group, pyrrolidinyl group, substituted exography, piperideine group, optionally substituted alkoxycarbonyl group or a carboxyl group, piperideine group, optionally substituted alkoxycarbonyl group or carboxialkilnuyu group, the Pipera ininna group, optionally substituted alkyl group, hexahydroazepin group, pyrimidinyl group, Peregrina group, DIOXOLANYL group, optionally substituted alkyl group, oxadiazolyl group, optionally substituted by exography, oxadiazolyl group, optionally substituted by exography, pyrrolidinylcarbonyl group, optionally substituted carboxyl group, piperidinyloxy, optionally substituted alkyl group, and phenyl group, optionally substituted morpholinyl group;

(h) phenyl group, optionally substituted by 1-3 substituents, independently selected from halogen atom, alkyl group and CNS group;

moreover, the specified CNS group or alkyl group may be further optionally substituted by 1-5 groups independently selected from the following groups:

halogen atom, cyano, hydroxyl group, carboxyl group, alkoxycarbonyl group, tetrataenia group, carnemolla group, mono - or dialkylanilines group (specified mono - or dialkylanilines group can be optionally substituted carboxyl group, alkoxycarbonyl group or a hydroxyl group), CNS group (specified CNS group can be optionally substituted, carbox the school group formyl group or a hydroxyl group), alkanoyloxy, alkylsulfanyl group, alkylsulfonyl group, alkylsulfonyl group, aminosulfonyl group, amino group, mono - or dialkylamino, optionally substituted carboxyl group or CNS group, mono - or dialkylaminoalkyl, mono - or dialkylamide, optionally substituted morpholinyl group, cycloalkyl group, optionally substituted carboxymethyl group, oxiranyl group, phenyl group, optionally substituted CNS group or a carboxyl group, morpholinyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl group or a carboxyl group, pyrrolidinyl group, optionally substituted alkoxycarbonyl group, pyrrolidinyl group, substituted oxopropoxy, piperideine group, optionally substituted alkoxycarbonyl group or a carboxyl group, piperideine group, optionally substituted alkoxycarbonyl group, piperazinilnom group, optionally substituted alkyl group, hexahydroazepin group, pyrimidinyl group, Peregrina group, DIOXOLANYL group, optionally substituted alkyl group, oxadiazolidine gr is the PAP optionally substituted by exography, oxadiazolyl group, optionally substituted by exography, pyrrolidinylcarbonyl group, optionally substituted carboxyl group, piperidinyloxy, optionally substituted alkyl group, and morpholinylcarbonyl group;

(i) oxoprop, substituted cycloalkyl group;

(j) hydroxyalkyl group; or

(k) a nitro-group;

or its pharmaceutically acceptable derivative.

8. The connection of the above variant of the invention 7 in which And1means pyrimidinyl group or pyridyloxy group;

And2means (a) a heterocyclic group selected from piperidino group and morpholinyl groups, each of which is optionally substituted by substituent(s)selected from a carboxyl group, carboxialkilnuyu group or alkyl group;

(b) CNS group substituted by a group selected from carboxyl group, hydroxyl group, CNS group and cyanopropyl;

(C) a halogen atom;

(d) amino group, optionally substituted with 1-2 substituents independently selected from carboxialkilnuyu group, hydroxyalkyl group, alkyl group, alkoxyalkyl group and aminoalkyl groups, respectively optionally substituted with 1-2 alkyl groups;

(e) a hydrogen atom;

In means a phenyl group optionally substituted by 1-4 groups independently selected from alkyl groups, optionally substituted by 1 to 3 halogen atoms, and CNS group, optionally substituted by 1 to 3 halogen atoms;

R1means

R2means (a) an amino group, optionally substituted with 1-2 groups independently selected from alkyl groups, alkoxyalkyl group, cycloalkylation group, alkoxycarbonyl group, alkylcarboxylic group, alkylcarboxylic group, carboxialkilnuyu group, cycloalkylation group, substituted carboxialkilnuyu group, hydroxyalkyl group, carboxylcontaining group, carboxymethyloxysuccinic group, carboxyethylgermanium group, phenylalaline group, alkoxycarbonyl group, alkoxycarbonyl groups, alkyl groups, substituted piperidine group, piperidylamine group, substituted carboxialkilnuyu group, and alkyl group, substituted phenyl group, which optionally is substituted by 1-2 alkyl group (this alkyl group may be optionally substituted by 1-3 by halogen atoms);

(b) a halogen atom;

(C) CNS group, optionally substituted by a group selected from carbox the school group, cycloalkyl group and CNS group;

(d) karbamoilnuyu group, optionally substituted with 1-2 substituents independently selected from alkyl groups and carboxialkilnuyu group;

(e) a hydroxyl group;

(f) oxoprop substituted heterocyclic group selected from pyrimidinyl group and tetrahydropyranyl group;

(g) a heterocyclic group selected from pyrimidinyl, peredelnoj, morpholinyl, piperidino, piperazinilnom, tetrazolyl, dihydroisoquinolines and pyrrolidino groups, each of which optionally is substituted by 1-2 substituents independently selected from alkyl groups, CNS group, phenyl group, carboxyl group, carboxylcontaining group and carboxialkilnuyu group;

(h) phenyl group, optionally substituted by 1-3 substituents, independently selected from halogen atom, alkyl group and CNS group;

(i) oxoprop, substituted cycloalkyl group;

(j) hydroxyalkyl group;

(k) a nitro-group;

or its pharmaceutically acceptable derivative.

9. The connection of the above variant embodiment of the invention 8 in which And2means an amino group substituted by 1-2 groups independently selected from piperidino group optionally substituted by carboxyl groups is th; morpholinyl group optionally substituted by carboxyl group; CNS group substituted by a group selected from carboxyl group, hydroxyl group, CNS group and cyanopropyl; an amino group substituted by 1-2 groups independently selected from carboxialkilnuyu groups and alkyl groups;

In means a phenyl group optionally substituted alkyl group, optionally substituted by 1 to 3 halogen atoms;

R1means

R2means (a) an amino group, optionally substituted with 1-2 groups independently selected from alkyl groups, cycloalkylation group, alkoxycarbonyl group, carboxialkilnuyu group and cycloalkylation group, substituted carboxialkilnuyu group;

(b) CNS group;

(C) a phenyl group optionally substituted by a group selected from halogen atom, alkyl group and CNS group;

(d) pyridyloxy group optionally substituted by a group selected from halogen atom, alkyl group and CNS group;

or its pharmaceutically acceptable derivative.

10. The compound according to any one of examples№ 7, 24, 75, 57, 13, 54, 12, 65, 63 and 64 or its pharmaceutically acceptable derivative.

11. The compound of the formula (I-A):

where

And1A means optionally substituted pyrimidine-2-ilen group or optionally substituted pyridine-2-ilen group;

R1Aand R1Bindependently represent cyano or alkyl group, optionally substituted by 1 to 3 halogen atoms;

E ring means optionally substituted phenyl group;

F denotes optionally substituted cyclic group;

or its pharmaceutically acceptable derivative.

12. The compound of the formula (I-B):

where

ZAndmeans N or CH;

And21Ameans optionally substituted homocyclic group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group optionally substituted alkyl group, a nitrogroup, hydroxyl group, cyano, optionally substituted alkenylphenol group, optionally substituted heterocyclic group, optionally substituted CNS group, halogen atom, amino group, optionally substituted by 1-2 substituents, karbamoilnuyu group, optionally substituted by 1-2 substituents, a carboxyl group or a hydrogen atom;

R1Ameans cyano or alkyl group, optionally substituted by 1 to 3 halogen atoms;

In' means group, n is dependent selected from a carbonyl group, ceanography, halogen atom, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, optionally substituted alkylsulfonyl group, amino group, optionally substituted by 1-2 substituents, hydroxyl group, optionally substituted heterocyclic group, optionally substituted cycloalkene group, optionally substituted cycloalkyl group, carboxyl group, carbamoyl group, optionally substituted by 1-2 substituents, optionally substituted alkyl group or optionally substituted CNS group;

RAndmeans an integer from 0 to 3;

D means pyrimidinyl group, pyridyloxy group, phenyl group, pyrimidinylidene, tetrazolyl group or oxazolidinyl group;

D' means a group independently selected from a halogen atom, alkoxyalkyl group, alkyl group, substituted by 1-5 halogen atoms, CNS group, substituted by 1-5 halogen atoms, alkenylphenol group, carbamoyl group, cycloalkyl group, mono - or dialkylaminoalkyl group, mono - or dialkylaminoalkyl group, carboxyl group, hydroxyl group, ceanography, carbonyl group, alkyl group, hydroxyalkyl group, alkoxycarbonyl group, carboxy Kilroy group, morpholinylmethyl group, phenylalaline group, alkanoyloxy group, hydroxyalkanoates group, alkoxyalkanols group, CNS group, generalkonsulat group, alkoxycarbonyl group, benzyloxycarbonyl group, mono - or dialkylamino, mono - or dialkylanilines group, mono - or dialkylamino group, alkylsulfonyl group, tetrazolyl group, benzyloxyaniline group, cycloalkylation group, benzyloxy, alkoxyalkyl group, carboxylcontaining group, carboxyaniline group, alkylcarboxylic, carboxylcontaining group, morpholinyl group or pyridylamino group;

qAndmeans an integer from 0 to 3;

or its pharmaceutically acceptable derivative.

13. The connection of the above variant embodiment of the invention 12, in which

And21Achoose from the following groups:

(a) a heterocyclic group selected from piperidino group and morpholinyl groups, respectively optionally substituted by substituent(s)selected from a carboxyl group, alkoxycarbonyl group, carboxialkilnuyu group or alkyl group;

(b) CNS group, optionally substituted by a group selected from carboxyl group, alkoxycarbonyl group, and the Ohm halogen, alkylsulfonyl group, mono - or dialkylamino, ceanography, tetrazolyl group, alkylsulfonyl group, alkylsulfonyl group, hydroxyl group or CNS group;

(C) a halogen atom;

(d) amino group, optionally substituted with 1-2 substituents independently selected from carboxialkilnuyu group, alkoxycarbonyl group, alkylsulfonyl group, alkylsulfonyl group, hydroxyalkyl group, alkyl group, alkoxyalkyl group or aminoalkyl group, optionally substituted with 1-2 alkyl groups;

(e) a hydrogen atom;

(f) an alkyl group optionally substituted by a group selected from carboxyl group, alkoxycarbonyl group, halogen atom, alkylsulfonyl group, mono - or dialkylamino, ceanography, tetrazolyl group, alkylsulfonyl group, alkylsulfonyl group, hydroxyl group or CNS group;

(g) a carboxyl group;

(h) carnemolla group, optionally substituted carboxialkilnuyu group; or

(i) Alchemilla group substituted by a group selected from carboxyl group, alkoxycarbonyl group, alkylsulfonyl group, ceanography, tetrazolyl group, alkylsulfonyl group, alkylsulfonyl group, hydroxyl GRU is dust or CNS group;

(j) morpholinyl group;

(k) piperidinyl group optionally substituted by carboxyl group or carboxialkilnuyu group;

In' means a group independently selected from a carbonyl group, halogen atom, alkyl group, optionally substituted by 1-3 halogen atoms, CNS group, optionally substituted by 1-3 halogen atoms, ceanography, hydroxyl group, cycloalkyl group, alkoxyalkyl group, cycloalkene group, alkylsulfonyl group, optionally substituted by 1-3 halogen atoms, alkylsulfonyl group, optionally substituted by 1-3 halogen atoms, or alkylsulfonyl group optionally substituted by 1 to 3 halogen atoms;

or its pharmaceutically acceptable derivative.

14. The connection of the above variant embodiment of the invention 13, in which

And21Ameans CNS group, optionally substituted by 1-2 groups selected from carboxyl group, halogen atom, alkoxycarbonyl group, CNS group, hydroxyl group, mono - or dialkylamino, alkylsulfonyl group, ceanography, tetrazolyl group, alkylsulfonyl group and alkylsulfonyl group; alkyl group, optionally substituted by 1-2 groups selected from carboxyl group, halogen atom, alkoxide onlineu group, CNS group, hydroxyl group, mono - or dialkylamino, alkylsulfonyl group, ceanography, tetrazolyl group, alkylsulfonyl group and alkylsulfonyl group; morpholinyl group; carboxyl group or carboxypeptidases group;

In' means a group independently selected from halogen atom, alkyl group, optionally substituted by 1-3 halogen atoms, or CNS group, optionally substituted by 1 to 3 halogen atoms;

D' means a group independently selected from CNS group, optionally substituted by 1 to 3 halogen atoms, halogen atom, ceanography, alkylsulfonyl group, mono - or dialkylamino, alkenylphenol groups, alkyl groups, optionally substituted by 1-3 halogen atoms, carboxyl group, hydroxyl group, carboxylcontaining group, carboxialkilnuyu group, alkoxycarbonyl group, carbonyl group, cycloalkyl group, hydroxyalkyl group, alkoxyalkyl group, carbamoyl group, mono - or dialkylanilines group, alkylcarboxylic, morpholinyl group or carboxylcontaining group;

or its pharmaceutically acceptable derivative.

15. The connection of the above variant embodiment of the invention 14, in which ZAndmeans N or headlamp is asepticheski acceptable derivative.

16. The connection of the above variant embodiment of the invention 14 in which R1Ameans alkyl group, optionally substituted by 1-3 halogen atoms, or its pharmaceutically acceptable derivative.

17. The connection of the above variant embodiment of the invention 14, in which D is phenyl group, or its pharmaceutically acceptable derivative.

18. The connection of the above variant embodiment of the invention 14, in which D' is a group independently selected from a halogen atom, CNS group or alkyl group, or its pharmaceutically acceptable derivative.

19. The connection of the above variant embodiment of the invention 14 in which And21Ameans morpholinyl group or CNS group, substituted carboxyl group, or its pharmaceutically acceptable derivative.

20. The compound according to any one of examples№ 91, 94, 96, 112, 114, 118-123, 131, 133, 136, 138-140, 142-153, 158-163, 165 to 169, 173-177, 179-182, 185, 186, 190-194, 198, 203, 208-216, 218-223, 231, 239, 240, 241, or its pharmaceutically acceptable derivative.

21. The compound according to any one of examples No. 154-157, 164, 170-172, 178, 183, 184, 187-189, 195-197, 199-202, 204-207, 217, 224-230, 232-238, 242-252 or its pharmaceutically acceptable derivative.

22. Pharmaceutical composition containing as active ingredient a compound according to any one of the above variations is tov the invention, 1-21 or its pharmaceutically acceptable derivative.

23. The method of prevention or treatment of arteriosclerosis such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, ischemia of the heart, stroke, myocardial infarction, impaired reperfusion injury, restenosis after reconstruction of blood vessels, hypertension, heart attack, brain damage, strokes, diabetes, vascular complication of diabetes, thrombotic disorders, obesity, endotoxicosis, metabolic syndrome, ischemic stroke, coronary artery disease, dysfunction of the ventricle, cardiac arrhythmia, vascular disease of the lung, vascular disease of the kidney, kidney disease, vascular disease of the internal organs, hemostatic vascular disease, fatty infiltration of the liver, steatohepatitis, inflammatory disease, autoimmune disorders and other systemic diseases, modulation of immune function, lung disease, anti-oxidant disease, impotence, impaired cognitive ability, schistosomiasis, cancer, relapse xanthomas or Alzheimer's disease, which includes an introduction to the needy to the subject an effective amount of a compound according to any one of the above options is sushestvennee invention 1-21 or its pharmaceutically acceptable derivative.

24. The use of compounds according to any one of the above embodiments of the invention 1-21 or its pharmaceutically acceptable derivative for the preparation of drugs for the treatment of subjects suffering from arteriosclerosis such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, ischemia of the heart, stroke, myocardial infarction, impaired reperfusion injury, restenosis after reconstruction of blood vessels, hypertension, heart attack, brain damage, strokes, diabetes, vascular complication of diabetes, thrombotic disorders, obesity, endotoxicosis, metabolic syndrome, cerebral circulation, coronary artery disease, dysfunction of the ventricle, cardiac arrhythmia, vascular disease of the lung, vascular disease of the kidneys, kidney disease, vascular disease of the internal organs, hemostatic vascular disease, fatty infiltration of the liver, steatohepatitis, inflammatory disease, autoimmune disorders and other systemic diseases, modulation of immune function, lung disease, anti-oxidant disease, impotence, impaired cognitive capable of the tee, schistosomiasis, cancer, relapse xanthomas or Alzheimer's disease.

25. The compound of General formula (1-1):

where the symbols have the above values, or its pharmaceutically acceptable derivative.

Connection (1) of the present invention, containing one or more asymmetric carbon atoms, includes the racemate, racemic mixture of the single enantiomers or diastereoisomers. Compounds of the present invention also includes all such isomers and their mixture.

In addition, the compound of the present invention, containing alkenylphenol or alkenylphenol group may have a CIS (Z)- and TRANS (E)form. Compounds of the present invention includes the individual stereoisomers of the compounds, not necessarily their individual tautomeric forms and the mixture.

Diastereoisomers or CIS - and TRANS-isomers can be separated by standard methods, such as fractional crystallization, chromatography, HPLC and the like. Drug containing specific stereoisomer may be obtained from the corresponding optically active intermediate product or an alternative means of separation of the corresponding racemate with an appropriate chiral media (e.g., HPLC) or perform fractionated crystallization diastereomeric salt obtained is the result of interaction of the corresponding racemate and acceptable optically active acid or base. An alternative mixture of enantiomers can be divided through the formation of new covalently linked compounds resulting from its interaction with acceptable chiral compound. For example, first carry out the reaction mix racemic carboxylic acid with a chiral amine or a chiral alcohol, thus obtaining a mixture of diastereoisomers (respectively, amide or ether complex), and then allocate the necessary enantiomer standard method, such as chromatography, HPLC or fractionated crystallization and the like. One diastereoisomer then you can turn in one enantiomer of the desired compounds by cleavage of a new covalent bonds as a result of performing acceptable chemical reactions, such as hydrolysis and the like.

Used in the description, the term “pharmaceutically acceptable derivative” means a pharmaceutically acceptable salt, MES or prodrug (e.g., ester) compounds of the present invention, which is able to form (directly or indirectly) a compound of the present invention, its active metabolite or residue. Such derivatives can be obtained by the person skilled in the art without undue experimentation. See, for example, the publication Burger''s Medicinal Chemistry and Drug Discovery 5thed. vol. 1st, “Principles and Practice”. repectfully pharmaceutically acceptable derivative is a salt, MES, ester, ester carbamino acid and an ester of phosphoric acid. Particularly preferred pharmaceutically acceptable derivative is a salt, MES and ester. The preferred pharmaceutically acceptable derivative is a salt and an ester.

Specialist in the field of organic chemistry it is known that many organic compounds can form a complex with the solvent of the reaction system and can be precipitated or bicrystalline of the solvent. Such complexes are widely known as the “solvate”. For example, a complex of water known as “hydrate”. MES compounds of the present invention is included in the scope of the invention.

Used in the description, the term “prodrug” means a compound that turns into acitivy form with pharmacological activity, by hydrolysis in vivo (e.g. in the blood). Examples of pharmaceutically acceptable prodrugs described in the scientific literature: T. Higuchi and V. Stera, Prodrugs as Novel Delivery Systems, "Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, A.C.S. Symposium Series, vol. 14th, (1987); and D. Freisher, S. Roman and Barbara H., Improved oral drug delivery: solubility limitations overcome by the use of prodrugs, Advanced Drug Delivery Reviews (1996) 19(2): 115-130).

A prodrug is a carrier, releasing the compound of formula (1), which covalently binds in vivo is ri introduction to the subject. Typically, the prodrug receive standard method or by modifying functional groups in such a way that the modified portion is cleaved in vivo with the formation of the original connection. Examples of prodrugs include a compound in which a hydroxyl, amino or sulfhydryl group is associated with an optional group that provides education hydroxyl, amino or sulfhydryl group in the breakdown with the introduction of the subject. Thus, representative examples of prodrugs include, but are not limited to, the derived complex ester of acetic acid, a complex ester of formic acid and a complex ester of benzoic acid formed in the provision of such functional groups such as alcohol, sulfhydryl or amine compounds of formula (1). In addition, when the functional group is a carboxylic acid, can be used such esters as methyl ester, complex ethyl ether, double ester, and the like. Esters have activity in humans and/or hydrolyzed in vivo to form the active compounds. Pharmaceutically acceptable esters, capable of either hydrolyzed in vivo, include esters, which are easily decomposed in the human body, releasing the original acid or salt.

The connection to the present is invention may be pharmaceutically acceptable salt. Acceptable salt described in the scientific literature (Berge et al., J. Pharm. Sci., 66: 1-19 (1977)).

Pharmaceutically acceptable salts can be easily obtained with the desired acid or base. The salts can be isolated by filtration after precipitation from solution or distillation of solvent.

Acceptable salt additive can be obtained with the acid, forming a non-toxic salt. Examples of salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, triptorelin, saharat, benzoate, methanesulfonate, aconsultant, bansilalpet and para-toluensulfonate.

Examples of the pharmaceutically acceptable salt with a base include alkali metal salts, such as ammonium salt, sodium salt and potassium salt; salts of alkaline earth metals such as calcium salt, magnesium salt, and salts with organic bases including primary, secondary and tertiary amine (for example, Isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine and N-methyl-D-glucamine).

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “alkyl group” or “alkyl” means a linear or branched saturated hydrocarbon chain with 1 to 10 carbon atoms and a cycle is a mini saturated hydrocarbon chain with 3-10 carbon atoms. Preferred linear or branched hydrocarbon chains are chains with 2-10 carbon atoms and more preferred are chain with 2 to 6 carbon atoms. More preferable examples are alkyl groups with a linear chain containing 1-6 carbon atoms, in particular alkyl groups with 1-4 carbon atoms. Examples of alkyl groups include methyl, ethyl, sawn, ISO-propyl, boutelou, second-boutelou, tert-boutelou, pentelow, isopentanol, neopentyl, tert-pentelow, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexeline, isohexyl and similar groups.

The term “CNS group” or “alkoxy” means alkyloxy with a linear or branched chain containing 1-10 carbon atoms, and cyclic alkyloxy containing 3-10 carbon atoms. Preferred linear or branched hydrocarbon chains are chains with 2-10 carbon atoms and more preferred are chain with 2 to 6 carbon atoms. More preferred examples are CNS group with a linear chain containing 1-6 carbon atoms, in particular CNS group with 1-4 carbon atoms. Examples of CNS groups include metaxylene, amoxilina, propoxyimino, isopropoxyphenol, betaxolol, isobutoxy, tert-butoxyl the Yu, pentoxil, isopentanol, neodenticula, tert-pentoxil, hexarelin, isohexanol and similar groups.

The term “Allenova group” or “alkylene” means a saturated hydrocarbon chain, in which the hydrogen atom is removed from the terminal carbon atoms of the linear hydrocarbon chain. Preferred examples include alkylenes group with 1-6 carbon atoms, in particular methylene, ethylene, trimethylene, tetramethylene and similar groups. When Allenova group used in the present invention contains 1-3 heteroatoms independently selected from nitrogen atoms, sulfur and oxygen, the term “alkylene” includes a group of the formula-O-(CH2)m-O-, -S-(CH2)m-S-, -NH-(CH2)m-NH - or-O-(CH2)m-NH (where m denotes an integer from 1 to 4) or a similar group.

The term “alcoolica group” or “alkanoyl” means alkylcarboxylic group with a linear or branched chain containing 1-10 carbon atoms, preferably alkylcarboxylic group containing 1-6 carbon atoms, more preferably alkylcarboxylic group containing 1-4 carbon atoms. Examples alkanoyloxy groups include acetyl, propionyl, butyryloxy, valerino, pivaloyloxy and similar groups.

The term “Alchemilla group” or “alkenyl” means the line is th or branched hydrocarbon chain, containing 2-10 carbon atoms and at least one double bond, preferably alkenylphenol group with 2-6 carbon atoms, more preferably alkenylphenol group with 2-4 carbon atoms. Examples alkenylphenol groups include vinyl, 1-propenyloxy, allyl, Isopropenyl, butenyloxy, butadienyl, pantanillo and similar groups.

The term “Alchemilla group” or “quinil” means linear or branched hydrocarbon chain containing 2-10 carbon atoms and at least one triple bond, preferably alkylamino group with 2-6 carbon atoms, more preferably alkylamino group with 2-4 carbon atoms. Examples alkenylphenol groups include etinilnoy, 1-propenyloxy, isopropylamino, Punchinello and similar groups.

The term “mono - or dialkyl used in the claims and the description and meaning of the dialkyl, alkyl part may have the same or different values.

Cycloalkyl or cycloalkyl group is used in the present description of the invention, means C3-10 cyclic hydrocarbon group and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptanol, cyclooctanol, cycloserine and similar groups, with the preferred group is a C3-6 cyclic pleva Hrodna group.

Cycloalkane and cycloalkene group is used in the present description of the invention, means oxygraph, substituted C3-10 cyclic hydrocarbon, and includes, for example, cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane and similar groups, with the preferred group is oxygraph, substituted C3-6 cyclic hydrocarbon group.

A heterocycle or heterocyclic group is used in the present description of the invention, means 5-8-membered heterocyclic group with 1 to 4 heteroatoms selected from oxygen atoms, sulfur and nitrogen, and decillions or tricyclic condensed heterocyclic group. Specific examples of heterocyclic groups include, for example, thienyl, follow, pyrrolidino, pyrrolidino, oxazolidinyl, thiazolidine, pyrazolidine, imidazolidine, imidazolylalkyl, isoxazolidine, isothiazolinone, oxadiazolidine, foratenolol, thiadiazolidine, triazolyl, triazinyl, diazolidinylurea, tetrazolyl, pyridyloxy, imidazopyridine, pyrimidinyl, thiomorpholine, morpholinyl, triazinyl, pyrrolidinyl, piperidino, pyranyloxy, tetrahydropyranyloxy, tipirneni, oxazinyl, chiudinelli, piperazinilnom, triazinyl, oxothiazolidine, pyridazine is inuu, personilnya, benzoperylene, benzothiazolyl, benzoxazolyl, tetrachlorethylene, triazolopyridazines, benzimidazolyl, pinolillo, izohinolinove, dihydroisoquinolyl, indolinyl, talinolol, chinazolinei, khinoksalinona, indolizinyl, dihydroindole, indolenine, hyalinella, naphthyridinone, parinello, pteridinyl, dibenzofurane, benzofuranyl, carbazolyl, criminology, phenanthridinium, romanello, benzoxazinone, pensininku, phenothiazinyl, phenoxazines, hexahydroazepin, imidazolidinyl, oxazolidinyl, tetrahydrofuranyl, DIOXOLANYL, oxiranyl, dihydropyrimidines, oxazolidinyl, dihydrooxazolo, dihydropyrazolo, imidazopyridine, dihydropyrimidine, tetrahydroquinoline, benzothiazoline, dihydrooxazolo, oxadiazolyl, dihydrooxazolo or tetrahydroquinoline and similar groups.

Gomoll or homozygocity group is used in the present description of the invention means, for example, optionally condensed 3-7-membered carbocyclic group, such as C6-10 aryl group (e.g. phenyl, naftalina and similar groups), a C3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl is, cyclopentamine, tsiklogeksilnogo, cycloheptyl and similar groups), a C3-10 cycloalkenyl group (for example, cyclopropylamine, cyclobutylamine, cyclopentadiene, cyclohexadiene, cycloheptadiene and similar groups).

Cyclic group is used in this description, means the above-mentioned heterocyclic and homocyclic group.

The effect of the invention

Connection (1) according to the present invention has the activity of inhibiting SETR, increase HDL cholesterol and reduce LDL cholesterol. Thus, this connection can be used for the prevention and treatment of diseases such as arteriosclerosis, hyperlipidemia and the like.

Connection (1) according to the present invention can be administered orally or parenterally and be used for the preparation of corresponding pharmaceutical preparations together with standard pharmaceutically acceptable carriers.

Pharmaceutically acceptable salts of the compounds (1) include, for example, alkali metal salts such as lithium salt, sodium or potassium; salts of alkaline earth metals such as calcium salt or magnesium; salts with zinc or aluminium, salts with organic bases, such as ammonium, choline, diethanolamine, lysine, Ethylenediamine, t-butylamine, tert-octylamine,Tris(hydroxymethyl)aminomethan, N-methylglucamine, triethanolamine or dehydroabietylamine; salts with inorganic acids, such as chloride-hydrogen acid, Hydrobromic acid, iodine-hydrogen acid, sulfuric acid, nitric acid or phosphoric acid; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid or toluensulfonate acid; or salts derived from acidic amino acids such as aspartic acid or glutamic acid.

In addition, pharmaceutically acceptable salts of the compounds of formula (1) include, for example, Quaternary salts derived from compounds of formula (1) and alkylhalogenide or phenylalkylamine.

Preferred pharmaceutical preparations for oral administration containing a compound of the present invention include solid preparations such as tablets, granules, capsules or powders, and liquid preparations such as solutions, suspensions or emulsions. Preferred pharmaceutical preparations for parenteral administration include injections or infusions, etc is prepared with the use of injectable distilled water, saline or aqueous glucose solution; suppository; drug inhalation and the like.

These pharmaceutically drugs include the compound (1) according to the present invention or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, usually used for oral or parenteral administration. Pharmaceutically acceptable carriers for oral administration include, for example, binder (syrup, Arabian gum, gelatin, sorbitol, tragakant, polyvinylpyrrolidone and the like), an excipient (lactose, sugar, corn starch, potassium phosphate, sorbitol, glycine, etc.), lubricating agent (magnesium stearate, talc, polyethylene glycol, silicon dioxide, and the like), a disintegrator (potato starch, and the like) and wetting agent (anhydrous sodium dodecyl sulfate and the like).

Pharmaceutically acceptable carriers for parenteral administration include, for example, injectable distilled water, physiological salt solution and an aqueous solution of glucose.

The dose of compound (1) according to the present invention or its pharmaceutically acceptable salt may vary depending on the method of administration, age, body weight, disease and health/disease severity of the subject. However, the dose usually is the range of about 0.001 to 1000 mg/kg/day, preferably within about 0.01-100 mg/kg/day, more preferably within about 0.1-10 mg/kg/day.

Compounds (1) according to the present invention have activity of inhibiting SETR, increase HDL cholesterol and reduce LDL cholesterol. Therefore, these compounds may be used for prevention or treatment of a subject (in particular a mammal, including humans)suffering from arteriosclerosis such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, ischemia of the heart, stroke, myocardial infarction, impaired reperfusion injury, restenosis after reconstruction of blood vessels, hypertension, heart attack, brain damage, strokes, diabetes, vascular complication of diabetes, thrombotic disorders, obesity, endotoxicosis, metabolic syndrome, stroke, coronary artery disease, dysfunction of the ventricle, cardiac arrhythmia, vascular disease of the lung, vascular disease of the kidneys, kidney disease, vascular disease of the internal organs, hemostatic vascular disease, fatty infiltration of the liver, steatohepatitis, inflammatory ill the tion, autoimmune disorders and other systemic diseases, modulation of immune function, lung disease, anti-oxidant disease, impotence, impaired cognitive ability, schistosomiasis, cancer, relapse xanthomas, Alzheimer's disease or the like.

In addition, the compounds of the present invention can be used in combination with other drugs used to treat these diseases. For example, the compound of the present invention can be used in combination with an inhibitor of cholesterol synthesis, such as an inhibitor of HMG-CoA reductase inhibitor; an inhibitor of cholesterol absorption, such as anion-exchange resin; means for reducing the level of triglycerides, such as fibrates, Niacin, and fish oil; anti-hypertensive agent, such as an ACE inhibitor, blocker angiotensin receptor, calcium antagonist and beta-blocker; a remedy for obesity, such as a drug, reduces appetite, a lipase inhibitor and antagonist SB; a remedy for diabetes, such as sensibilities insulin agonist D2, sulfonylurea, biguanide, an inhibitor of α-glucosidase, an SGLT inhibitor and a DPPIV inhibitor; or other means of reducing the level of cholesterol, such as an inhibitor of ACAT.

Connection (1) according to the present invention can be obtained in the following ways, do not limit what their scope of invention.

Each method of obtaining the above compounds of formula (1) protection of functional groups in any connection, if necessary, is carried out by any known method of choice. General provisions relating to protective groups and their use, are presented in the publication Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.

In addition, in every way, the reaction can be performed by the standard method and the method of isolation and purification can be selected from standard techniques such as crystallization, recrystallization, chromatography, preparative HPLC and the like, depending on the use either of these methods can big combined with each other.

[Method I]

The compound (1) can be obtained as described below I.

The way I

where XA1and XA2mean delete the group, and other symbols have the above values.

(Method I-1)

The compound (4) can be obtained by interaction of the compound (2) with compound (3) in a solvent in the presence of a base.

The solvent may be any solvent which does not impede the implementation of the reaction, which includes, for example, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-metakit is h, diglyme; hydrocarbons, such as benzene, toluene, hexane, xylene; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol; esters such as ethyl acetate, methyl acetate, butyl acetate; polar solvents such as acetone, N,N-dimethylformamide, dimethyl sulfoxide, which can be used separately or in combination. Preferred solvents used in the reaction include ethanol, dioxane, toluene and N,N-dimethylformamide.

As can be used a normal basis, which includes, for example, alkali metal hydride such as sodium hydride and potassium hydride; alkali metal alkoxide such as ethoxide sodium, sodium methoxide, tert-piperonyl sodium tert-piperonyl potassium; acility, such as n-utillity and second-utility; alkali metal amide, such as diisopropylamide lithium, sodium amide and bis(trimethylsilyl)amide lithium; a carbonate of an alkali metal such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydroxide such as lithium hydroxide, sodium hydroxide and potassium hydroxide; phosphate of an alkali metal such as sodium phosphate and potassium phosphate; organic base such as triethylamine, diisopropylethylamine, pyridine and N-methylmorpholine; preferred bases are Treaty the amine, sodium bicarbonate, tert-piperonyl sodium, diisopropylethylamine, sodium hydride and tert-piperonyl potassium.

Remove the group includes a halogen atom such as chlorine atom, bromine atom, iodine atom, and substituted sulfonyloxy, such as methanesulfonamido, a pair of toluensulfonate and triftormetilfullerenov.

(Method I-2)

The compound (1) can be obtained by interaction of the compound (4) with compound (5) is similar to method I-1 described below or the way I'-1.

(The way I'-1)

Method (I-1) can be replaced in the following way I'-1.

In the above method I-1 compound (4) can also be obtained by interaction of the compound (2) with compound (3) in the presence or in the absence or in the presence of a metal catalyst such as palladium-based catalyst, in an acceptable solvent.

As the palladium catalyst may be used a conventional palladium catalyst include palladium acetate, tetrakis(triphenylphosphine)palladium, Tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium, dichlorobis(tri-o-tolylphosphino)palladium acetate, bis(triphenylphosphine)palladium or the like.

As can be preferably used hydroxide WEL knogo metal, such as sodium hydroxide, potassium hydroxide; alkali earth metal hydroxide such as barium hydroxide; alkali metal alkoxide such as sodium methoxide, ethoxide sodium, atoxic potassium tert-piperonyl sodium tert-piperonyl potassium; a carbonate of an alkali metal such as sodium carbonate, potassium carbonate, cesium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate; a phosphate of an alkali metal such as potassium phosphate; amines, such as triethylamine, diisopropylethylamine, methylpiperidin, dicyclohexylmethane; and pyridine, such as pyridine, 4-dimethylaminopyridine.

In addition, when carrying out this reaction can be used phosphines. As phosphines can be preferably used triphenylphosphine, tributylphosphine, tetrafluoroborate three-tert-butylphosphine, 1,3-bis(diphenylphosphino)propane, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1,1'-bis(diphenylphosphino)ferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-(dicyclohexylphosphino)biphenyl and the like.

The solvent may preferably be used any solvent which does not impede the implementation of the reaction, which includes, for example, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-methoxyethane, diglyme; hydrocarbons, t is such as benzene, toluene, hexane, xylene; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol; esters such as ethyl acetate, methyl acetate, butyl acetate; polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, and these solvents may be used separately or in combination.

(The way I'-2)

The compound (1) can be obtained by interaction of the compound (4) with compound (5) is similar to the way I'-1 I-1.

[Method II]

The compound (1) can be obtained by method II.

Method II

where XA3means delete the group, and other symbols have the above values.

(Method II-1)

Compound (8) can be obtained by interaction of the compound (6) with compound (7) is similar to method I-1.

(Method II-2)

The compound (1) can be obtained by interaction of the compound (8) with compound (3) is similar to method I-1 or I-1.

[Method III]

The compound (1) can be obtained by method III.

Method III

where the symbols have the above values.

(Method III-1)

Compound (9) can be obtained by interaction of the compound (3) with compound (7) similarly, the ways the I-1 or the way I'-1.

(Method III-2)

The compound (1) can be obtained by interaction of the compound (9) with compound (6) is similar to method I-1.

[Method IV]

The compound of General formula (1-a):

where the symbols have the above values, similar to the case when Y represents a methylene group in the compound of formula (1)can be obtained in the following way IV.

The compound (1-a) can be obtained by restoring the compounds of General formula (6'):

where the symbols have the above values, the corresponding carboxylic acids or the corresponding complex ether carboxylic acid with the formation of compounds of General formula (6”):

where the symbols have the above values, with subsequent halogenoalkanes the compounds and coordination compounds obtained from the above compound (9) in a solvent in the presence of a base.

Recovery may be performed by treating the starting compound with the reducing agent in an acceptable solvent. As a reducing agent can be preferably used borhydride (sodium borohydride, and the like) and hydrides of aluminum (alumoweld lithium hydride diisobutylaluminum and the like.

Halogenoalkane can be performed by treating the starting compound halogenation agent in an acceptable solvent. As the halogenation agent can be preferably used conventional halogenation agent such as thionyl chloride, phosphorus oxychloride, and tetravalent carbon (e.g. carbon tetrachloride, tetrabromide carbon and the like) and phosphines (e.g. triphenylphosphine, trailerforum, triethylphosphine and the like).

As can be used a normal basis, which includes, for example, alkali metal hydride such as sodium hydride and potassium hydride; alkali metal alkoxide such as ethoxide sodium, sodium methoxide, tert-piperonyl sodium tert-piperonyl potassium; acility, such as n-utillity and second-utility; alkali metal amide, such as diisopropylamide lithium, sodium amide and bis(trimethylsilyl)amide lithium; a carbonate of an alkali metal such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydroxide such as lithium hydroxide, sodium hydroxide and potassium hydroxide; phosphate of an alkali metal such as sodium phosphate and potassium phosphate; organic base such as triethylamine, diisopropylethylamine, pyridine and N-methylmorpholine; the preferred base is triethyl is min, sodium bicarbonate, tert-piperonyl sodium, diisopropylethylamine, sodium hydride and tert-piperonyl potassium.

The solvent may preferably be used any solvent which does not impede the implementation of the reaction, which includes, for example, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-methoxyethane, diglyme; hydrocarbons, such as benzene, toluene, hexane, xylene; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol; esters such as ethyl acetate, methyl acetate, butyl acetate; polar solvents such as acetone, N,N-dimethylformamide, dimethyl sulfoxide, which can be used separately or in combination. Preferred solvents in the reaction include ethanol, dioxane, toluene and N,N-dimethylformamide.

[Method IV']

The compound (1-a) can also be obtained as described below IV'.

The compound (1-a) can also be obtained by halogenation of the above compound (6”) in the manner described above IV with subsequent implementation of the interaction of the compounds obtained from the above compound (7) in a solvent in the presence of a base to form compounds of General formula (8')

where the symbols have the above values, and the subsequent implementation of the receiving interaction of the obtained compound with compound (3) described above II-2.

[Method IV”]

Compound (8') can be obtained as described above IV' as a result of interaction of the compound (6') with compound (7) in a solvent in the presence of a reducing agent.

The solvent may preferably be used any solvent which does not impede the implementation of the reaction, which includes, for example, halogen, such as 1,2-dichloroethane, dichloromethane, chloroform, ethers, such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-methoxyethane, diglyme; hydrocarbons, such as benzene, toluene, hexane, xylene; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol; esters such as ethyl acetate, methyl acetate, butyl acetate; polar solvents such as acetone, N,N-dimethylformamide, dimethyl sulfoxide, which can be used separately or in combination. Especially preferred solvent in this reaction is 1,2-dichloroethane, dichloromethane and toluene. The reducing agent includes borhydride sodium, such as triacetoxyborohydride sodium, cyanoborohydride sodium; and hydrides of aluminum, such as alumalite lithium hydride diisobutylaluminum.

[Method V]

The compound of General formula (1-b):

where R3means alkyl group and the other symbols have the above the values, similar to the case when Y represents alkyl group in the compound (1)may be obtained by carrying out the normal Grignard reaction between the compound (6') and a reagent of General formula: R3MgBr, where the symbol R3has the above values, with the formation of compounds of General formula (6"'):

where the symbols have the above values, with subsequent halogenoalkanes the compounds obtained are similar to the above method IV and engagement of the obtained compound with the above compound (9) in a solvent in the presence of a base.

[Method V']

The compound (1-b) can also be obtained in the following way V'.

The compound (1-b) can also be obtained by halogenation of the above compound (6"') as described above V with the subsequent implementation of the interaction of the compounds obtained from the above compound (7) in a solvent in the presence of a base to form compounds of General formula (8”):

where the symbols have the above values, with the subsequent implementation of the interaction of the obtained compound with compound (3) described above II-2.

[Method VI]

The compound of General formula (1):

where the symbols have the decree is installed above the value similar to the case when Y represents a methylene group substituted by exography, in the compound (1)may be obtained by oxidation of compound (6') with the formation of compounds of General formula (6””):

where the symbols have the above values, with subsequent halogenoalkanes the compounds obtained as described above IV and implementation of the interaction of the compounds obtained from the above compound (9) in a solvent in the presence of a base.

[Method VI']

The compound (1-C) can also be obtained as described below VI':

The compound (1-C) can be obtained by halogenation of the above compound (6””) as described above VI and subsequent implementation of the interaction of the compounds obtained from the above compound (7) in a solvent in the presence of a base to form compounds of General formula (8"'):

where the symbols have the above values, with the subsequent implementation of the interaction of the obtained compound with compound (3) described above II-2.

[Method VII]

The compound (1-a) can be obtained as described below VII.

The compound (1-a) can also be obtained by recovering the compounds of General formula (6""'):

where SIM is Ola have the above values, with the formation of compounds of General formula (6”””):

where the symbols have the above values, with subsequent implementation of the interaction of the compounds obtained from the above compound (9) is similar to method IV” with the formation of compounds of General formula (1-d):

where the symbols have the above values, and performing interconversion part R2.

[Method VII']

The compound (1-a) can also be obtained as a result of interaction among the above compounds (6”””) with the above compound (7) as described above IV” with the formation of compounds of General formula (8”):

where the symbols have the above values, with the subsequent implementation of the interaction of the obtained compound with compound (3) described above II-2 with the formation of compound (1-d) and performing interconversion part R2.

In addition, the substituents in position a, b, R1and R2can be further subjected to vzaimoprevrascheny known method after or before the synthesis of the compound (1).

And2may be subject to vzaimoprevrascheny the methods described below (EA)-(EL).

Except where otherwise stated in the following way as can be site is preferably used a normal basis, for example, the alkali metal hydride such as sodium hydride, potassium hydride; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; alkali earth metal hydroxide such as barium hydroxide; alkali metal alkoxide such as sodium methoxide, ethoxide sodium, atoxic potassium tert-piperonyl potassium; a carbonate of an alkali metal such as sodium carbonate, potassium carbonate, cesium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate; amines, such as triethylamine, diisopropylethylamine, methylpiperidin, dimethylaniline, 1,8-diazabicyclo[5.4.0]undecene, 1,4-diazabicyclo-[2.2.2]octane, 1,5-diazabicyclo[4.3.0]nonan; pyridine, such as pyridine, dimethylaminopyridine.

In addition, in the following way as an acid can be preferably used a common acid, which, for example, except where otherwise indicated, is an inorganic acid (for example, chloride-hydrogen acid, nitric acid and sulfuric acid; organic acid represented sulfonic acids (for example, methanesulfonic acid, para-toluensulfonate acid, triftormetilfullerenov acid and similar acids).

In the following way as a solvent can be any solvent which does not impede the implementation is eacli, which includes hydrocarbons, such as pentane, hexane; aromatic hydrocarbons such as benzene, toluene, nitrobenzene; halogenated hydrocarbons such as dichloromethane, chloroform; ethers, such as diethyl ether, tetrahydrofuran; amides, such as dimethylformamide, N-organic, 1,3-dimethylimidazolidin-2-he; sulfoxidov, such as dimethyl sulfoxide; alcohols such as methanol, ethanol; esters such as ethyl acetate, butyl acetate; ketones, such as acetone, methyl ethyl ketone; NITRILES, such as acetonitrile; water, or a mixed solvent.

In the following way remove group contains a halogen atom such as chlorine atom, bromine atom, iodine atom, and substituted sulfonyloxy, such as methanesulfonamido, triftormetilfullerenov and toluensulfonate.

(EA) Compound, in which And1means tetrazolyl group and2means alkyl group or substituted alkyl group, can be obtained by alkylation of compounds in which And1means tetrazolyl group and2means a hydrogen atom.

The alkylation can be performed as a result of implementation of the interaction of the compounds of formula:

And2A-Z2,

where a2Ameans alkyl group or substituted alkyl group, and Z2 means delete the group, in an acceptable solvent in the presence or in the absence of a base or as a result of implementation interaction with the compound of the formula:

And2AHE

where the symbol has the above significance, in an acceptable solvent in the presence of phosphines and esters of azodicarboxylic acid.

N-alkylation of compounds in which And1means a nitrogen-containing heterocyclic group, can be performed similarly to the above-described method.

The reaction proceeds more efficiently when adding a catalytic amount of an iodide of an alkali metal (e.g. potassium iodide, and the like).

Can be preferably used phosphines and esters of azodicarboxylic acid, which is usually used when carrying out the reaction of Mitsunobu. Phosphines include, for example, triphenylphosphine, tributylphosphine and the like, and esters of azodicarboxylic acid include diethylazodicarboxylate, diisopropylethylamine and the like.

(EB) Union1mean 2-oxopiperidine group and2means alkyl group or substituted alkyl group, can be obtained by alkylation of compounds of formula (1), in which And1mean 2-hydroxypyrimidinone group and2means a hydrogen atom, soy is inanam formula:

And2A-Z2,

where the symbols have the above values.

This reaction can be performed similarly to the above method (EA).

(EU) Union2means optionally substituted by an amino group or a group of the formula:

where the symbols have the above meanings, can be obtained as a result of implementation of the interaction of the compounds of formula (1), in which And2means a halogen atom, with a corresponding amine or a compound of the formula:

where the symbols have the above values.

This reaction can be performed in the presence or in the absence of a base and in the presence or in the absence of a palladium catalyst in an acceptable solvent.

As the palladium catalyst may be used a conventional palladium catalyst such as palladium acetate, tetrakis(triphenylphosphine)palladium, Tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium, dichlorobis(tri-o-tolylphosphino)palladium acetate, bis(triphenylphosphine)palladium or the like.

As can be preferably used an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; alkali earth metal hydroxide such as barium hydroxide; Alcock the ID of an alkali metal, such as sodium methoxide, ethoxide sodium, atoxic potassium tert-piperonyl potassium; a carbonate of an alkali metal such as sodium carbonate, potassium carbonate, cesium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate; a phosphate of an alkali metal such as potassium phosphate; amines, such as triethylamine, diisopropylethylamine, methylpiperidin, dicyclohexylmethane; and pyridine, such as pyridine, 4-dimethylaminopyridine.

In addition, when performing this reaction can be used phosphines. As phosphines can be preferably used triphenylphosphine, tributylphosphine, tetrafluoroborate three-tert-butyl-phosphonium, 1,3-bis(diphenylphosphino)propane, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1,1'-bis(diphenylphosphino)ferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-(dicyclohexylphosphino)biphenyl and the like.

(ED), the Compound in which And2means optionally substituted by an amino group, can be obtained by performing the reaction of a combination of compounds of formula (1), in which And2means a halogen atom, with a compound of the formula:

(R20)3Sn-NR21R22,

where R20means alkyl group and NR21R22means optionally substituted by an amino group.

The reaction mix may be you who Olney in the presence of palladium catalyst in the presence or in the absence of a base in an acceptable solvent.

Palladium catalysts, bases and phosphines described in the above way (EU), can be used similarly to the above method (EC).

(IT) Connection, in which And2means cyano, can be obtained by cyanation of the compound of formula (1), in which And2means a halogen atom.

Cyanide can be made in the implementation of the interaction of initial connection with a metal cyanide such as sodium cyanide, potassium cyanide or cyanide zinc, in the presence of palladium catalyst in an acceptable solvent.

Can be preferably used palladium catalyst, similar to that described in the above way (EU).

(EF) Connection, in which And2means optionally substituted alkoxycarbonyl group, can be obtained as a result of implementation of the interaction of the compounds of formula (1), in which And2means a halogen atom, with a corresponding alkilany alcohol in an atmosphere of carbon monoxide using a palladium catalyst in the presence of a base in an acceptable solvent.

Can be preferably used palladium catalyst and a base, similar to those described in the above way (EU).

In addition, this reaction can be preferably performed with the addition of l is English, the ligand can be preferably used phosphines described in the above way (EU).

(EC) Connection, in which And2means optionally substituted alkenylphenol group, can be obtained by performing the reaction of a combination of compounds of formula (1), in which And2means a halogen atom, with an appropriate alkene.

The reaction mix can be performed in the presence of palladium catalyst in the presence or in the absence of a base in an acceptable solvent.

Can be preferably used palladium catalyst, similar to that described in the above way (EU).

Can be preferably used basis, similar to that described in the above way (EU), and silver carbonate.

In addition, this reaction can be preferably performed with the addition of the ligand, and the ligand can be preferably used phosphines described in the above way (EU).

(EG') Union2means optionally substituted alkenylphenol group, can be obtained by dehydration of compounds containing hydroxyalkyl group Deputy And2. Dehydration can be accomplished by treating the starting compound with acid.

As the e acid can be used a common acid. For example, there may be preferably used an inorganic acid (for example, chloride-hydrogen acid, nitric acid and sulfuric acid) or organic acid (for example, methanesulfonate acid, para-toluensulfonate acid, acetic acid, triperoxonane acid, triftormetilfullerenov acid and the like).

(EN) Union2means ester Bronevoy acid, can be obtained as a result of implementation of the interaction of compounds in which And2means delete the group, with dialkoxybenzene (trimethoxysilane, triisopropanolamine and the like), dialkoxybenzene (pinacolborane and the like) or tetraalkoxysilane (bis(pinacolato)diboron and the like) in the presence of palladium catalyst. Remove the group includes a halogen atom such as chlorine atom, bromine atom, iodine atom, and substituted sulfonyloxy, such as methanesulfonamido, triftormetilfullerenov and toluensulfonate. This reaction can be performed similarly to the above method (EC).

(EN') Union2means a hydroxyl group, can be obtained as a result of implementation of the interaction of compounds in which And2means ester Bronevoy acid with peroxide. In quality the ve peroxide may be preferably used an aqueous solution of hydrogen peroxide, meta-chloroperbenzoic acid, OXONE™ (DuPont Co. Ltd) and the like.

(EI) Connection, in which And2means CNS group or substituted CNS group, can be obtained by alkoxysilane compounds (1), in which And2means a halogen atom.

Alkoxysilane can be performed with the optional addition of a copper catalyst for interaction with the corresponding alcohol in an acceptable solvent or without solvent in the presence of a base.

Can be preferably used basis, similar to that described in the above way (EU), in particular cesium carbonate.

Can be preferably used copper catalyst comprising copper iodide, copper bromide, copper chloride, copper acetate, triftorbyenzola copper and the like.

In addition, this reaction proceeds more efficiently when adding 1,10-phenanthroline, 2-aminopyridine or the like.

(EJ) Connection, in which And2means optionally substituted alkyl group, optionally substituted heterocyclic group or optionally substituted aryl group, can be obtained by performing the reaction of a combination of compounds of formula (1), in which And2means delete the group, with the corresponding alkylboranes, arylboronic and the heterocyclic Bronevoy acid or the corresponding complex ether of alkylboranes, arylboronic or heterocyclic Bronevoy acid.

The reaction mix can be performed in the presence of a palladium catalyst and in the presence or in the absence of a base in an acceptable solvent.

This reaction can be performed similarly to the above method (EC).

Delete a group similar to the group specified in the method (EN).

(EJ') Union2means optionally substituted alkyl group, optionally substituted heterocyclic group or optionally substituted aryl group, can be obtained by performing the reaction of a combination of compounds of formula (1), in which And2means Bronevoy acid or ester Bronevoy acid, with alkyl, aryl or heterocyclic group containing a group to delete.

The reaction mix can be performed in the presence of a palladium catalyst and in the presence or in the absence of a base in an acceptable solvent. This reaction can be performed similarly to the above method (EU). Delete a group similar to the one mentioned in method (EN).

(EC) Connection, in which And2means alkoxycarbonylmethyl group, can be obtained as a result of implementation of the interaction of the compounds of formula (1), in which And2means a halogen atom,with an alkali metal salt alkoxycarbonylmethyl acid.

Salt of an alkali metal alkoxycarbonylmethyl acid can be obtained by a method described, for example, in the publication Baskin et al., Tetrahedron Lett., 43, 8479 (2002).

In addition, this reaction can be performed in the presence of copper catalyst in an acceptable solvent in the manner described in this publication.

Can be preferably used copper catalyst specified in the method (EI), in particular iodide of copper.

(EL) Compound, in which And2means a group of the formula:

where the symbols have the above meanings, can be obtained by condensing compounds in which And2means a hydroxyl group, with a compound of the formula:

where X11means OF, SO, SO2or NRR(RRmeans a protective group), and q denotes an integer from 1 to 4, with removal if necessary, the protective group for amino group.

As a protective group may be used a conventional protective group, including benzyloxycarbonyloxy group, tert-butoxycarbonyl group and the like.

This reaction can be performed in an acceptable solvent in the presence of phosphines and esters of azodicarboxylic acid. This reaction can be performed similarly to the above method (EA).

For itna group can be removed by a conventional method, including catalytic reduction, treatment with an acid, and the like, depending on the type of the protective group.

The way of transformation And2described in the above reactions (EA)-(EL), if necessary, can be used to turn another Deputy.

In addition, one or more of the substituents of the compounds (1) according to the present invention can be converted by the following methods into other compounds included in the compound (1).

The following methods as can be used in a regular basis and except where otherwise indicated, may be preferably used the basis described in the above method (EA).

In the following the methods as acid can be used conventional acid and except where otherwise indicated, may be preferably used mineral acid, including chloride-hydrogen acid, nitric acid, sulfuric acid, or organic acid represented sulfonic acids (for example, methanesulfonate acid, para-toluensulfonate acid, triftormetilfullerenov acid) or carboxylic acids (e.g. acetic acid, triperoxonane acid).

The following methods can be used any solvent which does not impede done is the reaction preferably the solvent described in the above method (EA).

Remove the group includes a halogen atom such as chlorine atom, bromine atom, iodine atom, and substituted sulfonyloxy, such as methanesulfonamido, triftormetilfullerenov and toluensulfonate.

(E1) a Compound in which a represents a heterocyclic group substituted by an optionally substituted amino group or a group of the formula:

where the symbols have the above meanings, can be obtained by interaction of the compound (1)in which a represents a heterocyclic group substituted by an optionally substituted alkylsulfonates, with a corresponding amine or a compound of the formula:

where the symbols have the above meanings, in the presence of a palladium catalyst and in the presence or in the absence of a base in an acceptable solvent or without solvent.

This reaction can be performed similarly to the above method (EC).

(E2) a Compound in which a represents a heterocyclic group substituted by an optionally substituted amino group or a group of the formula:

where the symbols have the above values, can also be obtained as a result of which westline interaction connection in which a represents a heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates, with a corresponding amine or a compound of the formula:

where the symbols have the above values.

This reaction can be performed with the optional addition of a copper catalyst in the presence or in the absence of a base in an acceptable solvent.

As the copper catalyst can be preferably used copper iodide, copper bromide, copper chloride, copper acetate, triftorbyenzola copper and the like.

Can be preferably used basis, similar to that described in the above way (EU).

In addition, this reaction proceeds more efficiently when adding N,N'-dimethylethylenediamine, 1,10-phenanthroline, ethylene glycol, phenylphenol, and the like.

(E3) a Compound in which a represents a heterocyclic group substituted by an optionally substituted alkylsulfanyl group, can be obtained as a result of implementation of the interaction of compounds in which a represents a heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates, with the corresponding alkylthio.

This reaction can be performed similarly to the above is the method (EI), moreover, it can be preferably lightened by adding 1,10-phenanthroline or ethylene glycol.

(E4) a Compound in which a represents a heterocyclic group substituted by optionally substituted heterocyclic group, can be obtained by performing the reaction of the combination of compounds in which a represents a heterocyclic group substituted by a halogen atom or optionally substituted alkylsulfonates, with the appropriate heterocyclic compound of tin, or a corresponding heterocyclic compound of boron.

This reaction can be performed similarly to the above method (ED) or (EI).

(E5) a Compound in which a represents a heterocyclic group, a substituted CNS group, can be obtained as a result of implementation of the interaction of compounds in which a represents a heterocyclic group substituted by a halogen atom or alkylsulphonyl group, with the appropriate alkali metal alkoxide in an acceptable solvent. The corresponding alkali metal alkoxide can be obtained by treating the corresponding Olkiluoto alcohol hydride of an alkali metal or alkaline metal in the specified solvent.

(E6) a Compound containing aminoalkyl group as the substituent at the position a, the mod is for can be obtained by catalytic reduction of the compound, containing cyano or cyanoaniline the group as a substituent in position A.

Catalytic reduction can be performed by a standard method using the catalyst in a hydrogen atmosphere in an acceptable solvent. The catalyst is a palladium catalyst include palladium carbon, Nickel catalyst comprising Nickel Raney catalyst, a platinum catalyst, comprising platinized charcoal, and the like.

(E7) a Compound containing optionally substituted mono - or dialkylaminoalkyl the group as a substituent in position And can be obtained as a result of implementation of the interaction of compounds containing aminoalkyl group as the substituent at the position a, with the corresponding halogenated mono - or dialkylamino.

This reaction can be performed in an acceptable solvent in the presence of a base.

(E8) a Compound containing optionally substituted monoalkanolamines the group as a substituent in position And can be obtained as a result of implementation of the interaction of compounds containing aminoalkyl the group as a substituent in position And, with the appropriate alkylsulfonates in an acceptable solvent.

(E) Compound containing g is the UPP formula:

where R9means alkyl group and the other symbols have the values indicated above as the substituent in position And can be obtained as a result of implementation of the interaction of compounds containing a group of the formula:

where the symbols have the values indicated above as the substituent in position And, with the appropriate alkylsulfonates (R9NCO). This reaction can be performed similarly to the above method (E8).

(E10) a Compound containing optionally substituted mono - or dialkylimidazolium the group as a substituent in position And can be obtained by condensation of compounds containing aminoalkyl the group as a substituent in position And optionally substituted mono - or dialkylamino when using Carboniferous agent in an acceptable solvent in the presence or in the absence of base.

Can be used carbonyloxy agent, such as carbonyldiimidazole, phosgene, triphosgene and the like.

(E11) the Compound containing morpholinylcarbonyl as Deputy in position And can be obtained by condensation of compounds containing the amino group as the substituent in position And, with morpholine using arboviruses agent in an acceptable solvent. This reaction can be performed similarly to the above method (E10).

(E12) a Compound containing a group of the formula:

where X12means O or NH, as a substituent in position And can be obtained by treating compounds containing a group of the formula:

N-X12-CH2-N-,

where the symbols have the above values, as the substituent in position And, carbonyliron agent in an acceptable solvent.

This reaction can be performed similarly to the above method (E10).

(E12') a Compound containing a group of the formula:

where X12means O or NH, as a substituent in position And can be obtained by treating compounds containing a group of the formula:

N-X12-CH2-CH2-NH-,

where the symbols have the above values, as the substituent in position And, carbonyliron agent in an acceptable solvent.

This reaction can be performed similarly to the above method (E10).

(E13) Compound containing optionally substituted karbamoilnuyu group as a substituent in position And can be obtained by condensation of compounds containing a carboxyl group as the substituent at the position a, with the desired amine.

To density can be performed when using a condensing agent in an acceptable solvent. Can be preferably used a conventional condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole and the like.

In addition, condensation can be more preferably performed by adding an activating agent comprising 1-hydroxybenzotriazole, 1-hydroxysuccinimide and the like.

(E14) the Compound containing a group of the formula:

where the symbols have the above values, as the substituent in position And can be obtained by condensation of compounds containing a carboxyl group as a substituent in position And, with the compound of the formula:

where the symbols have the above values.

This reaction can be performed similarly to the above method (E13).

(E15 motorway) Compound containing tetrazolyl the group as a substituent in position And can be obtained as a result of implementation of the interaction of compounds containing the cyano as a substituent in position And, with the alkali metal azide in the presence of acid in an acceptable solvent.

Azide of an alkali metal includes sodium azide, lithium azide, and the like.

The acid can be preferably used salt ammonium halo is enrevanche hydrogen, such as ammonium chloride.

(E) Compound containing optionally substituted alkyldiethanolamine the group as a substituent in position And may be obtained by alkylation of compounds containing tetrazolyl the group as a substituent in position A.

The alkylation can be performed similarly to the above method (EA).

(E17) Compound containing optionally substituted by an amino group or a group of the formula:

where the symbols have the above values, as the substituent in position And can be obtained as a result of implementation of the interaction of compounds containing halogen atom or optionally substituted alkylsulfonate as Deputy in position And, with a corresponding amine or a compound of the formula:

where the symbols have the above values.

This reaction can be preferably performed in the presence or in the absence of a base in an acceptable solvent.

(E18) Compound containing optionally substituted by alkylamino or a group of the formula:

where R13means alkyl group, optionally substituted hydroxyl group, alkoxycarbonyl group, morpholinyl group and phenyl group is Oh, and n has the values above as the substituent in position And can be obtained as a result of implementation of the interaction of compounds containing an amino group or a group of the formula:

where the symbols have the above values, as the substituent in position And, with the appropriate alkylhalogenide or corresponding complex alkilany ether sulfonic acid.

Can be preferably used complex alkalemia esters of sulfonic acid, including ester methanesulfonic acid, ester toluensulfonate acid, ester triftormetilfullerenov acid and the like.

This reaction can be preferably performed in the presence or in the absence of a base in an acceptable solvent.

(E19) a Compound containing a group of the formula:

where X13means O or NH, and another character has the values above as a substituent in position And can be obtained by shorting rings in the compound containing a group of the formula:

Z3-(CH2)n-X13-CH2-CONH-,

where Z3means delete the group, and other symbols have the above values, as the substituent in position A.

This reaction can be preferably is accomplished in the presence or in the absence of a base in an acceptable solvent.

(E20) the Compound containing a carboxyl group as a substituent in position And may be obtained by hydrolysis of compounds containing alkoxycarbonyl the group as a substituent in position A.

The hydrolysis may be carried out by treating the starting compound with base or acid in an acceptable solvent in the usual way. As can be preferably used an alkali metal hydroxide.

(E21) the Compound containing a carboxyl group as a substituent in position And may be obtained by hydrolysis of compounds containing the cyano as a substituent in position A.

The hydrolysis may be carried out by treating the starting compound with an acid or a base in an acceptable solvent.

(E22) Compound containing karbamoilnuyu group as a substituent in position And may be obtained by hydrolysis of compounds containing the cyano as a substituent in position A.

The hydrolysis may be carried out by treating the starting compound with an acid or a base in an acceptable solvent.

(E) Compound containing carboxialkilnuyu group as a substituent in position And may be obtained by catalytic reduction of compounds containing carboxyaniline group, insulationmaterial group or benzyloxycarbonylamino the group as a substituent in position A.

Catalytic reduction can be carried out similarly to the above method (E6).

(E) a Compound containing a hydroxyl group as a substituent in position And may be obtained by hydrolysis of compounds in which a contains alkanoyloxy.

The hydrolysis can be performed similarly to the above method (E20).

(E25) a Compound containing sulfoxide (SO) or sulfon (SO2in the substituent in position And may be obtained by oxidation of compounds containing S in the substituent in position (for example, a compound containing thiomorpholine group or alkylsulfonyl the group as a substituent in position A).

The oxidation may be carried out by treating the starting compound oxidant in an acceptable solvent.

As a developer can be preferably used peroxides such as hydrogen peroxide, meta-chloroperbenzoic acid, acetylhydrolase and the like.

(E) a Compound containing N-oxide in the substituent in position And may be obtained by oxidation of compounds containing N substituent in position (for example, a compound containing pyridyloxy the group as a substituent in position A).

The oxidation can be performed similarly to the above method (E25).

(E27) Connection, the soda is containing 1,2-dihydroxyethylene the group as a substituent in position And, can be obtained by treating compounds containing alkyl group, a substituted mono - or dialkyldiphenyl group as the substituent at the position a, the acid in an acceptable solvent.

In addition to the above acids may also be preferably used strong resin acid.

(E28) Compound containing alkyl group substituted with hydroxyl group, and optionally substituted CNS group as substituents in position And can be obtained as a result of implementation of the interaction of compounds containing oxiranemethanol the group as a substituent in position And, with the alkali metal salt of the appropriate alcohol in an acceptable solvent.

Salt of an alkali metal alcohol includes a lithium salt, sodium salt, potassium salt and the like.

(E) Compound containing alkyl group, a substituted hydroxyl group and amino group, or alkyl group substituted with hydroxyl group, and optionally substituted mono - or dialkylamino, as substituents in position And can be obtained as a result of implementation of the interaction of compounds containing oxiranemethanol the group as a substituent in position And, with ammonia or the corresponding mono - or dialkylamino in an acceptable solvent.

(the 30) Connection, containing hydroxycarbamoyl the group as a substituent in position And can be obtained as a result of implementation of the interaction of compounds containing the cyano as a substituent in position And, with hydroxylamine or its salt in an acceptable solvent. Can be used any solvent which does not impede the implementation of the reaction, and, in particular, can be preferably used a solvent described in the above method (EA).

(E) Compound containing oxodegradable the group as a substituent in position And can be obtained as a result of implementation of the interaction of compounds containing hydroxycarbamoyl the group as a substituent in position And, with Carboniferous agent in an acceptable solvent in the presence or in the absence of base.

Can be used carbonyloxy agent, similar to those described in the above method (E10).

(E) the Compound containing alphagroup as Deputy in position And may be obtained by hydrolysis of compounds containing alkoxycarbonylmethyl the group as a substituent in position A.

The hydrolysis can be performed similarly to the above method (E20).

(E) Compound containing sulfamoyl group as replaces the La in position And, can be obtained by condensation of compounds containing alphagroup as Deputy in position A, with the desired amine.

The condensation may be carried out by treating the compounds containing alphagroup as Deputy in position And, halogenation agent in an acceptable solvent and subsequent implementation of the interaction of the compounds with the desired amine in the presence or in the absence of base.

Can be used conventional halogenation agent, including thionylchloride, oxychlorine phosphorus or the like.

(E34) a Compound containing a hydroxyalkyl group as a substituent in position And can be obtained by recovering compounds containing carboxialkilnuyu group as a substituent in position A, or conversion of carboxyl groups in the acid anhydride or ester and subsequent reduction of the obtained compound.

The transformation of the acid anhydride may be carried out as a result of implementation of the interaction of the initial compounds with halogenated alkylphosphates in an acceptable solvent in the presence of a base.

The transformation of the ester can be performed as a result of implementation of the interaction of the parent compound with an alcohol in the presence of a condensing agent priemlemom solvent. This process can be performed similarly to the method (A) except for the use of the desired alcohol amine instead.

Recovery may be performed by treating the compounds obtained by the reducing agent in an acceptable solvent.

As a reducing agent can be preferably used borhydride (e.g., sodium borohydride), hydrides of aluminum (alumoweld lithium hydride diisobutylaluminum and the like).

(E) a Compound containing an aromatic group substituted with cyano as a substituent at R1not necessarily containing one to three heteroatoms independently selected from oxygen atom, sulfur atom and nitrogen atom (hereinafter referred to as “aromatic group”), can also be obtained by cyanation of the compound containing an aromatic group substituted by halogen atom as a substituent at R1.

Cyanide can be performed similarly to the above method ().

(E36) Compound in which a represents a hydrogen atom, can be obtained by treatment with acid or reconnection, in which a represents tert-butoxycarbonyl group or benzyloxycarbonyl group.

The acid treatment can be performed similarly to the above method (E27), and recovery can b shall be performed similarly to the above method (a).

(E) Compound in which a represents optionally substituted alkoxycarbonyl group or optionally substituted karbamoilnuyu group, can be obtained as a result of implementation of the interaction of compounds in which a represents a hydrogen atom, with Carboniferous agent, the required alcohol or desired amine in an acceptable solvent.

This reaction can be performed similarly to the above method (E10).

(E38) a Compound containing an amino group as a substituent in position And can be obtained by performing rearrangement of kurzius in the compound containing a carboxyl group as the substituent at position A.

The rearrangement reaction of kurzius can be performed using conventional aidarous agent (for example, diphenylphosphoryl and the like) in an appropriate solvent in the presence of a base.

This reaction can be also performed with the addition of alcohols to obtain compounds containing optionally substituted by alkoxycarbonylmethyl as Deputy in position And, with the subsequent removal alkoxycarbonyl group.

Alkoxycarbonyl group can be removed in the usual way, such as treatment with an acid or recovery depending on the type of the removed alkoxycarbonyl groups is. The acid treatment can be performed similarly to the above method (E27), and recovery can be performed similarly to the above method (a).

(E39) a Compound containing a hydroxyl group as a substituent in position And may be obtained by catalytic recovery of compounds containing benzyloxy as Deputy in position A. the Recovery may be performed similarly to the above method (a).

(E40) a Compound containing oxoprop as Deputy in position And may be obtained by oxidation of compounds containing a hydroxyl group as a substituent in position A.

The oxidation can be performed with the use of an oxidant in an acceptable solvent.

As a developer can be used conventional oxidant such as complex chromate and pyridine, chlorproma pyridinium, pyridinium dichromate, reagent dessa-Martin (1,1,1-Tris(acetoxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one), dimethylsulfoxide and the like.

(E) Compound containing optionally substituted CNS group as a substituent in position And may be obtained by alkylation of compounds containing oxoprop or hydroxyl group as a substituent in position A.

The alkylation can be carried the network using the appropriate connection similar to the above method (EA).

(E') a Compound containing optionally substituted by geterotsiklicheskikh or optional substituted alloctype as Deputy in position And can be obtained by performing the reaction of a combination of compounds containing a hydroxyl group as a substituent in position A, with the corresponding aryl compound or heterocyclic compounds containing a group to delete.

The reaction mix can be performed similarly to the above method (EC).

Remove the group has values similar to those described in the above way (EN).

(E) Compound containing optionally substituted by alkanolamines as Deputy in position And can be obtained by condensation of compounds containing the amino group as the substituent in position And, with the appropriate carboxylic acid or its reactive derivative.

Condensation with the corresponding carboxylic acid can be preferably performed in an acceptable solvent in the presence of a condensing agent. This reaction can be performed similarly to the above method (E13).

In addition, condensation with a reactive derivative of the corresponding carboxylic acid can be performed in an acceptable solvent or without solvent is in the presence or in the absence of base.

Reactive derivative include acid halide, acid anhydride, activated ester, activated amide, and the like.

(E43) a Compound containing a group of the formula:

where R14means alkanoyloxy group, optionally substituted hydroxyl group or CNS group, and n has the values above as the substituent in position And can be obtained by condensation of compounds containing a group of the formula:

where the symbol has the values above as the substituent in position And, with the appropriate carboxylic acid or its reactive derivative.

This reaction can be performed similarly to the above method (A).

(E) Compound containing maleimido the group as a substituent in position And can be obtained as a result of implementation of the interaction of compounds containing the amino group as the substituent in position And, with maleic anhydride. This reaction can be performed in an acceptable solvent.

(E) Compound containing alkyl group, substituted peredelnoj group, and a hydroxyl group as substituents in position And may be obtained by communicating soy is inane, containing alkyl group, substituted peredelnoj group in which the nitrogen atom is oxidized, as a substituent in position And, with triperoxonane anhydride. This reaction can be performed in an acceptable solvent.

(E) a Compound containing a halogen atom as a substituent in position And can be obtained by treating compounds containing a hydroxyl group as a substituent in position And, halogenation agent.

As the halogenation agent can be preferably used conventional halogenation agent include thionyl chloride, phosphorus oxychloride, and tetravalent carbon (e.g. carbon tetrachloride, tetrabromide carbon and the like) and phosphines (e.g. triphenylphosphine, trailerforum, triethylphosphine and the like).

(E') a Compound containing a halogen atom as a substituent in position And can be obtained by treating compounds of halogenation agent. As the halogenation agent can be preferably used conventional halogenation agent, such as bromine, N-bromosuccinimide, and the like.

(E) Compound containing cyanoaniline the group as a substituent in position And can be obtained by recovering compounds containing cyanoacetylene group as the batch is of Italia in position A.

Recovery may be performed by treating the starting compound with the reducing agent or by catalytic reduction in an acceptable solvent.

It may be preferable to use a reducing agent provided that it restores only the double bond without affecting the cyano. For example, bis(2-methoxyethoxy)alumoweld sodium in the presence of copper bromide.

Catalytic reduction can be carried out similarly to the above method (a).

(A) Compound (1)containing a hydroxyalkyl group as a substituent in position And can be obtained by recovering the compound containing a formyl group as a substituent in position A.

Recovery may be performed by treating the starting compound with the reducing agent in an acceptable solvent.

This reaction can be performed similarly to the above method (E34).

(E) Compound in which the substituent in position is a hydroxyl group, can be obtained by demethylation of compounds in which the substituent in position is metaxylene group.

Demethylation can be carried out by treating the starting compound demetrious agent in an acceptable solvent.

As demetrious agent can be the used conventional reagent, including trimethylsilylmethyl, hydrogen bromide/acetic acid, tribromide boron, concentrated sulfuric acid, and the like.

(E50) Compound in which the substituent in position is optionally substituted CNS group, can be obtained by alkylation of compounds in which the substituent in position is a hydroxyl group.

The alkylation can be performed similarly to the above method (EA).

(E) Compound in which the substituent in position is optionally substituted by alkylsulfonamides, can be obtained by alkylsulfonate compounds in which the substituent in position is a hydroxyl group.

Alkylsulfonamides can be achieved by interaction of the corresponding alkylhalogenide or the corresponding anhydride alkylsulfonic acid in an acceptable solvent in the presence or in the absence of base.

(E) Compound in which the substituent in position is cyano, can be obtained by cyanation of the compound in which the substituent in position is optionally substituted by alkylsulfonamides.

Cyanide can be performed similarly to the above method ().

(E) Connection, which mandated the tel in the situation is aminoalkyl group, can be obtained by reconnection, in which the substituent in position is cyano.

Recovery may be performed similarly to the above method (E6).

(E) Compound in which the substituent in position is an alkyl group, can be obtained by alkylation of compounds in which the substituent in position is optionally substituted by alkylsulfonamides.

The alkylation can be performed in the interaction alkylamine in the presence of a palladium catalyst, of a silver catalyst and a copper catalyst in an acceptable solvent.

As the palladium catalyst can be preferably used tetrakis(triphenylphosphine)palladium, a silver catalyst can be preferably used silver carbonate, as the copper catalyst can be preferably used chloride of copper(I).

(E') a Compound in which the substituent in position is optionally substituted alkyl group, can be obtained by catalytic reduction of the compound in which the substituent in position is optionally substituted alkenylphenol group. This reaction can be performed similarly to the above method (E6).

(E55) is Obedinenie, containing imidazolylalkyl group or oxazolidinyl the group as a substituent in position And may be obtained (i) as a result of implementation of the interaction of compounds containing the cyano as a substituent in position And with the desired alcohol in the presence of acid in an acceptable solvent or without solvent with the formation of compounds containing alkoxycarbonyl group as the substituent at the position a, and (ii) as a result of implementation vzaimodeystviya compounds containing alkoxycarbonyl group as the substituent at the position a, with 2 aminoethanol or Ethylenediamine in an acceptable solvent or without solvent.

(E) Compound containing a carboxyl group as a substituent in position And may be obtained (i) by oxidation of compounds containing a hydroxyalkyl group as a substituent in position And, similarly to the above method (E40) with the formation of compounds containing oxoprop as Deputy in the position a, and (ii) by oxidation of compounds containing oxoprop as Deputy in position A.

Oxidation of the second method can be accomplished by the use of an oxidant in an acceptable solvent. As a developer can be preferably used sodium chloride, oxide ser the bra(I), periodate sodium and the like.

(E) Compound containing a carboxyl group as a substituent in position And can be directly obtained by oxidation of compounds containing a hydroxyalkyl group as a substituent in position A.

The oxidation can be carried out using as the developer of the Jones reagent, potassium permanganate, and the like.

(E) Compound in which a represents a hydrogen atom, can be obtained by treating compounds in which a represents ethoxycarbonyl group, with similaroriginal or base. As silicalite can be preferably used trimethylsilylmethyl. As can be preferably used sodium hydroxide.

In each of the above-described production method of compound (1) sensitive functional group is any connection can be protected in the usual way, is suitable for this case. Protective groups and their use are described in the publication Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.

In the case of protection of the amino group benzyloxycarbonyloxy group, the protective group can be removed by catalytic reduction in a hydrogen atmosphere in an acceptable solvent.

In the case of protection of hydroxyl group, benzyl group, the protective group can is to be removed by catalytic reduction similar to the above method.

In the case of protection of the amino group, tert-butoxycarbonyl group, the protective group can be removed by treating the starting compound with acid (for example, chloride-hydrogen acid, triperoxonane acid, toluensulfonate acid and the like) in an acceptable solvent.

In the case of protection of the hydroxyl group tetrahydropyranyloxy group, the protective group can be removed by treating the starting compound with acid similarly to the above method.

Other substituents of the compounds (1) according to the present invention can be converted similarly to the above reactions (E1)-(e) the conversion of the above groups.

[Compound (6')]

Connection (6') can be obtained similar to that described below the method (a) or (b).

(a) Compound (6') can be obtained as a result of implementation of the interaction of compounds of General formula (10):

where XA4means delete the group, and other symbols have the above meanings, with a compound of General formula (11):

N-R2(11)

where the symbol has the above values, similarly to the above method I-1, or the way I'-1.

(b) Compound (6') can be obtained as a result of implementation of the interaction of compounds of General formula (12):

Recovery and oxidation in the above methods can be performed by a standard method.

[Compound (2)]

Compound (2) can be obtained by oxymorphine connection (6') with the formation of compounds of General formula (13):

where the symbols have the above values, with subsequent reduction of the obtained compound.

Oxymorphine can be performed by standard methods of oxymorphine, for example, by treating the compound (6') hydroxylamine salt in the presence of acids or bases, such as alkali metal hydroxide, sodium acetate or pyridine, in alcohol, acetic acid or pyridine. In addition, as an agent to obtain the salt of the hydroxylamine may be used any acidic substance, such as mineral acid (e.g. sulfuric acid, phosphoric acid, hydrogen bromide and hydroiodide) and organic acid (e.g. acetic acid, oxalic acid, trichloroacetic acid, methanesulfonate acid, para-toluensulfonate acid, 1,5-naphthalenedisulfonic acid).

Subsequent reaction vosstanovlenie which may be made in the usual way.

The compound (2) can also be obtained from compound (6”) method for the synthesis of Gabriel, described in detail in the publication Mitsunobu, O. Comp. Org. Syn. 1991, 6, 79-85.

[Connection (6""')]

Connection (6""') can be obtained from compounds of General formula (14):

where XA5means delete the group, and other symbols have the above values, the result of the implementation of the standard reaction include carbon monoxide using a catalyst based on a transition metal.

This reaction can be performed in an aprotic solvent such as tetrahydrofuran or DMF and the like. Preferred transition metal includes, for example, a palladium salt such as palladium(II) acetate and the like, or a compound of palladium(0), such as tetrakis(triphenylphosphine)palladium and the like. The reaction include carbon monoxide of this type can be carried out by the method described in the publication J. Org. Chem. 1992, 57, 5979 or "Organometallic compound-Synthesis and Application-(Tokyo Called Dozin Co., Ltd.), Metal-catalyzed Cross-coupling Reaction (WILLY-VCH), Handbook of Palladium-Catalyzed Organic Reactions (Academic Press)and the like.

The compound (1-a), where A1means tetrazolyl group and2means a hydrogen atom, can be obtained by zenderoudi the above compound (8') forming a connection obatala (8””):

where the symbols have the above values, with the subsequent implementation of the interaction with the azide of an alkali metal.

Zenderoudi can be made in the implementation of the interaction of initial connection halogenation in the presence of a base in an acceptable solvent.

Halogenation preferably is brazian.

As can be preferably used a common base such as a carbonate of an alkali metal (e.g. potassium carbonate or bicarbonate of an alkali metal (e.g. sodium bicarbonate).

The solvent may be any solvent which does not impede the implementation of the reaction, and preferably can be used a solvent represented by the above method I.

Cyano can be converted into tetrazolyl group as a result of the implementation of the interaction of compounds containing the cyano, azide of alkali metal in the presence of acid in an acceptable solvent.

Azide of an alkali metal includes sodium azide, lithium azide, and the like.

The acid can be preferably used salt ammonium galogenirovannami hydrogen, such as ammonium chloride.

In addition, for evaluation of performance of the above ways m which should apply to the international PCT publications WO04/020393, WO05/100298 and to the patent application of Japan 2003-221376 A.

Methods for obtaining compounds (1) are applicable to obtain the corresponding compounds of the formula (I-A), (I-B) and (1-I).

Many of the source materials and reagents used for the above compounds of formula 1, can be purchased commercially or described in the scientific literature and can be easily obtained by the method described in the scientific literature or commonly used in organic synthesis.

Experimental part

When performing this experiment was to test the activity of inhibiting SETR compounds of the present invention.

Getting acceptor microemulsions

Mixed solution of 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (3.5 mg), cholesterolaemia (3 mg) and triolein (0.7 g) in chloroform and the lipid was subjected to air drying in a nitrogen atmosphere to remove solvent. Then was added 1,4-dioxane (0.25 ml) and the mixture was stirred for dissolution. The obtained lipid solution (0.2 ml) was slowly injected with using a Hamilton syringe under the surface of the buffer solution of Tris-saline-EDTA (TSE) [10 mm Tris/HCl (pH 7.4), 0.15 M NaCl, 2 mm EDTA] (10 ml) with sonication in a bath with ice. The solution was treated with ultrasound in a bath with ice for 1 hour and then kept at 4°C.

Obtaining donor micromol is AI

Mixed solution of egg PC (phosphatidylcholine) (0.33 mg) and BODIPY-CE (0,62 mg) in chloroform. The solvent was removed, exposing the lipid air drying in a nitrogen atmosphere, was added a buffer solution TSE (3 ml) and the solution was treated with ultrasound in a bath with ice. This solution was sterilized by filtration through 0.22 μm filter and stored at 4°C.

Activity inhibition SETR in vitro

The test solution was obtained using dimethyl sulfoxide as a solvent. Plasma obtained from healthy volunteers, were bred to 0.64% TSE buffer, to the obtained solution plasma (187 μl) was added to the test solution (3 µl) or only the solvent and incubated at 37°C for 24 hours. Then added buffer solution TSE (10 μl)containing 5% donor microemulsions and 5% acceptor microemulsions, and the mixture is incubated at 37°C for 3 hours. Before and after incubation was measured intensity of fluorescence at the wavelength of excitation 550 nm and emission wavelength of 600 nm. Activity SETR was determined as the difference between measurements performed before incubation and after incubation. Reduction of the difference in the sample was determined as the degree of inhibition activity SER. IC50for each sample was calculated taking into account the degree of inhibition activity SER. Based on the results of this experiment it was found, chesedonia, presented in the examples are characterized by the activity of inhibiting SETR when the value of the IC50less than or equal to 50 microns.

Examples

The present invention is illustrated in more detail by examples and reference examples, which do not limit the scope of the invention.

Example 1

(1) 2-Fluoro-5-triftormetilfosfinov (2.7 g) and ethyl-(2-methoxyethyl)Amin (2,18 g) dissolved in toluene (20 ml), add potassium carbonate (of 5.83 g) and the mixture was stirred at 120°C during the night. The reaction solution is cooled to room temperature, add ethyl acetate and a saturated salt solution, the mixture is separated, the organic layer was washed with saturated salt solution, the mixture is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), while receiving 2-[ethyl-(2-methoxyethyl)amino]-5-triftormetilfosfinov (3.75 g). MS (m/z): 276 [M+H]+.

(2) 2-[Ethyl-(2-methoxyethyl)amino]-5-triftormetilfosfinov (3.7 g), 3,5-bis-triftormetilfosfinov (to 4.23 g), acetic acid (1,15 ml) dissolved in 1,2-dichloroethane (30 ml), add borohydride createtextarea (of 5.68 g) at room temperature and the mixture is stirred at room temperature overnight. To the reaction solution was added methylene chloride and saturated aqueous sodium bicarbonate solution, MES share, the organic layer was washed with saturated salt solution, the mixture is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), get {2-[(3,5-bis-triphtalocyaninine)methyl]-4-triptoreline}ethyl-(2-methoxyethyl)Amin (3,38 g), MS (m/z): 503 {M+H]+.

(3) {2-[(3,5-Bis-triphtalocyaninine)methyl]-4-trifluoromethyl-phenyl}ethyl-(2-methoxyethyl)Amin (3,37 g), 5-bromo-2-chloropyrimidine (2.6 g) and N-ethyldiethanolamine (3,51 ml) dissolved in toluene (50 ml) and the mixture was stirred at 120°C during the night. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, the mixture is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→19:1), while receiving (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-{2-[ethyl-(2-methoxyethyl)amino]-5-trifloromethyl}amine (4,06 g). MS (m/z): 659/661 [M+H]+.

(4) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-{2-[ethyl-(2-methoxyethyl)amino]-5-trifloromethyl}amine (350 mg) was dissolved in toluene (5 ml), add Tris(dibenzylideneacetone)dipalladium (49 mg), tert-piperonyl sodium (77 mg), 2-(di-tert-builtof the but)biphenyl (63 mg) and ethylpiperidine-4-carboxylate (119 μl) and the mixture stirred in a stream of nitrogen at room temperature over night. To the reaction solution was added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→3:1), thus obtaining the ethyl 1-[2-((3,5-bis-trifloromethyl)-{2-[ethyl-(2-methoxyethyl)amino]-5-trifloromethyl}amino)pyrimidine-5-yl]piperidine-4-carboxylate (212 mg). MS (m/z): 736 [M+H]+.

(5) Ethyl 1-[2-((3,5-bis-trifloromethyl)-{2-[ethyl-(2-methoxyethyl)amino]-5-trifloromethyl}amino)pyrimidine-5-yl]piperidine-4-carboxylate (205 mg) was dissolved in ethanole (2 ml)is added 2 n aqueous sodium hydroxide solution (418 μl) and the mixture is stirred at room temperature overnight. Then add ethyl acetate and a saturated aqueous solution of citric acid, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:1→0:1), while receiving 1-[2-((3,5-bis-trifloromethyl)-{2-[ethyl-(2-methoxyethyl)amino]-5-trifloromethyl}amino)pyrimidine-5-yl]piperidine-4-carboxylic acid (155 mg). The obtained carboxylic acid is dissolved in ethanol (1 ml), to which ablaut 2 n aqueous sodium hydroxide solution (110 μl) and the reaction solution was concentrated under reduced pressure, thus the sodium salt of 1-[2-((3,5-bis-trifloromethyl)-{2-[ethyl-(2-methoxyethyl)amino]-5-trifloromethyl}amino)pyrimidine-5-yl]piperidine-4-carboxylic acid (159 mg). MS (m/z):706 [M-Na]-.

Example 2

(1) 2-Fluoro-5-triftormetilfosfinov (5.0 g) and butylethylamine (3,95 g) dissolved in toluene (50 ml), add potassium carbonate (10,78 g) and the mixture heated under reflux overnight. The reaction solution is cooled to room temperature, add water and diethyl ether, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining 2-(butylamino)-5-triftormetilfosfinov (6,54 g). MS (m/z): 274 [M+H]+.

(2) 2-(Butylamino)-5-triftormetilfosfinov (6.5 g), 3,5-bis-triftormetilfosfinov (7,52 g), acetic acid (2,04 ml) dissolved in 1,2-dichloroethane (50 ml), add borohydride createtextarea (10,1 g) at room temperature and the mixture is stirred for 2 hours. To the reaction solution was added 1 n aqueous sodium hydroxide solution and methylene chloride, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. About what occasioned the residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), get {2-[(3,5-bis-triphtalocyaninine)methyl]-4-triptoreline}butylethylamine (10,48 g). MS (m/z): 501 [M+H]+.

(3) {2-[(3,5-Bis-triphtalocyaninine)methyl]-4-triptoreline}butylethylamine (4.6 g), 5-bromo-2-chloropyrimidine (of 3.56 g) and N-ethyldiethanolamine (4.8 ml) dissolved in toluene (100 ml) and the mixture heated under reflux overnight. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→9:1), while receiving (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-[2-(butylamino)-5-trifloromethyl]amine (5,24 g). MS (m/z): 657/659 [M+H]+.

(4) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-[2-(butylamino)-5-trifloromethyl]amine (3.0 g), complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and methylene chloride (112 mg), potassium acetate (1,34 g) and bis(pinacolato)LIBOR (1,74 g) dissolved in dimethyl sulfoxide (20 ml), the mixture is heated to 80°C. in a nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature, add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated what astora salt, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (70 ml) and added dropwise a 30% aqueous hydrogen peroxide solution (15 ml) under cooling with ice. After one hour add saturated aqueous sodium thiosulfate solution under ice cooling to absorb excess hydrogen peroxide, then add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and contentious under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→3:1), while receiving 2-{(3,5-bis-trifloromethyl)-[2-(butylethylamine)5-trifloromethyl]amino}pyrimidine-5-ol (263 mg). MS (m/z): 595 [M+H]+.

(5) 2-{(3,5-Bis-trifloromethyl)-[2-(butylamino)-5-trifloromethyl]amino}pyrimidine-5-ol (150 mg) and ethyl 4-bromobutyrate (44 μl) dissolved in N,N-dimethylformamide (3 ml), add potassium carbonate (42 mg) and the mixture is stirred at room temperature overnight. Then add ethyl acetate and a saturated salt solution, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→3:1), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(butylamino)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (117 mg). MS (m/z): 709 [M+H]+.

(6) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(butylamino)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (110 mg) was dissolved in ethanol (2 ml)is added 2 n aqueous sodium hydroxide solution (233 μl) and the mixture is stirred at room temperature overnight. Then add ethyl acetate and a saturated aqueous solution of citric acid, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 9:1 to 7:3), thus obtaining 4-(2-{(3,5-bis-trifloromethyl)-[2-(butylamino)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (69 mg). The obtained carboxylic acid is dissolved in ethanol (0.2 ml), is added 2 n aqueous sodium hydroxide solution (50 μl) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt of 4-(2-{(3,5-bis-trifloromethyl)-[2-(butylamino)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (70 mg). MS (m/z): 679 [M-Na]-.

Example 3

(1) 2-{(3,5-Bis-trifloromethyl)-[2-(cyclohexyldimethylamine)-5-tripto methylbenzyl]amino}pyrimidine-5-ol (250 mg) and 3-bromo-1-propanol (43 μl) dissolved in N,N-dimethylformamide (1 ml), add potassium carbonate (65 mg) and the mixture is stirred at room temperature overnight. Then add ethyl acetate and a saturated salt solution, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→3:1), while receiving 3-(2-{(3,5-bis-trifloromethyl)-[2-(cyclohexyldimethylamine)-5-trifloromethyl]amino}pyrimidine-5-yloxy)propan-1-ol (150 mg). MS (m/z): 693 [M+H]+.

(2) 3-(2-{(3,5-Bis-trifloromethyl)-[2-(cyclohexyldimethylamine)-5-trifloromethyl]amino}pyrimidine-5-yloxy)propan-1-ol (140 mg) is dissolved in methylene chloride (2 ml), added 1,1,1-Tris(atomic charges)-1,1-dihydro-1,2-benzodioxol-3-(1H)-he (188 mg) at room temperature and the mixture is stirred at room temperature overnight. Then add ethyl acetate and a saturated salt solution, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in a mixed solvent of tert-butanol (4 ml) and water (1 ml)is added 2-methyl-2-butene (128 μl), dihydrate sodium dihydrophosphate (44 mg) and sodium chlorite (73 mg) and the mixture is stirred at room temperature for the of 30 minutes. Then add ethyl acetate and 1 n solution of chloride-hydrogen of the acid, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→2:3), while receiving 3-(2-{(3,5-bis-trifloromethyl)-[2-(cyclohexyldimethylamine)-5-trifloromethyl]amino}pyrimidine-5-yloxy)propionic acid (60 mg). The obtained carboxylic acid is dissolved in ethanol (0.5 ml), was added 1 n aqueous solution of sodium hydroxide (85 ml) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt of 3-(2-{(3,5-bis-trifloromethyl)-[2-(cyclohexyldimethylamine)-5-trifloromethyl]amino}pyrimidine-5-yloxy)propionic acid (60 mg). MS (m/z): 705 [M-Na]-.

Example 4

(1) Ethyl 4-{2-[[2-(benzylideneamino)-5-trifloromethyl]-(3,5-bis-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (4,07 g) dissolved in ethanol (60 ml), add 10% palladium carbon (500 mg) and the mixture is stirred in hydrogen atmosphere at room temperature for 30 minutes. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 19:1→17:3), on the of learn while ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-ethylamino-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (3.1 g). MS (m/z): 653 [M+H]+.

(2) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-ethylamino-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (200 mg) and pyridine (371 μl) dissolved in methylene chloride (5 ml) and add ethylchloride (293 μl) under ice cooling. The reaction solution was stirred at room temperature overnight and the organic solvent is concentrated under reduced pressure. To the residue is added ethyl acetate and aqueous citric acid solution and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(ethoxycarbonylmethylene)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (176 mg). MS (m/z): 725 [M+H]+.

(3) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(ethoxycarbonylmethylene)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (170 mg) was dissolved in ethanol (2 ml)is added 2 n aqueous sodium hydroxide solution (352 μl), the mixture is stirred at room temperature for 1.5 hours and concentrated under reduced pressure. To the residue is added ethyl acetate and 1 n solution of chloride-hydrogen of the acid, the mixture is separated, the organic layer was washed with saturated RA is tworoom salt, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining 4-(2-{(3,5-bis-reformational)-[2-(ethoxycarbonylmethylene)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (147 mg). The obtained carboxylic acid is dissolved in ethanol (1 ml)is added 2 n aqueous sodium hydroxide solution (106 ml) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt of 4-(2-{(3,5-bis-trifloromethyl)-[2-(ethoxycarbonylmethylene)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (151 mg). MS (m/z): 695 [M-Na]-.

Example 5

(1) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-ethylamino-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (100 mg) and pyridine (19 ml) is dissolved in methylene chloride (1 ml) and add butyrylcholine (19 μl) at room temperature. The reaction solution was stirred at room temperature for 30 minutes, add methylene chloride and 1 n solution of chloride-hydrogen acid and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(butylethylamine)-5-trifloromethyl]amino}pyrimid is n-5-yloxy)butyrate (84 mg). MS (m/z): 723 [M+H]+.

(2) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(butylethylamine)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (78 mg) was dissolved in ethanol (1 ml)is added 2 n aqueous sodium hydroxide solution (162 μl) and the mixture is stirred at room temperature for 3 hours. Then add ethyl acetate and 1 n solution of chloride-hydrogen of the acid, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining 4-(2-{(3,5-bis-trifloromethyl)-[2-(butylethylamine)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid. The obtained carboxylic acid is dissolved in ethanol (0.5 ml), is added 2 n aqueous sodium hydroxide solution (47 ml) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt of 4-(2-{(3,5-bis-trifloromethyl)-[2-(butylethylamine)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (68 mg). MS (m/z): 693 [M-Na]-.

Example 6

(1) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-ethylamino-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (200 mg) and triethylamine (51 μl) dissolved in methylene chloride (1 ml) and add a small amount of triphosgene (36 mg) at room temperature. The reaction solution was stirred at room temperature in those who tell 10 minutes and concentrated under reduced pressure. The residue is dissolved in tetrahydrofuran (1 ml)is added 2 M solution of ethylamine in tetrahydrofuran (1 ml) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution was added ethyl acetate and 1 n solution of chloride-hydrogen of the acid, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→1:1), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(1,3-diethylurea)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (181 mg). MS (m/z): 724 [M+H]+.

(2) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(1,3-diethylurea)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (165 mg) was dissolved in ethanol (3 ml)is added 2 n aqueous sodium hydroxide solution (342 μl) and the mixture is stirred at room temperature overnight. To the reaction solution was added ethyl acetate and 1 n solution of chloride-hydrogen of the acid, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→17:3), while receiving 4-(2-{(3,5-bis-trifloromethyl)-[2-(1,3-diethylurea)5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (68 mg). MS (m/z): 696 [M+H]+.

Example 7

(1) 2-Fluoro-5-triftormetilfosfinov (1.3 g) and cyclopropanemethylamine (1,15 g) dissolved in toluene (13 ml), add potassium carbonate (2,81 g) and the mixture was stirred at 120°C during the night. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→97:3), thus obtaining 2-(cyclopropylamino)-5-triftormetilfosfinov (1.7 g). MS (m/z): 286 [M+H]+.

(2) 2-(Cyclopropylamino)-5-triftormetilfosfinov (1,69 g) dissolved in ethanol (10 ml), add sodium borohydride (224 mg) and the mixture is stirred for 15 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in methylene chloride (10 ml), add thionyl chloride (492 μl) under ice cooling and the mixture is stirred for 10 minutes. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (2.7 g) was dissolved in N,N-dimethylformamide (10 ml), add sodium hydride (62%) (343 mg) at room temperature and the mixture is stirred for 30 minutes. Then added dropwise a solution of the residue obtained above in N,N-dimethylformamide (10 ml) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution was added ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→9:1), while receiving (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-[2-(cyclopropylamino)-5-trifloromethyl]amine (3,38 g). MS (m/z): 669/671 [M+H]+.

(3) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-[2-(cyclopropylamino)-5-trifloromethyl]amine (3,35 g), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (817 mg), potassium acetate (1.47 g), bis(pinacolato)LIBOR (2,54 g) dissolved in dimethyl sulfoxide (20 ml), the mixture is heated to 80°C in atmosphere nitrogen and stirred for 1 hour. The reaction solution is cooled on the room temperature, add water and ethyl acetate, the insoluble matter is removed by filtration through celite (Celite™), the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (20 ml) and added dropwise a 30% aqueous hydrogen peroxide solution (10 ml) under cooling with ice. After one hour add saturated aqueous sodium thiosulfate solution under ice cooling to absorb excess hydrogen peroxide, then add water and ethyl acetate and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→4:1), while receiving 2-{(3,5-bis-trifloromethyl)-[2-(cyclopropylamino)-5-trifloromethyl]amino}pyrimidine-5-ol (1.8 g). MS (m/z): 607 [M+H]+.

(4) 2-{(3,5-Bis-trifloromethyl)-[2-(cyclopropylamino)-5-trifloromethyl]amino}pyrimidine-5-ol (300 mg) and ethyl 4-bromobutyrate (85 μl) dissolved in N,N-dimethylformamide (1 ml), add potassium carbonate (82 mg) and the mixture is stirred at room temperature overnight. Then add ethyl acetate and a saturated salt solution, the mixture is separated, the organic layer is raybaut saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 97:3→17:3), while receiving 4-(2-{(3,5-bis-trifloromethyl)-[2-(cyclopropylamino)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (296 mg). MS (m/z): 721 [M+H]+.

(5) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(cyclopropylamino)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (290 mg) was dissolved in ethanol (5 ml)is added 2 n aqueous sodium hydroxide solution (604 μl) and the mixture is stirred at room temperature overnight. Then add ethyl acetate and 1 n solution of chloride-hydrogen of the acid, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining 4-(2-{(3,5-bis-trifloromethyl)-[2-(cyclopropylamino)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (277 mg). The obtained carboxylic acid is dissolved in ethanol (1 ml)is added 2 n aqueous sodium hydroxide solution (200 μl) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt of 4-(2-{(3,5-bis-trifloromethyl)-[2-(cyclopropylamino)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (278 mg) MS (m/z): 691 [M-Na] -.

Example 8

(1) To toluene (5 ml) is added 2-fluoro-5-triftormetilfosfinov (650 mg) and dimethylamine hydrochloride (2.76 g), then add potassium carbonate (1.4 g) and the mixture was stirred at 120°C during the night. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 49:1→4:1), while receiving 2-dimethylamino-5-triftormetilfosfinov (529 mg). MS (m/z): 218 [M+H]+.

(2) 2-Dimethylamino-5-triftormetilfosfinov (144 mg) was dissolved in ethanol (10 ml), add sodium borohydride (224 mg) at room temperature and the mixture is stirred for 15 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in methylene chloride (2 ml), add thionyl chloride (58 μl) under ice cooling and the mixture is stirred at room temperature for 10 minutes. To the reaction solution was added saturated aqueous sodium bicarbonate solution and etelaat is, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. Ethyl 4-[2-(3,5-bis-triphtalocyaninine)pyrimidine-5-yloxy]butyrate (200 mg) is dissolved in N,N-dimethylformamide (1.5 ml), add sodium hydride (62%) (26 mg) under ice cooling and the mixture is stirred for 15 minutes. Then add a solution of the residue obtained above in N,N-dimethylformamide (1.5 ml) and the mixture is stirred at the same temperature for 15 minutes. To the reaction solution was added ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→9:1), thus obtaining the ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-dimethylamino-5-trichoroethylene)amino]pyrimidine-5-yloxy}butyrate (97 mg). MS (m/z): 653 [M+H]+.

(3) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-dimethylamino-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (90 mg) is dissolved in ethanol (2 ml)is added 2 n aqueous solution of sodium hydroxide (207 μl) and the mixture is stirred at room temperature overnight. Then add ethyl acetate and 1 n solution of chloride-hydrogen of the acid, the mixture is separated, the organic layer washed asystem salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→1:4), while receiving 4-{2-[(3,5-bis-trifloromethyl)-(2-dimethylamino-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyric acid (29 mg). The obtained carboxylic acid is dissolved in ethanol (0.5 ml), is added 2 n aqueous sodium hydroxide solution (23 ml) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt complex ethyl ester 4-{2-[(3,5-bis-trifloromethyl)-(2-dimethylamino-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyric acid (30 mg). MS (m/z): 623 [M-Na]-.

Example 9

(1) 2-Fluoro-5-triftormetilfosfinov (2.0 g) is dissolved in 1,4-dioxane (10 ml), add N,N-diisopropylethylamine (2.7 ml) and 5-bromo-2-chloropyrimidine (3,02 g) and the mixture heated under reflux overnight. The reaction solution is cooled to room temperature and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 9:1 to 7:3)to give (5-bromopyrimidine-2-yl)-(2-fluoro-5-trifloromethyl)Amin (1,69 g), MS (m/z): 350/352 [M+H]+.

(2) (5-Bromopyrimidine-2-yl)-(2-fluoro-5-trifloromethyl)amine (2.10 g) was dissolved in N,N-dimethylformamide (10 ml), add hidri the sodium (62,7%) (345 mg) under ice cooling and the mixture is stirred for 30 minutes, then add 1-methyl bromide-3,5-bis-triptoreline (2.76 g) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→9:1), while receiving (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(2-fluoro-5-trifloromethyl)Amin (3,30 g). MS (m/z): 576/578 [M+H]+.

(3) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(2-fluoro-5-trifloromethyl)amine (300 mg) is dissolved in toluene (5 ml), add Tris(dibenzylideneacetone)dipalladium (48 mg), 2-(di-tert-butylphosphino)biphenyl (62 mg), tert-piperonyl sodium (75 mg) and morpholine (68 μl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 19:1→9:1), while receiving (3,5-bis-trifloromethyl)-(2-f the PR-5-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amine (176 mg). MS (m/z): 583 [M+H]+.

Example 10

(1) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(2-fluoro-5-trifloromethyl)amine (300 mg) is dissolved in toluene (5 ml), add Tris(dibenzylideneacetone)dipalladium (48 mg), 2-(di-tert-butylphosphino)biphenyl (62 mg), tert-piperonyl sodium (75 mg) and ethylpiperidine-4-carboxylate (120 μl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 19:1→9:1), while receiving 1-{2-[(3,5-bis-trifloromethyl)-(2-fluoro-5-trifloromethyl)amino]pyrimidine-5-yl}ethyl piperidine-4-carboxylate (111 mg). MS (m/z): 653 [M+H]+.

(2) 1-{2-[(3,5-Bis-trifloromethyl)-(2-fluoro-5-trifloromethyl)amino]pyrimidine-5-yl}ethyl piperidine-4-carboxylate (105 mg) was dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (2 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, the tub over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving 1-{2-[(3,5-bis-trifloromethyl)-(2-fluoro-5-trifloromethyl)amino]pyrimidine-5-yl}piperidine-4-carboxylic acid (81 mg). MS (m/z): 625 [M+H]+.

Example 11

(1) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(2-fluoro-5-trifloromethyl)amine (300 mg) is dissolved in tetrahydrofuran (3 ml), add complex ethyl ester ethylcarbamate acid (67 mg) and sodium hydride (60%) (23 mg) and the mixture was stirred at 120°C in a microwave oven with a capacity of 192 watts for 1 hour, then add complex ethyl ester ethylcarbamate acid (134 mg) and sodium hydride (60%) (46 mg) and the mixture was stirred at 120°C in a microwave oven with a capacity of 192 watts for 1 hour. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→9:1), while receiving (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(2-ethoxy-5-trifloromethyl)amine (220 mg). MS (m/z): 602/604 [M+H]+.

(2) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(2-ethoxy-5-trifloromethyl)amine (210 mg) was dissolved in toluene (5 ml), dabavlyaytes(dibenzylideneacetone)dipalladium (32 mg), 2-(di-tert-butylphosphino)biphenyl (42 mg), tert-piperonyl sodium (50 mg) and ethyl piperidine-4-carboxylate (80 μl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 1:0→17:3), while receiving ethyl-1-{2-[(3,5-bis-trifloromethyl)-(2-ethoxy-5-trifloromethyl)amino]pyrimidine-5-yl}piperidine-4-carboxylate (121 mg). MS (m/z): 679 [M+H]+.

(3) Ethyl 1-{2-[(3,5-bis-trifloromethyl)-(2-ethoxy-5-trifloromethyl)amino]pyrimidine-5-yl}piperidine-4-carboxylate (110 mg) was dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving 1-{2-[(3,5-bis-trifluoromethyl shall ensil)-(2-ethoxy-5-trifloromethyl)amino]pyrimidine-5-yl}piperidine-4-carboxylic acid (63 mg). MS (m/z): 651 [M+H]+.

Example 12

(1) 2-Fluoro-5-triftormetilfosfinov (1 g) dissolved in toluene (5 ml), add ethyl-7-ethylaminoethanol (3.98 g) and potassium carbonate (2,88 g) and the mixture heated under reflux overnight. The reaction solution is cooled to room temperature, add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. Obrazovavshijsya the residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 97:3→83:17), thus ethyl 7-[ethyl-(2-formyl-4-triptoreline)amino]heptanoate (1.29 g). MS (m/z): 374 [M+H]+.

(2) Ethyl 7-[ethyl-(2-formyl-4-triptoreline)amino]heptanoate (1.29 g) was dissolved in a mixed solvent of toluene (5 ml) and ethanol (1 ml), add sodium borohydride (156 mg) and the mixture is stirred for 2 hours and 30 minutes. To the reaction solution was added saturated aqueous solution of ammonium chloride and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→3:1), thus ethyl 7-[ethyl-(2-hydroxymethyl-4-triptoreline)amino]heptanoate (589 mg). MS (m/z): 376 [M+H +.

(3) Ethyl 7-[ethyl-(2-hydroxymethyl-4-triptoreline)amino]-heptanoate (580 mg) was dissolved in toluene (10 ml), add thionyl chloride (135 μl) under ice cooling and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in N,N-dimethylformamide (10 ml), add (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (740 mg) and tert-piperonyl sodium (178 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added saturated aqueous solution of ammonium chloride and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 23:2→41:9), thus ethyl 7-[(2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)ethylamino]heptanoate (760 mg). MS (m/z): 757/759 [M+H]+.

(4) Ethyl 7-[(2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)ethylamino]heptanoate (300 mg) is dissolved in toluene (5 ml), add Tris(dibenzo identicon)-dipalladium (37 mg), 2-(di-tert-butylphosphino)biphenyl (48 mg), tert-piperonyl sodium (58 mg) and morpholine (53 μl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 9:1→4:1), thus ethyl 7-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylamino]heptanoate (254 mg). MS (m/z): 764 [M+H]+.

(5) Ethyl 7-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylamino]heptanoate (250 mg) is dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→19:1), while receiving 7-[(2-{[(3,5-bis-thrift methylbenzyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylamino]heptane acid (131 mg). The obtained 7-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylamino]-heptane acid (131 mg) was dissolved in ethanol (1 ml)was added 1 n aqueous solution of sodium hydroxide (178 μl) and concentrated under reduced pressure, thus obtaining the sodium salt of 7-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylamino]heptane acid (133 mg). MS (m/z): 734 [M-Na]-.

Example 13

(1) Ethyl TRANS(4-{[(2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)ethylamino]methyl}cyclohexyl)acetate (obtained by treating the corresponding starting compound analogously to example 12 (1)-(3)) (2,6 g) dissolved in dimethyl sulfoxide (15 ml), add complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (73 mg), potassium acetate (977 mg) and bis(pinacolato)LIBOR (1.26 g), the mixture is heated to 80°C. in a nitrogen atmosphere and stirred for 2 hours. The reaction solution is cooled to room temperature, add a saturated salt solution and ethyl acetate, the mixture is separated, the organic layer is again washed with a saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (30 ml) and added dropwise a 30% aqueous solution of Perak the IDA hydrogen (30 ml) under cooling with ice. The mixture is stirred for 1 hour, add saturated aqueous solution of sodium thiosulfate to absorb excess hydrogen peroxide, then add water and ethyl acetate and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 19:1 to 7:3), thus obtaining the ethyl TRANS(4-{[2-{[(3,5-bis-trifloromethyl)-(5-hydroxypyrimidine-2-yl)amino]methyl}-4-triptoreline)ethylamino]methyl}cyclohexyl)acetate (1.29 g). MS (m/z): 721 [M+H]+.

(2) Ethyl TRANS(4-{[(2-{[(3,5-bis-trifloromethyl)-(5-hydroxypyrimidine-2-yl)amino]methyl}-4-triptoreline)ethylamino]methyl}cyclohexyl)acetate (300 mg) is dissolved in N,N-dimethylformamide (4 ml), add 2-bromoethanol (87 μl) and potassium carbonate (172 mg) and the mixture was stirred at 60°C for 1 day. The reaction solution is cooled to room temperature, add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 7:3→1:1), thus obtaining the ethyl TRANS - [4-({[2-({(3,5-bis-trifloromethyl)-[5-(2-hydroxyethoxy)pyrimidine-2-yl]amino}is ethyl)-4-triptoreline]ethylamino}methyl)cyclohexyl]acetate (138 mg). MS (m/z): 765 [M+H]+.

(3) Ethyl TRANS - [4-({[2-({(3,5-bis-trifloromethyl)-[5-(2-hydroxyethoxy)pyrimidine-2-yl]amino}methyl)-4-triptoreline]-ethylamino}methyl)cyclohexyl]acetate (122 mg) was dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at 60°C for 2 hours. The reaction solution is cooled to room temperature, was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 7:3→3:7), while receiving TRANS[4-({[2-({(3,5-bis-trifloromethyl)-[5-(2-hydroxyethoxy)pyrimidine-2-yl]amino}methyl)-4-triptoreline]ethylamino}methyl)cyclohexyl]acetic acid (50 mg). MS (m/z): 737 [M+H]+.

Example 14

Tert-butyl 3-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylamino]-propionate (obtained by treating the corresponding starting compound analogously to example 12 (1)-(4)) (205 mg) dissolved in a 4 n solution of chloride-hydrogen acid in ethyl acetate (5 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added saturated aqueous solution b is sodium carbonate and ethyl acetate, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:1→0:1), while receiving 3-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylamino]propionic acid (133 mg). MS (m/z): 680 [M+H]+.

Example 15

(1) Ethyl 7-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)-(2-tert-butoxyethyl)amino]heptanoate (obtained by treating the corresponding starting compound analogously to example 12(1)-(4)) (260 mg) dissolved in a 4 n solution of chloride-hydrogen acid in ethyl acetate (4 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→3:2), thus ethyl 7-[(2-acetoxyethyl)-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)amino]heptanoate (162 mg). MS (m/z): 822 [M+H]+ .

(2) Ethyl 7-[(2-acetoxyethyl)-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)-amino]heptanoate (156 mg) was dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 4 hours. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→19:1), while receiving 7-[(2-acetoxyethyl)-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)amino]heptane acid (144 mg). The obtained 7-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)-(2-hydroxyethyl)amino]heptane acid (144 mg) was dissolved in ethanol (1 ml)was added 1 n aqueous sodium hydroxide solution (172 μl) and concentrated under reduced pressure, thus obtaining the sodium salt of 7-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)-(2-hydroxyethyl)amino]heptane acid (133 mg). MS (m/z): 750 [M-Na]-.

Example 16

(1) Ethyl 6-[(2-{[(3,5-bis-trifloromethyl)-(5-GI is oxypyridine-2-yl)amino]methyl}-4-triptoreline)ethylamino]hexanoate (120 mg) dissolved in tetrahydrofuran (1 ml), add 2-methoxyethanol (21 μl) and triphenylphosphine (69 mg), and then added dropwise 40% diethylazodicarboxylate in toluene (115 ml) under cooling with water and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate = 6:1), thus obtaining the ethyl-6-{[2-({(3,5-bis-trifloromethyl)-[5-(2-methoxyethoxy)pyrimidine-2-yl]amino}methyl)-4-triptoreline]ethylamino}hexanoate (120 mg). MS (m/z): 739 [M+H]+.

(2) Ethyl 6-{[2-({(3,5-bis-trifloromethyl)-[5-(2-methoxyethoxy)pyrimidine-2-yl]amino}methyl)-4-triptoreline]ethylamino}hexanoate (113 mg) was dissolved in a mixed solvent of ethanol (2 ml) and tetrahydrofuran (1 ml)was added 1 M aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. The reaction solution do weakly acidic by adding 10% aqueous citric acid solution, the mixture is extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified of chromatography the th on a column of silica gel (chloroform:methanol= 1:0→49:1), while receiving 6-{[2-({(3,5-bis-trifloromethyl)-[5-(2-methoxyethoxy)pyrimidine-2-yl]amino}methyl)-4-triptoreline]ethylamino}hexanoic acid (111 mg). MS (m/z): 711 [M+H]+.

(3) 6-{[2-({(3,5-Bis-trifloromethyl)-[5-(2-methoxyethoxy)pyrimidine-2-yl]amino}methyl)-4-triptoreline]ethylamino}hexanoic acid (105 mg) was dissolved in ethanol (1 ml)is added 2 M aqueous solution of sodium hydroxide (74 μl) and the mixture is stirred at room temperature for 5 minutes. The reaction solution is concentrated under reduced pressure, thus obtaining the sodium salt of 6-{[2-({(3,5-bis-trifloromethyl)-[5-(2-methoxyethoxy)pyrimidine-2-yl]amino}methyl)-4-triptoreline]ethylamino}hexanoic acid (102 mg). MS (m/z): 709 [M-Na]-.

Example 17

(1) (2-BROMOTRIFLUOROMETHANE)methanol (5 g) dissolved in N,N-dimethylformamide (45 ml), add palladium acetate (440 mg), 1,1'-bis(diphenylphosphino)ferrocene (2.17 g) and triethylamine (5 ml) and the mixture is stirred in a stream of carbon monoxide at room temperature for 5 minutes and at 90°C for 1 day. The reaction solution is cooled to room temperature, was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified of HRO what ecografia on a column of silica gel (hexane:ethyl acetate= 4:1→3:2), while receiving 6-trifluoromethyl-3H-isobenzofuran-1-he (2,77 g). MS (m/z): 203 [M+H]+.

(2) 6-Trifluoromethyl-3H-isobenzofuran-1-he (1.77 g) was dissolved in methylene chloride (20 ml), the mixture is cooled to -78°C. add 1.0 M solution of hydride diisobutylaluminum in toluene (19,5 ml) and the mixture is stirred for 1 hour and 20 minutes. The reaction solution is cooled to room temperature, add saturated aqueous solution of ammonium chloride and utilized, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→3:2), while receiving 6-trifluoromethyl-1,3-dihydroisobenzofuran-1-ol (1,36 g). MS (m/z): 187 [M+H-H2O]+.

(3) 6-Trifluoromethyl-1,3-dihydroisobenzofuran-1-ol (4.12 g) was dissolved in 1,2-dichloroethane (75 ml), add 3,5-bis-triftormetilfosfinov (of 5.89 g), mixing createtextarea (9.0 g) and acetic acid (2.3 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on columns is e silica gel (hexane:ethyl acetate= 7:3→1:1), get {2-[(3,5-bis-triphtalocyaninine)methyl]-4-triptoreline}methanol (7,06 g). MS (m/z): 432 [M+H]+.

(4) {2-[(3,5-Bis-triphtalocyaninine)methyl]-4-triptoreline}methanol (7.0 g) was dissolved in toluene (70 ml), add 5-bromo-2-chloropyrimidine (4.7 g) and N,N-diisopropylethylamine (4,23 ml) and the mixture is heated at reflux for 3 days. The reaction solution is cooled to room temperature, add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→3:2), while receiving (2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)methanol (7,37 g). MS (m/z): 588/590 [M+H]+.

(5) (2-{[(3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)methanol (225 mg) was dissolved in acetone (5 ml), add 1,94 M solution of Jones reagent (290 μl) under ice cooling and the mixture is stirred for 30 minutes. To the reaction solution add hydrosulfite sodium, water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified of chromatogr is via on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving 2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triftorperasin acid (181 mg). MS (m/z): 602/604 [M+H]+.

(6) 2-{[(3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triftorperasin acid (1 g) dissolved in tetrahydrofuran (10 ml), add Diphenoxylate (540 μl), triethylamine (695 μl) and ethanol (6 ml) and the mixture is heated, with stirring, at 60°C for 3 days. The reaction solution is cooled to room temperature, was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 1:0→4:1 → chloroform:methanol = 4:1), thus obtaining the ethyl (2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)carbamate (660 mg). MS (m/z): 645/647 [M+H]+.

(7) Ethyl (2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)carbamate (980 mg) was dissolved in N,N-dimethylformamide (10 ml), add sodium hydride (60%) (91 mg) under ice cooling and the mixture is stirred for 30 minutes, then add ethyliodide (182 μl) and the mixture is stirred at room temperature overnight. Add water and utilized is t, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 19:1→4:1, thus obtaining the ethyl (2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate (425 mg). MS (m/z): 673/675 [M+H]+.

(8) Ethyl (2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)carbamate (412 mg) was dissolved in toluene (5 ml), add Tris(dibenzylideneacetone)dipalladium (112 mg), 2-(di-tert-butylphosphino)biphenyl (146 mg), tert-piperonyl sodium (176 mg) and ethylpiperidine-4-carboxylate (140 μl) and the mixture is stirred under nitrogen atmosphere at room the temperature during the night. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 19:1→4:1), while receiving 1-(2-{(3,5-bis-trifloromethyl)-[2-(ethoxycarbonylmethylene)-5-trifloromethyl]amino}pyrimidine-5-yl)ethyl piperidine-4-carboxylate (72 mg). MS (m/z): 750 [M+H]+.

(9) 1-(2-{(3,5-Bis-trifloromethyl-[2-(ethoxycarbonylmethylene)-5-trifloromethyl]amino}pyrimidine-5-yl)ethylpiperidine-4-carboxylate (70 mg) was dissolved in ethanol (4 ml), add 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving 1-(2-{(3,5-bis-trifloromethyl)-[2-(ethoxycarbonylmethylene)-5-trifloromethyl]amino}pyrimidine-5-yl)piperidine-4-carboxylic acid (44 mg). The obtained 1-(2-{(3,5-bis-trifloromethyl)-[2-(ethoxycarbonylmethylene)-5-trifloromethyl]amino}pyrimidine-5-yl)piperidine-4-carboxylic acid (44 mg) was dissolved in ethanol (1 ml)was added 1 n aqueous sodium hydroxide solution (44 ml) and the mixture is concentrated under reduced pressure, thus obtaining the sodium salt of 1-(2-{(3,5-bis-trifloromethyl)-[2-(ethoxycarbonylmethylene)-5-trifloromethyl]amino}pyrimidine-5-yl)piperidine-4-carboxylic acid (45 mg). MS (m/z): 720 [M-Na]-.

Example 18

(1) Ethyl (2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)carbamate (614 mg) was dissolved in toluene (6.5 ml), add Tris(dibenzylideneacetone)dipalladium(0) (87 mg), 2-(di-tert-butylphosphino)biphenyl 114 mg), morpholine (166 μl) and tert-piperonyl sodium (183 mg) and the mixture is stirred in a stream of nitrogen at 60°C for 2 hours. To the reaction mixture is added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 9:1→4:1), thus obtaining the ethyl (2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)carbamate (476 mg). MS (m/z): 652 [M+H]+.

(2) Ethyl (2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)carbamate (140 mg) is dissolved in N,N-dimethylformamide (1 ml), add sodium hydride (63%) (12 mg) under ice cooling and the mixture is stirred at the same temperature for 30 minutes. To the reaction mixture are added ethyl 5-bromopentanoate (68 μl) and the mixture is stirred at a temperature of from 0°C. to room temperature over night. To the reaction mixture is added a saturated solution of salt, the mixture is extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 2:1), obtaining PR is the ethyl 5-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethoxycarbonyl]pentanoate (137 mg). MS (m/z): 780 [M+H]+.

(3) Ethyl 5-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethoxycarbonyl]pentanoate (134 mg) was dissolved in methanol (1 ml)was added 1 M aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 1 hour and 30 minutes. The reaction solution do weakly acidic by adding 10% aqueous citric acid solution, the mixture is extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol = 19:1), while receiving 5-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethoxycarbonyl]pentane acid (123 mg). MS (m/z): 752 [M+H]+.

Example 19

(1) 2-{[(3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triftorperasin acid (2.5 g) dissolved in tetrahydrofuran (25 ml), add Diphenoxylate (1,34 ml), triethylamine (174 ml) and benzyl alcohol (1.3 ml) and the mixture is heated while stirring at 60°C over night. The reaction solution is cooled to room temperature, was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with nassen the m salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→9:1→4:1), while receiving benzyl (2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)carbamate (2.66 g). MS (m/z): 707/709 [M+H]+.

(2) Benzyl (2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)carbamate (1.5 g) is dissolved in N,N-dimethylformamide (15 ml), add sodium hydride (60%) (127 mg) under ice cooling and the mixture is stirred for 30 minutes, then add ethyliodide (255 μl) and the mixture is stirred at room temperature overnight. Add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→17:3), while receiving benzyl (2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate (1.30 grams). MS (m/z): 735/737 [M+H]+.

(3) Benzyl (2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate (1.28 g) was dissolved in toluene (15 ml), add Tris(dibenzylideneacetone)dipalladium (159 mg), 2-(di-tert-butylphosphino)biphenyl (208 m is), tert-piperonyl sodium (250 mg) and morpholine (230 μl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution was added Tris(dibenzylideneacetone)dipalladium (159 mg), 2-(di-tert-butylphosphino)biphenyl (208 mg) and tert-piperonyl sodium (250 mg) and the mixture is stirred for 3 hours 30 minutes. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 19:1→4:1), while receiving benzyl (2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate (724 mg). MS (m/z): 742 [M+H]+.

(4) Benzyl (2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate (720 mg) was dissolved in ethanol (10 ml), add 10% palladium carbon (200 mg) and the mixture is stirred in hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate = 9:1 to 7:3)to give (3,5-bis-Tr is formatives)-(2-ethylamino-5-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amine (569 mg). MS (m/z): 608 [M+H]+.

(5) (3,5-Bis-trifloromethyl)-(2-ethylamino-5-trifloromethyl)-(5-morpholine-4-Yeremey-2-ID)amine (200 mg) and triethylamine (55 μl) dissolved in methylene chloride (5 ml), add triphosgene (39 mg) under ice cooling and the mixture is stirred under nitrogen atmosphere at room temperature for 30 minutes. To the reaction solution was added saturated aqueous sodium bicarbonate solution and chloroform, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (5 ml), added tert-butyl 3-hydroxypropionate (73 μl) and sodium hydride (60%) (20 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 9:1 to 7:3), while receiving tert-butyl 3[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate]propionate (120 mg). MS (m/z): 780 [M+H]+.

(6) Tert-butyl 3-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]METI the}-4-triptoreline)ethylcarbamate]propionate (114 mg) was dissolved in a 4 n solution of chloride-hydrogen acid in ethyl acetate (5 ml) and the mixture is stirred at room temperature for 1 hour and 30 minutes. Then add saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→19:1), while receiving 3-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate]propionic acid (81 mg). The obtained 3-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate]propionic acid (81 mg) is dissolved in ethanol (1 ml)was added 1 n aqueous solution of sodium hydroxide (115 ml) and concentrate under reduced pressure, thus obtaining the sodium salt of 3-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate]propionic acid (78 mg). MS (m/z): 722 [M-Na]-.

Example 20

(1) (3,5-Bis-trifloromethyl)-(2-ethylamino-5-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amine (400 mg) is dissolved in methylene chloride (5 ml), add triethylamine (110 μl) and triphosgene (78 mg) under ice cooling and the mixture is stirred under nitrogen atmosphere at room temperature for 2 hours. To the reaction solution was added saturated aqueous dissolve the sodium bicarbonate and chloroform, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (5 ml), add hydrochloride difficult methyl ester (S)-2-amino-3-tert-butoxypropyl acid (279 mg) and triethylamine (183 μl) and the mixture is stirred at room temperature for 1 day. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:1→3:7), thus the methyl (S)-2-[3-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)-3-ethylurea]-3-tert-butoxypropan (462 mg). MS (m/z): 809 [M+H]+.

(2) Methyl (S)-2-[3-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)-3-ethylurea]-3-tert-butoxypropan (455 mg) was dissolved in a 4 n solution of chloride-hydrogen acid in dioxane (5 ml) and the mixture is stirred at room temperature for 8 hours. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated Rast is or salt, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:1→0:1), thus the methyl (S)-2-[3-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)-3-ethylurea]-3-hydroxypropionate (285 mg). MS (m/z): 753 [M+H]+.

(3) Methyl (S)-2-[3-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)-3-ethylurea]-3-hydroxypropionate (280 mg) and pyridine (72 μl) dissolved in methylene chloride (5 ml) and the mixture is cooled to -20°C, then add the anhydride triftormetilfullerenov acid (150 μl) and the mixture was stirred at -20°C for 1 hour 30 minutes. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 4:1→1:1), thus the methyl (S)-2-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylamino]-4,5-dihydrooxazolo-4-carboxylate (197 mg). MS (m/z): 735 [M+H]+.

(4) Methyl (S)-2-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-three is timeteller)ethylamino]-4,5-dihydrooxazolo-4-carboxylate (190 mg) was dissolved in methanol (4 ml), add 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→4:1), thus the (S)-2-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylamino]-4,5-dihydrooxazolo-4-carboxylic acid (130 mg). The obtained (S)-2-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylamino]-4,5-dihydrooxazolo-4-carboxylic acid (130 mg) was dissolved in ethanol (1 ml)was added 1 n aqueous sodium hydroxide solution (180 μl) and concentrated under reduced pressure, thus obtaining the sodium salt of (S)-2-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylamino]-4,5-dihydrooxazolo-4-carboxylic acid (120 mg). MS (m/z): 729 [M-Na]-.

Example 21

(1) (3,5-Bis-trifloromethyl)-(2-ethylamino-5-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amine (164 mg) was dissolved in methylene chloride (5 ml), add ethyl 6-(chloroformyl)hexanoate (67 mg) and t is ethylamin (26 μl) and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 17:3→7:3), thus obtaining the ethyl 6-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate]hexanoate (147 mg). MS (m/z): 778 [M+H]+.

(2) Ethyl-6-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate]hexanoate (140 mg) is dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving 6-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)ethylcarbamate]hexanoic acid (137 mg). MS (m/z): 750 [M+H]+.

Example 22

(1) 2-{[(3,5-Bi is-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-triftorperasin acid (250 mg) is dissolved in tetrahydrofuran (5 ml), add tert-butyl 3-ethylenepropylene (103 mg), dihydrate 1-hydroxybenzotriazole (81 mg, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (114 mg) and triethylamine (83 μl) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), while receiving tert-butyl 3-[(2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-trifloromethyl)ethylamino]propionate (310 mg). MS (m/z): 757/759 [M+H]+.

(2) Tert-butyl 3-[(2-{[(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amino]methyl}-4-trifloromethyl)ethylamino]propionate (300 mg) is dissolved in toluene (5 ml), add Tris(dibenzylideneacetone)dipalladium (36 mg), 2-(di-tert-butylphosphino)biphenyl (47 mg), tert-piperonyl sodium (57 mg) and morpholine (52 μl) and the mixture is stirred in the atmosphere nitrogen at room temperature over night. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The image is vasica the residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate = 17:3→7:3) and then by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→3:2), while receiving tert-butyl 3-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-trifloromethyl)ethylamino]propionate (13.3 mg). MS (m/z): 764 [M+H]+.

(3) Tert-butyl 3-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-trifloromethyl)ethylamino]propionate (13.3 mg) was dissolved in a 4 n solution of chloride-hydrogen acid in ethyl acetate (2 ml) and the mixture is stirred at room temperature for 4 hours. Then add saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining 3-[(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-trifloromethyl)ethylamino]propionic acid (12 mg). MS (m/z): 780 [M+H]+.

Example 23

(1) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (8,55 g) dissolved in N,N-dimethylformamide (20 ml), add sodium hydride (60%) (855 mg) under ice cooling and the mixture is stirred for 15 minutes. To the reaction solution was added 2-methyl bromide-1-fluoro-4-triptoreline (5 g) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated of rest the rum salt, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→9:1), while receiving (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(2-fluoro-5-trifloromethyl)amine (11.1 g). MS (m/z): 576/578 [M+H]+.

(2) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(2-fluoro-5-trifloromethyl)amine (11.1 g) was dissolved in tetrahydrofuran (20 ml), add benzyl alcohol (6 ml) and sodium hydride (60%) (2,32 g) and the mixture heated under reflux overnight. The reaction solution is cooled to room temperature, add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 97:3→9:1), while receiving (2-benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (12.9 g). MS (m/z): 664/666 [M+H]+.

(3) (2-Benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (12.9 g) was dissolved in dimethyl sulfoxide (150 ml), add complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (3,17 g), potassium acetate (5,71 g) and bis(pinacolato)LIBOR (9,85 g) and the mixture is heated to 80°C. in the atmosphere is e nitrogen for 1 hour and 30 minutes. The reaction solution is cooled to room temperature, add a saturated salt solution and ethyl acetate, the mixture is separated, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (150 ml) and added dropwise a 30% aqueous hydrogen peroxide solution (40 ml) under cooling with ice. After 2 hours, add saturated aqueous solution of sodium thiosulfate to absorb excess hydrogen peroxide, then add ethyl acetate and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 9:1 to 7:3), thus obtaining 2-[(2-benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)amino]pyrimidine-5-ol (7.68 in). MS (m/z): 602 [M+H]+.

(4) 2-[(2-Benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)amino]pyrimidine-5-ol (of 7.68 g) dissolved in N,N-dimethylformamide (100 ml), add ethyl 4-bromobutyrate (2.3 ml) and potassium carbonate (2,22 g) and the mixture is stirred at room temperature overnight. To the reaction solution was added ethyl 4-bromobutyrate (2.3 ml) and potassium carbonate (2,22 g) and the mixture is stirred at room temperature for 3 days. To the reaction solution was added water and ethyl acetate, MES share, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→4:1), thus obtaining the ethyl 4-{2-[(2-benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate in the form of the crude product (11.3 g). MS (m/z): 716 [M+H]+.

(5) the Crude ethyl 4-{2-[(2-benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (11.3 g) was dissolved in ethanol (100 ml), add 10% palladium charcoal (3 g) and the mixture is stirred in hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining the ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (6,03 g). MS (m/z): 626 [M+H]+.

(6) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (200 mg) is dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 3 hours. To the reaction solution was added 1 n races the thief chloride-hydrogen acid and ethyl acetate, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→19:1), while receiving 4-{2-[(3,5-bis-trifloromethyl)-(2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyric acid (182 mg). The obtained 4-{2-[(3,5-bis-trifloromethyl)-(2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyric acid (184 mg) was dissolved in ethanol (5 ml)was added 1 n aqueous solution of sodium hydroxide (305 μl) and concentrated under reduced pressure, thus obtaining the sodium salt of 4-{2-[(3,5-bis-trifloromethyl)-(2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}oil acid (184 mg). MS (m/z): 598 [M+H]+.

Example 24

(1) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (300 mg) and 3-pentanol (63 mg) was dissolved in tetrahydrofuran (4 ml), added dropwise triphenylphosphine (189 mg) and 40% diethylazodicarboxylate in toluene (130 ml) under ice cooling and the mixture is stirred at room temperature overnight. Then add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure is I. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→9:1), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(1-ethylpropoxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (195 mg). MS (m/z): 696 [M+H]+.

(2) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(1-ethylpropoxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (190 mg) was dissolved in ethanol (5 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→93:7), while receiving 4-(2-{(3,5-bis-trifloromethyl)-[2-(1-ethylpropoxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (158 mg). The obtained 4-(2-{(3,5-bis-trifloromethyl)-[2-(1-ethylpropoxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (158 mg) was dissolved in ethanol (1 ml)was added 1 n aqueous sodium hydroxide solution (237 μl) and concentrated under reduced pressure, thus obtaining the sodium salt of 4-(2-{(3,5-bis-trifloromethyl)-[2-(1-ACELP is epoxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (149 mg). MS (m/z): 666 [M-Na]-.

Example 25

(1) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (200 mg) is dissolved in N,N-dimethylformamide (3 ml), add 2-chloropyrimidine (45 mg) and potassium carbonate (55 mg) and the mixture was stirred at 85°C during the night. The reaction solution is cooled to room temperature, add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 41:9→13:7), while receiving ethyl-4-(2-{(3,5-bis-trifloromethyl)-[2-(pyrimidine-2-yloxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (120 mg). MS (m/z): 704 [M+H]+.

(2) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(pyrimidine-2-yloxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (115 mg) was dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified chromatography the raffia on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving 4-(2-{(3,5-bis-trifloromethyl)-[2-(pyrimidine-2-yloxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (96 mg). MS (m/z): 676 [M+H]+.

Example 26

(1) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (3 g) and pyridine (580 μl) dissolved in methylene chloride (45 ml), add anhydride triftormetilfullerenov acid (1.2 ml) under ice cooling and the mixture is stirred under nitrogen atmosphere for 2 hours. The reaction solution is cooled to room temperature, add saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining the ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-tripterocalyx-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (3,44 g). MS (m/z): 758 [M+H]+.

(2) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-tripterocalyx-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (200 mg) is dissolved in 1,4-dioxane (3 ml), add phenylboric (64 mg), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (22 mg) and cesium carbonate (172 mg) and the mixture per mesilat in nitrogen atmosphere at 80°C during the night. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 19:1→17:3), thus obtaining the ethyl 4-{2-[(3,5-bis-trifloromethyl)-(4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (192 mg). MS (m/z): 686 [M+H]+.

(3) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (185 mg) was dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→19:1), while receiving 4-{2-[(3,5-bis-trifloromethyl)-(4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (160 mg). The obtained 4-{2-[(3,5-bis-trifloromethyl)-(4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (160 mg) was dissolved in ethanol (1 ml), to which ablaut 1 n aqueous solution of sodium hydroxide (245 μl) and concentrated under reduced pressure, thus the sodium salt of 4-{2-[(3,5-bis-trifloromethyl)-(4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (158 mg). MS (m/z): 656 [M-Na]-.

Example 27

(1) (2-Benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (3.75 g) was dissolved in toluene (50 ml), add Tris(dibenzylideneacetone)dipalladium (516 mg), 2-(di-tert-butylphosphino)biphenyl (673 mg), tert-piperonyl sodium (813 mg) and morpholine (740 μl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 9:1→4:1), while receiving (2-benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amine (2,46 g). MS (m/z): 671 [M+H]+.

(2) (2-Benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amine (2,46 g) dissolved in ethanol (35 ml), add 10% palladium carbon (750 mg) and the mixture is stirred in hydrogen atmosphere at room temperature for 1 hour and 30 minutes. The catalyst was removed by filtration, filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→3:2), while receiving 2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline (1,53 g). MS (m/z): 581 [M+H]+.

(3) 2-{[(3,5-Bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline (150 mg) is dissolved in N,N-dimethylformamide (4 ml), add ethyl 4-bromobutyrate (74 μl) and potassium carbonate (71 mg) and the mixture was stirred at 80°C during the night. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 22:3→7:3), thus obtaining the ethyl 4-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)butyrate (123 mg). MS (m/z): 695 [M+H]+.

(4) Ethyl 4-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)butyrate (115 mg) was dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 4 hours. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic SL is th is washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→19:1), while receiving 4-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)butyric acid (108 mg). MS (m/z): 667 [M+H]+.

Example 28

(1) 2-{[(3,5-Bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline (300 mg) and pyridine (50 μl) is dissolved in methylene chloride (5 ml), add anhydride triftormetilfullerenov acid (104 μl) under ice cooling and the mixture is stirred under nitrogen atmosphere for 1 hour. The reaction solution is cooled to room temperature, add saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 9:1 to 7:3), thus obtaining 2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-cryptomaterial ether triftormetilfullerenov acid (330 mg). MS (m/z): 713 [M+H]+.

(2) 2-{[(3,5-Bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-cryptomaterial ether cryptomaterial the background acid (200 mg) is dissolved in 1,4-dioxane (3 ml), add phenylboric (69 mg), the complex [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (23 mg) and cesium carbonate (183 mg) and the mixture is stirred under nitrogen atmosphere at 80°C for 1 day. The reaction solution is cooled to room temperature, add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 19:1→4:1), while receiving (3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)-(4-triptorelin-2-ylmethyl)amine (52 mg). MS (m/z): 641 [M+H]+.

Examples 29-35

The corresponding starting compound is treated analogously to example 1 to give the compounds shown in table 1.

Example 36

The corresponding original connection is treated analogously to example 1 (1)-(3), thus obtaining the compound shown in table 1.

Example 37-46

The corresponding starting compound is treated analogously to example 2 to give the compounds shown in table 1.

Examples 47-48

The corresponding starting compound is treated analogously to example 4, thus obtaining the compounds listed in table 1.

Example 49

The corresponding source from the unification process as in example 5, while receiving the connection, shown in table 1.

Examples 50-53

The corresponding starting compound is treated analogously to example 8 to give the compounds shown in table 1.

Examples 54-60

The corresponding starting compound is treated analogously to example 12 to give the compounds shown in table 1.

Examples 61-62

The corresponding starting compound is treated analogously to example 12 (1)-(3)to give the compounds shown in table 1.

Examples 63-64

The corresponding starting compound is treated analogously to example 13 to give the compounds shown in table 1.

Example 65

The corresponding original connection is treated analogously to example 16, thus obtaining the compound shown in table 1.

Example 66

The corresponding initial connection process analogous to example 18, thus obtaining the compound shown in table 1.

Example 67

The corresponding original connection is treated analogously to example 20, thus obtaining the compound shown in table 1.

Examples 68-71

The corresponding starting compound is treated analogously to example 24 to give the compounds shown in table 1.

Examples 72-75

The relevant source is soedineniya treated analogously to example 26, thus the compounds listed in table 1.

Example 76

(1) 2-Fluoro-5-triftormetilfosfinov (5 g) and cyclopropanemethylamine (5,57 ml) dissolved in toluene (50 ml), add potassium carbonate (10.7 g) and the mixture was stirred at 120°C during the night. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 20:1), thus obtaining 2-(cyclopropylamino)-5-triftormetilfosfinov (6.8 g). MS (m/z): 286 [M+H]+.

(2) To ethanol (30 ml) is added 2-(cyclopropylamino)-5-triftormetilfosfinov (6.8 g), hydroxylamine hydrochloride (1.66 g) and sodium acetate (1,95 g) and the mixture is stirred at room Tempe is the atur during the night. The ethanol is removed by evaporation under reduced pressure, add chloroform and water and the mixture is stirred. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 10:1→2:1), while receiving the reaction of 2-(cyclopropylamino)-5-triftormetilfullerenov (5,78 g). MS (m/z): 301 [M+H]+.

(3) Alumoweld lithium (1.4 g) is suspended in tetrahydrofuran (50 ml), added dropwise, the reaction of 2-(cyclopropylamino)-5-triftormetilfullerenov (5.7 g) in tetrahydrofuran (20 ml) under ice cooling and the mixture is stirred at room temperature overnight. To the reaction solution was successively added water (1.4 ml), 2 n aqueous sodium hydroxide solution (2.8 ml) and water (2.8 ml) under ice cooling, the insoluble matter is removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (chloroform:ethyl acetate = 10:1), obtaining (2-aminomethyl-4-triptoreline)cyclopropanemethylamine in the form of the crude product (5.1 g).

(4) the Crude (2-aminomethyl-4-triptoreline)cyclopropanemethylamine obtained at stage (3) (of 5.06 g) was dissolved in dioxane (25 ml), to relax the Ute N-ethyldiethanolamine (9,19 ml) and 5-bromo-2-chloropyrimidine (8,48 g) and the mixture heated under reflux for 4 hours and 20 minutes. Insoluble matter is removed by filtration, the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (hexane:ethyl acetate = 15:1), obtaining (5-bromopyrimidine-2-yl)-[2-(cyclopropylamino)-5-trifloromethyl]amine (6,33 g). MS (m/z): 443/445 [M+H]+.

(5) (5-Bromopyrimidine-2-yl)-[2-(cyclopropylamino)-5-trifloromethyl]amine (2,33 g) dissolved in N,N-dimethylformamide (16,8 ml), add sodium hydride (60%) (273 mg) under ice cooling. Twenty minutes later, add 3-methyl bromide-5-cryptomathematical (2,08 g) and the mixture is stirred at room temperature for 1 hour and 15 minutes. To the reaction solution was added acetic acid to absorb excess sodium hydride, then add ethyl acetate and water and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate, concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (hexane:ethyl acetate = 10:1), thus obtaining 3-({(5-bromopyrimidine-2-yl)-[2-(cyclopropylamino)-5-trifloromethyl]amino}methyl)-5-cryptomathematical (2,81 g). MS (m/z): 626/628 [M+H]+.

(6) 3-({(5-Bromopyrimidine-2-yl)-[2-(cyclopropylamino)-5-trifloromethyl]amino}methyl)-5-cryptomathematical (2,81 is) dissolved in dimethyl sulfoxide (12,6 ml), the mixture Tegaserod under reduced pressure and rinsed with gaseous nitrogen. Then add potassium acetate (1,32 g), bis(pinacolato)LIBOR (2,88 g) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and methylene chloride (732 mg), the mixture is heated at 80°C. in a nitrogen atmosphere and stirred for 1 hour and 40 minutes. The reaction solution is cooled to room temperature, add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (26 ml) and added dropwise a 30% aqueous hydrogen peroxide solution (15.7 ml) under cooling with ice. After two hours, add saturated aqueous sodium thiosulfate solution under ice cooling to absorb excess hydrogen peroxide, then add water and ethyl acetate and the mixture is separated. The organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 4:1), thus obtaining 3-{[[2-(cyclopropylamino)-5-trifloromethyl]-(5-hydroxypyrimidine-2-yl)amino]methyl}-5-cryptomathematical (1,94 g). MS (m/z): 564 [M+H]+.

(7) Ethyl 3-{[[2-(cyclopropylamino)-5-triptime Ventil]-(5-hydroxypyrimidine-2-yl)amino]methyl}-5-cryptomathematical (250 mg) and 4-bromobutyrate (76,9 μl) dissolved in N,N-dimethylformamide (3,7 ml), add potassium carbonate (74 mg) and the mixture is stirred at room temperature overnight. Then add ethyl acetate and a saturated salt solution, the mixture is separated, the organic layer was washed with saturated salt solution, dried and concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate = 8:1), thus obtaining the ethyl 4-(2-{(3-cyano-5-trifloromethyl)-[2-(cyclopropylamino)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (220 mg). MS (m/z): 678 [M+H]+.

(8) Ethyl-4-(2-{(3-cyano-5-trifloromethyl)-[2-(cyclopropyl-methylpropylamine)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (240 mg) was dissolved in tetrahydrofuran (2.6 ml), was added 1 n aqueous sodium hydroxide solution (2.6 ml) and the mixture was stirred at 40°C for 30 minutes, heated to 50°C. and stirred for 3 hours. Then added 2 n aqueous sodium hydroxide solution (650 ml) and the mixture was stirred at 60°C for 20 minutes. The reaction solution is cooled to room temperature, add ethyl acetate and 1 n solution of chloride-hydrogen of the acid, the mixture is separated, the organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloro what ORM:methanol = 19:1), while receiving 4-(2-{(3-cyano-5-trifloromethyl)-[2-(cyclopropylamino)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (189 mg). MS (m/z): 650 [M+H]+.

Example 77

The corresponding original connection is treated analogously to example 76 to give the compounds shown in table 2.

Example 78

(1) {2-[(3,5-Bis-triphtalocyaninine)methyl]-4-triptoreline}butylethylamine (2.0 g), 4.6 dichloropyrimidine (1.19 g) and N-ethyldiethanolamine (2,09 ml) dissolved in toluene (10 ml) and the mixture heated under reflux for 3 hours. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→17:3), while receiving (3,5-bis-trifloromethyl)-[2-(butylamino)-5-trifloromethyl]-(6-chloropyrimidine-4-yl)amine (1.8 g). MS (m/z): 613 [M+H]+.

(2) (3,5-Bis-trifloromethyl)-[2-(butylamino)-5-trifloromethyl]-(6-chloropyrimidine-4-yl)amine (300 mg) is dissolved in toluene (5 ml), add hydrochloride complex tert-butyl ester 3-aminopropionic acid (888 mg) and N-ethyldiethanolamine is (1.7 ml) and the mixture was stirred at 120°C during the night. To the reaction solution was added ethyl acetate and 1 n solution of chloride-hydrogen acid and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column (hexane:ethyl acetate= 9:1→3:1), while receiving tert-butyl 3-(6-{(3,5-bis-trifloromethyl)-[2-(butylamino)-5-trifloromethyl]amino}pyrimidine-4-ylamino)propionate (70 mg). MS (m/z): 722 [M+H]+.

(3) Tert-butyl 3-(6-{(3,5-bis-trifloromethyl)-[2-(butylamino)-5-trifloromethyl]amino}pyrimidine-4-ylamino)propionate (60 mg) was dissolved in a 4 n solution of chloride-hydrogen acid in ethyl acetate (0.5 ml) and the mixture is stirred at room temperature for 1.5 hours. To the reaction solution was added ethyl acetate and water, then add saturated aqueous sodium bicarbonate solution, bringing the pH value of the aqueous layer to about 4, and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and the mixture is concentrated under reduced pressure, thus obtaining 3-(6-{(3,5-bis-trifloromethyl)-[2-(butylamino)-5-trifloromethyl]amino}pyrimidine-4-ylamino)propionic acid (57 mg). MS (m/z): 666 [M+H]+.

Examples 79-83

The corresponding starting compound is treated analogously to example 8(2), thus the compounds listed in table 3.

Example 84

(1) 3,5-Bis-triftormetilfosfinov (3.00 g) was dissolved in 1,2-dichloroethane (50 ml), added 70% aqueous solution of ethylamine (0,80 ml) and acetic acid (2.1 ml), then add the borohydride createtextarea (13,1 g), stirring at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 30 minutes, add saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is successively washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 4:1)to give (3,5-bis-trifloromethyl)ethylamine (1.52 g). MS (m/z): 272 [M+H]+.

(2) (3,5-Bis-trifloromethyl)ethylamine (1,03 g) dissolved in N,N-dimethylformamide (10 ml)is added 2-fluoro-5-triftormetilfosfinov (1.45 g) and potassium carbonate (1.48 g) and the mixture is stirred under nitrogen atmosphere at 90°C for 3 hours and at room temperature over night. To the reaction mixture is added a saturated solution of salt and water, the mixture is extracted five times with ethyl acetate, the organic layer twice protivotumanki salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 10:1), thus obtaining 2-[(3,5-bis-trifloromethyl)ethylamino]-5-trifluoromethyl-benzaldehyde (282 mg). MS (m/z): 444 [M+H]+.

(3) 2-[(3,5-Bis-trifloromethyl)ethylamino]-5-trifluoromethyl-benzaldehyde (275 mg) was dissolved in ethanol (2.5 ml), add chloride of hydroxylamine (86 mg) and sodium acetate (102 mg) and the mixture was stirred at 60°C. in a nitrogen atmosphere for 1 hour and 30 minutes. To the reaction solution was added a saturated solution of salt and water, the mixture extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 24:1→83:17), while receiving the reaction of 2-[(3,5-bis-trifloromethyl)ethylamino]-5-triftormetilfullerenov (244 mg). MS (m/z): 459 [M+H]+.

(4) the Reaction of 2-[(3,5-bis-trifloromethyl)ethylamino]-5-triftormetilfullerenov (241 mg) was dissolved in methanol (10 ml), add Nickel Raney catalyst (0.5 g) and the mixture is stirred in hydrogen atmosphere at room temperature overnight. Nickel Raney catalyst is removed by filtration and the filtrate concentrated under reduced DAVLENIYa the residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→0:1), while receiving (2-aminomethyl-4-triptoreline)-(3,5-bis-trifloromethyl)ethylamine (210 mg). MS (m/z): 445 [M+H]+.

(5) (2-Aminomethyl-4-triptoreline)-(3,5-bis-trifloromethyl)ethylamine (165 mg) was dissolved in toluene (3 ml), added tert-butyl 4-(2-chloropyrimidine-5-yloxy)butyrate (202 mg), Tris(dibenzylideneacetone)dipalladium(0) (68 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (92 mg) and tert-piperonyl sodium (71 mg) and the mixture is stirred in a stream of pid at 80°C for 5 hours. To the reaction mixture is added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate = 7:1), while receiving tert-butyl-4-(2-{2-[(3,5-bis-trifloromethyl)ethylamino]-5-triphtalocyaninine}pyrimidine-5-yloxy)butyrate (73 mg). MS (m/z): 681 [M+H]+.

(6) tert-butyl 4-(2-{2-[(3,5-bis-trifloromethyl)ethylamino]-5-triphtalocyaninine}pyrimidine-5-yloxy)butyrate (84 mg) is added 4 n solution of chloride-hydrogen acid in dioxane (1.5 ml) and the mixture is stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, make slightly acidic by adding 10% aqueous solution l is money acid, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol = 19:1), thus obtaining 4-(2-{2-[(3,5-bis-trifloromethyl)ethylamino]-5-triphtalocyaninine}pyrimidine-5-yloxy)butyric acid (47 mg). MS (m/z): 625 [M+H]+.

Example 85

(1) 2-Fluoro-5-triftormetilfosfinov (5,38 g) and cyclopropyl-methylpropylamine and 4.75 g) dissolved in toluene (50 ml), add potassium carbonate (11.6 g) and the mixture was stirred at 120°C for 4 hours. The reaction solution is cooled to room temperature and water is added, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining 2-(cyclopropylamino)-5-triftormetilfosfinov (8.0 g). MS (m/z): 286 [M+H]+.

(2) 2-(Cyclopropylamino)-5-triftormetilfosfinov (6.0 g) is dissolved in diethyl ether (50 ml)is added 2 M solution of bromide Metalmania in diethyl ether (7,35 ml) in a stream of nitrogen at -70°C. the Mixture is stirred at the same temperature in those which begins 30 minutes, the reaction solution is quenched with saturated aqueous ammonium chloride and the mixture extracted with diethyl ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→3:2), while receiving 1-[2-(cyclopropylamino)-5-triptoreline]ethanol (5,43 g). MS (m/z): 302 [M+H]+.

(3) 1-[2-(Cyclopropylamino)-5-triptoreline]ethanol (500 mg) is dissolved in methylene chloride (5 ml), add thionyl chloride (133 μl) under ice cooling and the mixture is stirred at room temperature for 15 minutes. To the reaction solution was added methylene chloride and saturated aqueous sodium bicarbonate solution, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue and the ethyl 4-[2-(3,5-bis-triphtalocyaninine)pyrimidine-5-yloxy]butyrate (749 mg) dissolved in N,N-dimethylformamide (5 ml), add sodium hydride (62%) (64 mg) under ice cooling and the mixture is stirred for 1 hour. Then add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure the AI. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→4:1), thus obtaining the ethyl 4-[2-((3,5-bis-trifloromethyl){1-[2-(cyclopropylamino)-5-triptoreline]ethyl}amino)pyrimidine-5-yloxy]butyrate (144 mg) as a crude product. The obtained ester is dissolved in ethanol (2 ml) and added 2 n aqueous sodium hydroxide solution (500 μl), the mixture is stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue is added ethyl acetate and a dilute chloride-hydrogen acid, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→24:1), while receiving 4-[2-((3,5-bis-trifloromethyl)-{1-[2-(cyclopropylamino)-5-triptoreline]ethyl}amino)pyrimidine-5-yloxy]butyric acid (11 mg). MS (m/z): 707 [M+H]+.

Example 86

1-[2-(Cyclopropylamino)-5-triptoreline]ethanol (1.0 g) is dissolved in methylene chloride (10 ml) and added dropwise thionyl chloride (266 μl) under ice cooling, the mixture is stirred for 30 minutes and concentrated under reduced pressure. (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (1,33 g) dissolve the N,N-dimethylformamide (5 ml), add sodium hydride (62%) (142 mg) under ice cooling and the mixture is stirred for 15 minutes. Add a solution of the residue obtained above in N,N-dimethylformamide (5 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and diethyl ether, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→49:1), while receiving (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl){1-[2-(cyclopropylamino)-5-triptoreline]ethyl}amine (816 mg). MS (m/z): 683/685 [M+H]+.

Example 87

(1) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl){1-[2-(cyclopropylamino)-5-triptoreline]ethyl}amine (200 mg) is dissolved in toluene (3 ml), add Tris(dibenzylideneacetone)dipalladium (27 mg), tert-piperonyl sodium (42 mg), 2-(di-tert-butylphosphino)biphenyl (35 mg) and ethylpiperidine-4-carboxylate (66 μl) and the mixture is stirred at room temperature the flow of nitrogen overnight. To the reaction solution was added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. About atwebsite the residue is purified by chromatography on a column (hexane:ethyl acetate= 19:1→21:4), thus obtaining the ethyl 1-[2-((3,5-bis-trifloromethyl)-{1-[2-(cyclopropylamino)-5-triptoreline]ethyl}amino)pyrimidine-5-yl]piperidine-4-carboxylate (78 mg). MS (m/z): 760 [M+H]+.

(2) Ethyl 1-[2-((3,5-bis-trifloromethyl){1-[2-(cyclopropylamino)-5-triptoreline]ethyl}amino)pyrimidine-5-yl]piperidine-4-carboxylate (75 mg) is dissolved in ethanol (1 ml)is added 2 n aqueous solution of sodium hydroxide (148 μl) and the mixture is stirred at room temperature overnight. Then add ethyl acetate and dilute chloride-hydrogen acid, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→49:1), while receiving 1-[2-((3,5-bis-trifloromethyl){1-[2-(cyclopropylmethyl-amino)-5-triptoreline]ethyl}amino)pyrimidine-5-yl]piperidine-4-carboxylic acid (54 mg). MS (m/z): 732 [M+H]+.

Example 88

(1) 2-(Butylamino)-5-triftormetilfosfinov (1,72 g) dissolved in a mixed solvent of tert-butanol (8 ml) and water (2 ml)is added 2-methyl-2-butene (4 ml), dihydrate sodium dihydrophosphate (1,37 g) and sodium chlorite (1,82 g) under ice cooling and the mixture is stirred for 2 hours. Then d is billaut ethyl acetate and 1 n solution of chloride-hydrogen acid, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), thus obtaining 2-(butylamino)-5-triftorperasin acid (1,29 mg). MS (m/z): 290 [M+H]+.

(2) 2-(Butylamino)-5-triftorperasin acid (1.28 g) was dissolved in methylene chloride (10 ml), add oxalicacid (578 μl) and a catalytic amount of N,N-dimethylformamide under ice cooling, the mixture is stirred for 30 minutes and evaporated to dryness under reduced pressure. The resulting residue is dissolved in methylene chloride (10 ml) and added dropwise a solution of (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (1.77 g) and triethylamine (924 μl) under ice cooling. The reaction solution was stirred at room temperature overnight, the mixture was washed with 1 n NaCl-hydrogen acid and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving N-(3,5-bis-trifloromethyl)-N-(5-bromopyrimidine-2-yl)-2-(butylamino)-5-cryptomelane (842 mg). MS (m/z): 671/673 [M+H]+.

Examples 89-90

The corresponding starting compound is treated similarly to any of the above examples to give the compounds shown in table 7.

Examples 91-102

The corresponding starting compound is treated analogously to example 26 to give the compounds listed in table 8.

Example 103

(1) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-tripterocalyx-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (1.0 g) is dissolved in 1,4-dioxane (10 ml), add complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (216 mg), bis(pinacolato)LIBOR (670 mg) and potassium acetate (389 mg) and the mixture is stirred under nitrogen atmosphere at 80°C during the night. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)Buti is at (805 mg). MS (m/z): 736 [M+H]+.

(2) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (200 mg) is dissolved in 1,4-dioxane (4 ml)is added 2-bromo-4-methylpyridin (70 mg), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (22 mg) and cesium carbonate (133 mg) and the mixture is stirred under nitrogen atmosphere at 80°C for 5 days. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(4-methylpyridin-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (85 mg). MS (m/z): 701 [M+H]+.

(3) Ethyl-4-(2-{(3,5-bis-trifloromethyl)-[2-(4-methylpyridin-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (85 mg) was dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with a saturated solution of salt, su is at over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→23:2), while receiving 4-(2-{(3,5-bis-trifloromethyl)-[2-(4-methylpyridin-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (68 mg). The obtained carboxylic acid is dissolved in ethanol (1 ml)was added 1 n aqueous solution of sodium hydroxide (101 μl) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt of 4-(2-{(3,5-bis-trifloromethyl)-[2-(4-methylpyridin-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (69 mg). MS (m/z): 671 [M-Na]-.

Examples 104-112

The corresponding starting compound is treated analogously to example 103, thus obtaining the compounds listed in table 9.

Example 113

(1) 2-{[(3,5-Bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-cryptomaterial ether triftormetilfullerenov acid (1.19 g) was dissolved in 1,4-dioxane (10 ml), add complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (273 mg), bis(pinacolato)LIBOR (848 mg) and potassium acetate (492 mg) and the mixture is stirred under nitrogen atmosphere at 80°C throughout the night. The reaction solution is cooled to room temperature, add water and ethyl acetate and insoluble substance is removed by filtration through celite (Celite™). The filtrate is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane: ethyl acetate= 9:1→7:3), while receiving (3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)-[2-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-5-trifloromethyl]amine (648 mg). MS (m/z): 691 [M+H]+.

(2) (3,5-Bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)-[2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-5-trifloromethyl]amine (250 mg) is dissolved in 1,4-dioxane (5 ml), add ethyl 4-chloro-2-cryptomaterial-5-carboxylate (140 mg), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (30 mg) and cesium carbonate (177 mg) and the mixture is stirred under nitrogen atmosphere at 80°C during the night. The reaction solution is cooled to room temperature, add water and ethyl acetate and insoluble substances are removed by filtration through celite (Celite™). The filtrate is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→4:1), thus obtaining the ethyl 4-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triform terphenyl)-2-trifluoromethyl-pyrimidine-5-carboxylate (199 mg). MS (m/z): 783 [M+H]+.

(3) Ethyl 4-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)-2-cryptomaterial-5-carboxylate (194 mg) was dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→7:3), while receiving 4-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-triptoreline)-2-cryptomaterial-5-carboxylic acid (165 mg). MS (m/z): 755 [M+H]+.

Example 114

(1) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (300 mg) is dissolved in 1,4-dioxane (5 ml), add 4-chloro-5-methoxy-2-methylsulfonylamino (117 mg), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (33 mg) and cesium carbonate (199 mg) and the mixture is stirred under nitrogen atmosphere at 80°C during the night. The reaction solution is cooled to room temperature, add chlorine the forms and water, and insoluble materials are removed by filtration through celite (Celite™). The filtrate is separated, the organic layer is dried and concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→7:3), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(5-methoxy-2-methylsulfonylamino-4-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (165 mg). MS (m/z): 764 [M+H]+.

(2) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(5-methoxy-2-methylsulfonylamino-4-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (162 mg) dissolved in chloroform (5 ml), add meta-chloroperbenzoic acid (70%) (63 mg) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution was added saturated aqueous sodium thiosulfate solution and chloroform, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→19:1), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(2-methanesulfonyl-5-methoxypyridine-4-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (143 mg). MS (m/z): 780 [M+H]+.

(3) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(2-methanesulfonyl-5-methoxypyridine-4-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (139 mg) is astonaut in methanol (5 ml), add sodium methoxide (48 mg) and the mixture is stirred at room temperature overnight, then add an additional amount of sodium methoxide (48 mg) and the mixture is stirred over night. The reaction solution is concentrated under reduced pressure, to the residue is added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 7:3→1:1), while receiving methyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(2,5-dimethoxypyrimidine-4-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (54 mg). MS (m/z): 734 [M+H]+.

(4) Methyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(2,5-dimethoxypyrimidine-4-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (52 mg) was dissolved in methanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 3 hours. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), �aluca with 4-(2-{(3,5-bis-trifloromethyl)-[2-(2,5-dimethoxypyrimidine-4-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (49 mg). MS (m/z): 720 [M+H]+.

Example 115

(1) 2-{[(3,5-Bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4-cryptomaterial ether triftormetilfullerenov acid (620 mg) was dissolved in 1,4-dioxane (10 ml), add 2-benzyloxypropionic acid (398 mg), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (142 mg) and cesium carbonate (567 mg) and the mixture is stirred under nitrogen atmosphere at 80°C throughout the night. The reaction solution is cooled to room temperature, add water and ethyl acetate and insoluble substances are removed by filtration through celite (Celite™). The filtrate is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), while receiving (2'-benzyloxy-4-triptorelin-2-ylmethyl)-(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amine (617 mg). MS (m/z): 747 [M+H]+.

(2) (2'-Benzyloxy-4-triptorelin-2-ylmethyl)-(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amine (606 mg) was dissolved in ethanol (10 ml), add 10% palladium carbon (100 mg) and the mixture is stirred in hydrogen atmosphere at room temperature for 3.5 hours. The catalyst was removed by filtration and the filtrate concentrate is their under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→7:3), while receiving 2'-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4'-triptorelin-2-ol (374 mg). MS (m/z): 657 [M+H]+.

Example 116

(1) 2'-{[(3,5-Bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4'-triptorelin-2-ol (150 mg) is dissolved in N,N-dimethylformamide (3 ml), add ethyl 4-bromobutyrate (50 μl) and potassium carbonate (47 mg) and the mixture is stirred at room temperature for 2 hours and at 80°C for 2 hours. The reaction solution is cooled to room temperature and add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining the ethyl 4-(2'-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4'-triptorelin-2-yloxy)butyrate (163 mg). MS (m/z): 771 [M+H]+.

(2) Ethyl 4-(2'-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4'-triptorelin-2-yloxy)butyrate (157 mg) was dissolved in ethanol (4 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature in those who tell 2 hours. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving 4-(2'-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4'-triptorelin-2-yloxy)butyric acid (146 mg). The obtained carboxylic acid is dissolved in ethanol (1 ml)was added 1 n aqueous sodium hydroxide solution (197 μl) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt of 4-(2'-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-4'-triptorelin-2-yloxy)butyric acid (146 mg). MS (m/z): 741 [M-Na]-.

Example 117

(1) 2-Chloro-5-(trifluoromethyl)benzaldehyde (12.00 g) was dissolved in toluene (200 ml) and the mixture Tegaserod under reduced pressure. To the resulting solution was added tetrakis(triphenylphosphine)palladium (to 13.29 g), 5-isopropyl-2-methoxybenzeneboronic acid (14,51 g), ethanol (26 ml), distilled water (13 ml) and 2 M aqueous sodium carbonate solution (57,5 ml), the mixture Tegaserod under reduced pressure, heated at 85°C. in a nitrogen atmosphere and stirred over night. The reaction solution is constitute to cool to room temperature, add a saturated solution of salt and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 99:1→19:1), while receiving 5'-isopropyl-2'-methoxy-4-triptorelin-2-carbaldehyde (14,25 mg). MS (m/z): 323 [M+H]+.

(2) 5'-Isopropyl-2'-methoxy-4-triptorelin-2-carbaldehyde (5.0 mg) was dissolved in 1,2-dichloroethane (20 ml), add 3,5-bis(trifluoromethyl)benzylamine (3.8 g), acetic acid (1.1 ml) and mixing createtextarea (4.0 g) and the mixture is stirred at room temperature overnight. To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate = 10:1)to give (3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amine (7.2 g). MS (m/z): 550 [M+H]+.

(3) (3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amine (3.0 g) dissolved in toluene (20 ml), add 5-bromo-2-chloropyrimidine (1.6 g) and N,N-dies populationin (1,4 ml) and the mixture heated under reflux overnight. The reaction solution is allowed to cool to room temperature, water is added and the mixture was extract with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 40:1)to give (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amine (2.6 g). MS (m/z): 708/706 [M+H]+.

(4) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amine (1.2 g) is dissolved in N,N-dimethylformamide (6 ml), add palladium(II) acetate (76 mg), 1,1'-bis(diphenylphosphino)ferrocene (376 mg), ethanol (4.0 ml) and triethylamine (4.8 ml) and the mixture is stirred in an atmosphere of carbon monoxide at 90°C during the night. The reaction solution is allowed to cool to room temperature, water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 20:1→10:1), thus obtaining the ethyl 2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]-pyrimidine-5-carboxyl the t (1.1 g). MS (m/z): 700 [M+H]+.

(5) Ethyl 2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-carboxylate (1.1 g) is dissolved in a mixed solvent of ethanol (18 ml) and tetrahydrofuran (20 ml)is added 2 M aqueous sodium hydroxide solution (3 ml) and the mixture was stirred at 50°C for 1 hour and 30 minutes. The reaction solution is concentrated under reduced pressure, was added 1 n solution of chloride-hydrogen acid and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol = 25:1), thus obtaining 2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (700 mg). MS (m/z): 672 [M+H]+.

Example 118

(1) 2-[(3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (200 mg) is dissolved in N,N-dimethylformamide (5 ml), add the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (86 mg), 1-hydroxybenzotriazole (60 mg), triethylamine (125 μl) and hydrochloride complex ethyl ester of 4-aminobutyric acid (75 mg) and the mixture is stirred at room temperature overnight. To the PE klonoa mixture is added a saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 5:2), thus obtaining the ethyl 4-({2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-carbonyl}amino)butyrate (230 mg). MS (m/z): 785 [M+H]+.

(2) Ethyl 4-({2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-carbonyl}amino)butyrate (230 mg) was dissolved in ethanol (5 ml)is added 2 M aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture are added 2 n solution of chloride-hydrogen acid and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol = 25:1), thus obtaining 4-({2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-carbonyl}amino)butyric acid (220 mg). MS (m/z): 757 [M+H]+.

Example 119

(1) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(5'-isopropyl-2'-methoxy-4-trifloromethyl enyl-2-ylmethyl)amine (1.06 g) was dissolved in dimethyl sulfoxide (5 ml), the mixture Tegaserod and add dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) (61 mg), potassium acetate (442 mg) and bis(pinacolato)LIBOR (571 mg). The mixture Tegaserod, heated to 80°C in a stream of nitrogen and stirred for 45 minutes. The reaction solution is allowed to cool to room temperature, add a saturated solution of salt and the mixture is extracted with ethyl acetate. The organic layer is washed twice with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (5 ml), added dropwise a 30% aqueous hydrogen peroxide solution (1.5 ml) under ice cooling and stirred at the same temperature for 1 hour and 30 minutes. To the reaction mixture is added dropwise a saturated aqueous sodium thiosulfate solution under ice cooling, then add saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→3:1), while receiving 2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-ol (866 mg). MS (m/z): 644 [M+H]+.

(2) 2-{(3,5-Bis-trifloromethyl)-[4-(cyclopropylmethyl the propyl-amino)-2-methoxypyridine-5-ylmethyl]amino}pyrimidine-5-ol (300 mg) is dissolved in N,N-dimethylformamide (2 ml), add potassium carbonate (193 mg) and 4-bromobutyronitrile (139 μl) and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer is washed twice with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 17:3→3:1), while receiving 4-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyronitrile (308 mg). MS (m/z): 711 [M+H]+.

Example 120

4-{2-[(3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyronitrile (240 mg) was dissolved in N,N-dimethylformamide (7.5 ml), the mixture Tegaserod add sodium azide (220 mg) and ammonium chloride (181 mg), heated to 110°C and stirred overnight. The reaction solution is allowed to cool to room temperature, then add saturated salt solution and 10% aqueous citric acid solution and the mixture extracted with ethyl acetate. The organic layer is washed twice with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with silicagel the m (chloroform: methanol= 99:1→19:1), while receiving (3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-{5-[3-(1H-tetrazol-5-yl)propoxy]pyrimidine-2-yl}amine (127 mg). MS (m/z): 754 [M+H]+.

Example 121

(1) 2-[(2-Benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)amino]pyrimidine-5-ol (1,33 ml) dissolved in tetrahydrofuran (20 ml), add 2-methylsulfonylamino (290 mg), triphenylphosphine (870 mg) and 40% solution of diethylazodicarboxylate in toluene (1.5 ml) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 99:1→9:1), while receiving (2-benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)-[5-(2-methylsulfonylmethane)pyrimidine-2-yl]amine (1,21 g). MS (m/z): 676 [M+H]+.

(2) (2-Benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)-[5-(2-methylsulfonylmethane)pyrimidine-2-yl]amine (1,21 g) dissolved in chloroform (15 ml), add meta-chloroperbenzoic acid (75%) (906 mg) and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added saturated aqueous sodium thiosulfate solution and chloro is Orme, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→7:3), while receiving (2-benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)-[5-(2-methansulfonate)pyrimidine-2-yl]amine (1,09 g). MS (m/z): 708 [M+H]+.

(3) (2-Benzyloxy-5-trifloromethyl)-(3,5-bis-trifloromethyl)-[5-(2-methansulfonate)pyrimidine-2-yl]amine (1.07 g) was dissolved in ethanol (15 ml), add 10% palladium carbon (320 mg) and the mixture is stirred in hydrogen atmosphere at room temperature for 7 hours. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 2:1), thus obtaining 2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methansulfonate)pyrimidine-2-yl]amino}methyl)-4-triptoreline (400 mg). MS (m/z): 618 [M+H]+.

(4) 2-({(3,5-Bis-trifloromethyl)-[5-(2-methansulfonate)pyrimidine-2-yl]amino}methyl)-4-triptoreline (400 mg) and pyridine (79 μl) dissolved in methylene chloride (10 ml), add anhydride triftormetilfullerenov acid (163 μl) under ice cooling and the mixture is stirred atmophere nitrogen at 0°C for 30 minutes. Re clanny the solution is cooled to room temperature and stirred for 50 minutes, add anhydride triftormetilfullerenov acid (81 ml) and the mixture is stirred for 10 minutes. Then add saturated aqueous sodium bicarbonate solution and chloroform, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→2:1), thus obtaining 2-({(3,5-bis-trifloromethyl)-[5-(2-methansulfonate)pyrimidine-2-yl]amino}methyl)-4-cryptomaterial ether triftormetilfullerenov acid (386 mg). MS (m/z): 750 [M+H]+.

(5) 2-({(3,5-Bis-trifloromethyl)-[5-(2-methansulfonate)pyrimidine-2-yl]amino}methyl)-4-cryptomaterial ether triftormetilfullerenov acid (110 mg) was dissolved in 1,4-dioxane (2 ml), add 2,4-dimethoxypyrimidine-5-Bronevoy acid (70 mg), palladium acetate (13.2 mg), 1,1'-bis(di-tert-butylphosphino)ferrocene (28 mg) and tribalistic (62 mg) and the mixture is stirred in nitrogen atmosphere at 80°C for 4 hours. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate =2:1), while receiving (3,5-bis-trifloromethyl)-[2-(2,4-dimethoxypyrimidine-5-yl)-5-trifloromethyl][5-(2-methansulfonate)pyrimidine-2-yl]amine (34 mg). MS (m/z): 740 [M+H]+.

Example 122

The corresponding original connection is treated analogously to example 121, thus obtaining the compound shown in table 10.

Example 123

(1) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(6-Isopropenyl-3-methoxypyridine-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (76 mg) was dissolved in ethanol (5 ml), add 10% palladium charcoal (15 mg) and the mixture is stirred in hydrogen atmosphere for 1.5 hours. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure, thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(6-isopropyl-3-methoxypyridine-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (70 mg). MS (m/z): 759 [M+H]+.

(2) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(6-isopropyl-3-methoxypyridine-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (70 mg) was dissolved in ethanol (2 ml)was added 1 n aqueous sodium hydroxide solution (0.5 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic is the third layer is washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving 4-(2-{(3,5-bis-trifloromethyl)-[2-(6-isopropyl-3-methoxypyridine-2-yl)-5-reformational]amino}pyrimidine-5-yloxy)butyric acid (62 mg). The obtained carboxylic acid is dissolved in ethanol (1 ml)was added 1 n aqueous solution of sodium hydroxide (85 ml) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt of 4-(2-{(3,5-bis-trifloromethyl)-[2-(6-isopropyl-3-methoxypyridine-2-yl)-5-trifluoromethyl-benzyl]amino}pyrimidine-5-yloxy)butyric acid (729 mg). MS (m/z): 729 [M-Na]-.

Example 124

(1) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (300 mg) is dissolved in N,N-dimethylformamide (5 ml), add sodium hydride (60%) (29 mg) and 4,6-dichloropyrimidine (107 mg) under ice cooling and the mixture is stirred for 30 minutes, the reaction solution is cooled to room temperature, add 4,6-dichloropyrimidine (107 mg) and the mixture is stirred within 30 minutes. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. Forming the different residue purified by chromatography on a column of silica gel (hexane: ethyl acetate= 49:1→17:1), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(6-chloropyrimidine-4-yloxy)-5-trifluoromethyl-benzyl]amino}pyrimidine-5-yloxy)butyrate (244 mg). MS (m/z): 738/740 [M+H]+.

(2) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(6-chloropyrimidine-4-yloxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (170 mg) was dissolved in toluene (5 ml), add diisopropylethylamine (136 ml), 2.0 M solution of dimethylamine in tetrahydrofuran (0.4 ml) and the mixture was stirred at 50°C for 1 day. The reaction solution is cooled to room temperature, add aqueous solution of citric acid and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→2:1), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(6-dimethylamino-pyrimidine-4-yloxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (115 mg). MS (m/z): 747 [M+H]+.

(3) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-(6-dimethylaminopyridine-4-yloxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (110 mg) was dissolved in ethanol (5 ml)was added 1 n aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added 1 n solution of chloride-bodoro the Noah acid and ethyl acetate, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving 4-(2-{(3,5-bis-trifloromethyl)-[2-(6-dimethylamino-pyrimidine-4-yloxy)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (107 mg). MS (m/z): 719 [M+H]+.

Example 125

The corresponding original connection is treated analogously to example 124, thus obtaining the compound shown in table 11.

Example 126

(1) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-tripterocalyx-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (260 mg) was dissolved in 1,2-dimethoxyethane (1 ml) and added dropwise (S)-1-(tert-butyldimethylsilyloxy)Propylamine (140 mg), Tris(dibenzylideneacetone)dipalladium (31 mg), 2-(di-tert-butylphosphino)biphenyl (41 mg) and tribalistic (146 mg), the mixture Tegaserod under reduced pressure and stirred in nitrogen atmosphere at 80°C during the night. The reaction solution is allowed to cool to room temperature, add a saturated solution of salt and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under decreased the pressure. The resulting residue is purified by chromatography on a column (hexane:ethyl acetate= 1:0→10:1), while receiving ethyl-4-[2-((3,5-bis-trifloromethyl)-{2-[(S)-1-(tert-butyldimethylsilyloxy)propylamino]-5-trifloromethyl}amino)pyrimidine-5-yloxy]butyrate (186 mg). MS (m/z): 811 [M+H]+.

(2) Ethyl 4-[2-((3,5-bis-trifloromethyl)-{2-[(S)-1-(tert-butyldimethylsilyloxy)propylamino]-5-trifloromethyl}amino)pyrimidine-5-yloxy]butyrate (183 mg) was dissolved in tetrahydrofuran (3 ml), was added 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1 ml) and the mixture is stirred at room temperature for 20 minutes. The reaction solution is concentrated under reduced pressure, add a saturated solution of salt and the mixture is extracted with ethyl acetate. The organic layer is washed twice with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→2:1), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-((S)-1-hydroxymethylpropane)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (93 mg). MS (m/z): 697 [M+H]+.

(3) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-((S)-1-hydroxymethylpropane)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (40 mg) was dissolved in a mixed solvent IU is anola (0.3 ml) and tetrahydrofuran (1 ml), added 1 M aqueous sodium hydroxide solution (0.5 ml) and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added 10% aqueous citric acid solution and saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining 4-(2-{(3,5-bis-trifloromethyl)-[2-((S)-1-hydroxymethylpropane)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (41 mg). MS (m/z): 669 [M+H]+.

Example 127

(1) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-((S)-1-hydroxymethylpropane)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (102 mg) was dissolved in methylene chloride (1.5 ml) and add triethylamine (31 μl), then add triphosgene (17 mg) under cooling with water and the mixture is stirred at room temperature overnight. To the reaction mixture is added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column (hexane:ethyl acetate= 9:1→7:3), thus obtaining the ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-((S)-4-ethyl-2-oxoacridine-3-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)is atirat (94 mg). MS (m/z): 723 [M+H]+.

(2) Ethyl 4-(2-{(3,5-bis-trifloromethyl)-[2-((S)-4-ethyl-2-oxoacridine-3-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (90 mg) was dissolved in a mixed solvent of methanol (0.5 ml) and tetrahydrofuran (1 ml)was added 1 M aqueous sodium hydroxide solution (0.5 ml) and the mixture is stirred at room temperature for 1 hour. The reaction mixture was acidified with 10% aqueous citric acid solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→97:3), while receiving 4-(2-{(3,5-bis-trifloromethyl)-[2-((S)-4-ethyl-2-oxazolidin-3-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (64 mg). MS (m/z): 695 [M+H]+.

Example 128

(1) 2-[(3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-ol (300 mg) is dissolved in tetrahydrofuran (2 ml) and add 2-(methylthio)ethanol (162 μl) and triphenylphosphine (488 mg), and then added dropwise a 40% solution of diethylazodicarboxylate in toluene (424 μl) under cooling with water and the mixture was stirred at 50°C during the night. Add 2-(methylthio)ethanol (243 μl) and triphenylphosphine (244 mg) is then added dropwise, diisopropylcarbodiimide (361 μl) under cooling with water and the mixture is stirred at 60°C for 2 hours. To the reaction mixture is added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 99:1→9:1), while receiving (3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-[5-(2-methylsulfonylmethane)pyrimidine-2-yl]amine (300 mg). MS (m/z): 718 [M+H]+.

(2) (3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-[5-(2-methylsulfonylmethane)pyrimidine-2-yl]amine (296 mg) was dissolved in chloroform (3 ml), add meta-chloroperbenzoic acid (152 mg) and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous sodium bicarbonate solution, the mixture is stirred at room temperature for 10 minutes and extracted with chloroform, the organic layer is successively washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 19:1→2:1 and chloroform: methanol= 97:3→19:1), while receiving (3,5-bis-trifloromethyl)-(5'-and propyl-2'-methoxy-4-triptorelin-2-ylmethyl)-[5-(2-methansulfonate)pyrimidine-2-yl]amine (203 mg) MS (m/z): 750 [M+H] +and (3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-[5-(2-methansulfonate)pyrimidine-2-yl]amine (65 mg) MS (m/z): 734 [M+H]+.

Example 129

(1) (3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amine (2.0 g) dissolved in ethanol (20 ml), add brazian (578 mg) and sodium bicarbonate (928 mg) and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 10:1→5:1), while receiving (3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)cyanamide (1.8 g). MS (m/z): 575 [M+H]+.

(2) (3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)cyanamide (1.8 g) is dissolved in N,N-dimethylformamide (10 ml), add sodium azide (407 mg) and ammonium chloride (335 mg), the mixture is heated to 100°C and stirred for 6 hours. The reaction solution is allowed to cool to room temperature, add 10% aqueous citric acid solution and the mixture extracted with what dilatatum. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol = 30:1)to give (3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(2H-tetrazol-5-yl)amine (1.9 g). MS (m/z): 618 [M+H]+.

(3) (3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(2H-tetrazol-5-yl)amine (400 mg) dissolved in N,N-dimethylformamide (3 ml), add triethylamine (2 ml) and ethyl-4-bromobutyrate (278 μl) and the mixture was stirred at 50°C for 3 hours. To the reaction mixture are added water and extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 10:1), thus obtaining the ethyl 4-{5-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]tetrazol-2-yl}butyrate (360 mg). MS (m/z): 732 [M+H]+.

(4) Ethyl 4-{5-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]tetrazol-2-yl}butyrate (180 mg) was dissolved in ethanol (3 ml)is added 2 M aqueous sodium hydroxide solution (0.5 ml) and the mixture was stirred at the room for the Noah temperature for 1 hour and 30 minutes. The reaction mixture was acidified with 1 n NaCl-hydrogen acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol = 20:1), while receiving 4-{5-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]tetrazol-2-yl}butyric acid (160 mg). MS (m/z): 704 [M+H]+.

(5) 4-{5-[(3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]tetrazol-2-yl}butyric acid (154 mg) is dissolved in ethanol (3 ml), was added 1 M aqueous sodium hydroxide solution (225 ml) and concentrate under reduced pressure, thus obtaining the sodium salt of 4-{5-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)amino]tetrazol-2-yl}butyric acid (153 mg). MS (m/z): 702 [M-Na]-.

Example 130

(1) (3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(2H-tetrazol-5-yl)amine (300 mg) is dissolved in tetrahydrofuran (5 ml), add triphenylphosphine (191 mg), 2-(methylthio)ethanol (63 ml), 40% solution of diethyl-azodicarboxylate in toluene (332 μl) and the mixture is stirred at room temperature for 2 hours and 30 minutes. To the reaction mixture add the water and the mixture extracted with simple ether. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 12:1)to give (3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-[2-(2-methylsulfonylamino)-2H-tetrazol-5-yl]amine (270 mg). MS (m/z): 692 [M+H]+.

(2) (3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-[2-(2-methylsulfonylamino)-2H-tetrazol-5-yl]amine (270 mg) was dissolved in chloroform (3 ml), add meta-chloroperbenzoic acid (168 mg) and the mixture is stirred at room temperature for 3 hours. To the reaction solution was added saturated aqueous sodium bicarbonate solution, the mixture is extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol = 40:1)to give (3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-[2-(2-methansulfonate)-2H-tetrazol-5-yl]amine (157 mg). MS (m/z): 708 [M+H]+.

Example 131

(1) 5'-Isopropyl-2'-methoxy-4-triptorelin-2-carbaldehyde (3.00 g) restauraut ethanol (40 ml), add the chloride of hydroxylamine (1.29 g) and sodium acetate (1,53 g) and the mixture is stirred under nitrogen atmosphere at 60°C for 1 hour and 30 minutes. The reaction solution is concentrated under reduced pressure, add a saturated solution of salt and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue (3.3 g) dissolved in methanol (40 ml), add Nickel Raney catalyst (5 g) and the mixture is stirred in hydrogen atmosphere at room temperature overnight. Nickel Raney catalyst is removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→19:1), while receiving S-(5'-isopropyl-2'-methoxy-4-triptorelin-2-yl)methylamine (1,57 g). MS (m/z): 324 [M+H]+.

(2)-(5'-Isopropyl-2'-methoxy-4-triptorelin-2-yl)methylamine (1.54 g) was dissolved in toluene (25 ml), added tert-butyl 4-(2-chloropyrimidine-5-yloxy)butyrate (1,96 g), palladium(II) acetate (195 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (543 mg), iodide, Tetra-n-butylamine (359 mg) and tert-piperonyl sodium (560 mg) and the mixture is stirred in a stream of nitrogen at 85°C during the night. The reaction solution is allowed to cool to room temperature and DOB is given in a saturated solution of salt, the mixture is extracted with ethyl acetate, the organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane: ethyl acetate= 47:3→3:1), while receiving tert-butyl 4-{2-[(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (895 mg). MS (m/z): 560 [M+H]+.

(3) Tert-butyl 4-{2-[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (180 mg) was dissolved in N,N-dimethylformamide (1.0 ml) and added 1,3-dichloro-5-chlorodibenzo (252 mg), and then add sodium hydride (60%) (34 mg) under ice cooling and the mixture is stirred at room temperature for 3 hours. To the reaction solution was added a saturated solution of salt, the mixture is extracted with ethyl acetate, the organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→9:1), while receiving tert-butyl 4-{2-[(3,5-dichlorobenzyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (184 mg). MS (m/z): 720/718 [M+H]+.

(4) tert-butyl 4-{2-[(3,5-dichlorobenzyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (180 mg) is added 4 n solution of chloride of vodorodny the th acid in dioxane (2 ml) and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→19:1), while receiving 4-{2-[(3,5-dichlorobenzyl)-(5'-isopropyl-2'-methoxy-4-reformational-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (136 mg). MS (m/z): 664/662 [M+H]+.

Examples 132-133

The corresponding starting compound is treated analogously to example 131, thus obtaining the compounds listed in table 15.

Example 134

(1) toluene (1 ml) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (62 mg) and palladium (II) acetate (16 mg) and the mixture is stirred under nitrogen atmosphere at room temperature for 5 minutes. To a mixed solvent added a mixed solution of tert-butyl 4-{2-[(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (200 mg), 1-bromo-3,5-bis-triptoreline (126 mg) and toluene (1.5 ml), the mixture Tegaserod under reduced pressure, add tert-piperonyl sodium (51 mg) and the mixture is stirred in a stream of nitrogen at 80°C during the night. The reaction solution is allowed to cool to room temperature and add acadeny salt solution, the mixture is extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate = 10:1), while receiving tert-butyl 4-{2-[(3,5-bis-triptoreline)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (204 mg). MS (m/z): 772 [M+H]+.

(2) tert-butyl 4-{2-[(3,5-bis-triptoreline)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (197 mg) is added 4 n solution of chloride-hydrogen acid in dioxane (2.5 ml) and the mixture is stirred at room temperature for 3 hours. To the reaction mixture is added a saturated solution of salt, the mixture is extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→19:1), while receiving 4-{2-[(3,5-bis-triptoreline)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (104 mg). MS (m/z): 716 [M+H]+.

Example 135

(1)-(5'-Isopropyl-2'-methoxy-4-triptorelin-2-yl)methylamine (3,47 g) dissolved in dioxane (50 ml), to which ablaut 5-bromo-2-chloropyrimidine (5.30 g) and N,N-diisopropylethylamine (5,74 ml) and the mixture was stirred at 100°C for 2 hours and 30 minutes. The reaction solution is allowed to cool to room temperature and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 50:1→22:3), while receiving (5-bromopyrimidine-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)Amin (4,82 g). MS (m/z): 482/480 [M+H]+.

(2) (5-Bromopyrimidine-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)Amin (3,30 g) dissolved in toluene (30 ml) and add Tris(dibenzylideneacetone)dipalladium (1.26 g), 2-(di-tert-butylphosphino)biphenyl (1,23 g), morpholine (2.4 ml) and tert-piperonyl sodium (1,32 g), the mixture Tegaserod under reduced pressure and stirred in a stream of nitrogen at 50°C throughout the night. To the reaction mixture is added a saturated salt solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→3:1), while receiving (5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amine (1,11 g). MS (m/z): 487 [M+H]+.

(3) (5'-Isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amine (500 mg) is dissolved in N,N-dimethylformamide (3 ml) and add 3-fluoro-5-(trifluoromethyl)Benzimra is d (528 mg), then add sodium hydride (60%) (82 mg) under ice cooling and the mixture is stirred at room temperature for 2 hours and 30 minutes. To the reaction solution was added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 49:1→22:3), while receiving (3-fluoro-5-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amine (440 mg). MS (m/z): 663 [M+H]+.

(4) To tetrahydrofuran (6 ml) is added sodium hydride (60%) (390 mg) in a nitrogen atmosphere, then added dropwise benzyl alcohol (1,01 ml) under cooling with water and the mixture is stirred at the same temperature for 30 minutes. To the reaction mixture is added a mixture of (3-fluoro-5-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amine (430 mg) and tetrahydrofuran (4 ml) and the mixture is stirred under nitrogen atmosphere at 70°C during the night. To the reaction solution was added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. Obrazovash is the action scene the residue purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 97:3→17:3), while receiving (3-benzyloxy-5-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amine (221 mg). MS (m/z): 751 [M+H]+.

(5) (3-Benzyloxy-5-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amine (215 mg) was dissolved in methanol (10.5 ml), add 10% palladium charcoal and the mixture is stirred in hydrogen atmosphere at room temperature for 1 hour. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate = 4:1→1:2 chloroform:methanol= 19:1→9:1), while receiving 3-{[(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-5-triptoreline (98 mg). MS (m/z): 661 [M+H]+.

(6) 3-{[(5'-Isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-5-triptoreline (95 mg) was dissolved in N,N-dimethylformamide (1 ml), add potassium carbonate (90 mg) and ethyl 4-bromobutyrate (93 μl) and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added a saturated solution of salt, the mixture is extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate the ri reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 10:1→4:1), thus obtaining the ethyl 4-(3-{[(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-5-triptoreline)butyrate (92 mg). MS (m/z): 775 [M+H]+.

(7) Ethyl 4-(3-{[(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-5-triptoreline)butyrate (88 mg) was dissolved in a mixed solvent of ethanol (1 ml) and tetrahydrofuran (1 ml)was added 1 M aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 1 hour. The reaction mixture was acidified with 10% aqueous citric acid solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→1:1), while receiving 4-(3-{[(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-5-triptoreline)butyric acid (71 mg). MS (m/z): 747 [M+H]+.

(8) 4-(3-{[(5'-Isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-5-triptoreline)butyric acid (69 mg) was dissolved in ethanol (1 ml) and DOB is given in 1 M aqueous sodium hydroxide solution (92 ml), the mixture is stirred at room temperature for 3 minutes and concentrated under reduced pressure, thus obtaining the sodium salt of 4-(3-{[(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-5-triptoreline)butyric acid (66 mg). MS (m/z): 745 [M-Na]+.

Example 136

(1) (2-Benzyloxy-3-chloro-5-trifloromethyl)-(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (obtained by treating the corresponding starting compound analogously to example 23 (1)-(2)) (700 mg) is treated analogously to example 87 (1), thus obtaining 1-{2-[(2-benzyloxy-3-chloro-5-trifloromethyl)-(3,5-bis-trifloromethyl)amino]pyrimidine-5-yl}ethyl piperidine-4-carboxylate (422 mg). MS (m/z): 775/777 [M+H]+.

(2) Ethyl 1-{2-[(2-benzyloxy-3-chloro-5-trifloromethyl)-(3,5-bis-trifloromethyl)amino]pyrimidine-5-yl}piperidine-4-carboxylate (412 mg) is treated analogously to example 23(5), thus obtaining the ethyl 1-{2-[(3,5-bis-trifloromethyl)-(3-chloro-2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yl}piperidine-4-carboxylate (277 mg). MS (m/z): 685/687 [M+H]+.

(3) Ethyl 1-{2-[(3,5-bis-trifloromethyl)-(3-chloro-2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yl}piperidine-4-carboxylate (274 mg) is treated with the appropriate starting compound analogously to example 26, while e is ω 1-{2-[(3,5-bis-trifloromethyl)-(6-chloro-3'-isopropyl-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yl}piperidine-4-carboxylic acid (180 mg). MS (m/z): 759/761 [M+H]+.

Example 137

The corresponding original connection is treated analogously to example 136, thus obtaining the compound listed in table 17.

Example 138

(1) (2-Benzyloxy-3-chloro-5-trifloromethyl)-(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (2,11 g) is treated analogously to example 23(3)-(5), thus obtaining the ethyl 4-{2-[(3,5-bis-trifloromethyl)-(3-chloro-2-hydroxy-5-trifloromethyl)-amino]pyrimidine-5-yloxy}butyrate (163 mg). MS (m/z): 660/662 [M+H]+.

(2) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(3-chloro-2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (160 mg) is treated with the appropriate starting compound analogously to example 26, while receiving sodium salt of 4-{2-[(3,5-bis-trifloromethyl)-(6-chloro-3'-isopropyl-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (87 mg). MS (m/z): 762/764 [M-Na]-.

Example 139

(1) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)-(5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amine (obtained as in example 117(1)-(3)) (532 mg) is treated with the appropriate starting compound analogously to example 2(4), thus obtaining 2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-ol (371 mg). MS (m/z): 636 [M+H]+.

(2) 2-[(3,5-Bis-triptorelin who yl)-(5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-ol (160 mg) is treated analogously to example 2(5)-(6), thus the sodium salt of 4-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (128 mg). MS (m/z): 720 [M-Ma]-.

Example 140

(1) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (1.39 g) was dissolved in chloroform (20 ml) and add N-bromosuccinimide (475 mg), the mixture is stirred at room temperature for 2 hours and the reaction solution was concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining the ethyl 4-{2-[(3,5-bis-trifloromethyl)-(3-bromo-2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (1.29 g). MS (m/z): 704/706 [M+H]+.

(2) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(3-bromo-2-hydroxy-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (1.29 g) and pyridine (220 μl) dissolved in methylene chloride (15 ml), add anhydride triftormetilfullerenov acid (460 μl) under ice cooling and the mixture is stirred under nitrogen atmosphere at 0°C for 45 minutes. To the reaction solution was added saturated aqueous sodium bicarbonate solution and chloroform, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. Education is asisa the residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining the ethyl 4-{2-[(3,5-bis-trifloromethyl)-(3-bromo-2-tripterocalyx-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (907 mg). MS (m/z): 836/838 [M+H]+.

(3) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(3-bromo-2-tripterocalyx-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (300 mg) is dissolved in 1,4-dioxane (4 ml), add complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (58 mg), melborne acid (32 mg) and cesium carbonate (175 mg) and the mixture is stirred under nitrogen atmosphere at 80°C for 3 days. The reaction solution is cooled to room temperature, add ethyl acetate and saturated aqueous sodium bicarbonate solution, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→17:3), while receiving the crude product containing ethyl 4-{2-[(3,5-bis-trifloromethyl)-(3-methyl-2-tripterocalyx-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (207 mg). The crude product (200 mg) is dissolved in 1,4-dioxane (4 ml), add complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (42 mg), 5-isopropyl-2-methoxyphenyl Borat (150 mg) and cesium carbonate (127 mg, and the mixture is stirred under nitrogen atmosphere at 80°C during the night. The reaction solution is cooled to room temperature, add ethyl acetate and saturated aqueous sodium bicarbonate solution, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate = 49:1→17:3) and then gel chromatography (JAIGEL; chloroform), thus obtaining the ethyl 4-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-6-methyl-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (20 mg). MS (m/z): 772 [M+H]+.

(4) Ethyl 4-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-6-methyl-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (20 mg) dissolved in ethanol (2 ml)was added 1 n aqueous sodium hydroxide solution (0.5 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added 1 n solution of chloride-hydrogen acid and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving 4-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-6-methyl-4-trifloromethyl enyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (21 mg). The obtained carboxylic acid is dissolved in ethanol (1 ml)was added 1 n aqueous solution of sodium hydroxide (28 ml) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt of 4-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-6-methyl-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (19 mg). MS (m/z): 742 [M-Na]-.

Example 141

(3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-[2-(2-methansulfonate)-2H-tetrazol-5-yl]amine (129 mg) dissolved in chloroform (2 ml), add meta-chloroperbenzoic acid (50 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate solution, the mixture is extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 2:1)to give (3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)-[2-(2-methanesulfonyl)-2H-tetrazol-5-yl]amine (81 mg). MS (m/z): 724 [M+H]+.

Example 142

(1) Tert-butyl 4-(2-chloropyrimidine-5-yloxy)butyrate (5.0 g) p is straut in toluene (100 ml), add palladium acetate (412 mg) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.26 g) and the mixture is stirred under nitrogen atmosphere at 50°C for 1 hour. The reaction solution is cooled to room temperature, add 3,5-bis-triftormetilfosfinov (5.35 g) and tert-piperonyl sodium (3.88 g) and the mixture was stirred at 35°C for 2 hours. Then add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 9:1→2:1) and chromatography on a column with NH-silica gel (hexane:ethyl acetate= 4:1→2:1), while receiving tert-butyl 4-[2-(3,5-bis-triphtalocyaninine)pyrimidine-5-yloxy]butyrate (5.59 in). MS (m/z): 480 [M+H]+.

(2) (2-Bromo-4,5-acid)methanol (2,47 g) dissolved in methylene chloride (30 ml), add thionyl chloride (875 μl) and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure, added to the hexane and the resulting crystal was filtered, thus obtaining 1-bromo-2-chloromethyl-4,5-dimethoxybenzene (2.25 g). MS (m/z): 229/231 [M+H]+.

(3) Tert-butyl 4-[2-(3,5-bis-triphtalocyaninine)pyrimidine-5-yloxy]butyrate (100 mg) dissolved in DMF (1 ml), add sodium hydride (60%) (10,8 mg) under cooling with ice and the CME is ü stirred under ice cooling for 15 minutes. Then add 1-bromo-2-chloromethyl-4,5-dimethoxybenzene (83,1 mg) and the mixture is stirred under ice cooling for 1 hour. To the reaction solution was added an aqueous solution of ammonium chloride and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 10:1→4:1), while receiving tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(2-bromo-4,5-dimethoxybenzyl)amino]pyrimidine-5-yloxy}butyrate (116 mg). MS (m/z): 708/710 [M+H]+.

(4) Tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(2-bromo-4,5-dimethoxybenzyl)amino]pyrimidine-5-yloxy}butyrate (150 mg) is dissolved in 1,4-dioxane (3 ml), add (4-fluoro-5-isopropyl-2-methoxyphenyl)baronova acid (128 mg), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (32 mg) and cesium carbonate (196 mg) and the mixture is stirred under nitrogen atmosphere at 80°C during the night. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 19:1→17:3), while receiving tert-butyl 4-{2-[(3,5-bis-cryptomite is benzyl)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (140 mg). MS (m/z): 796 [M+H]+.

(5) To tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (129 mg) is added 4 n hydrochloride solution in dioxane (3 ml) and the mixture is stirred at room temperature for 7 hours. To the reaction solution was added saturated aqueous solution of sodium hydroxide and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), while receiving 4-{2-[(3,5-bis-trifloromethyl)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (100 mg). MS (m/z): 740 [M+H]+.

(6) Carboxylic acid obtained in the above stage (5), dissolved in ethanol (1 ml)was added 1 n aqueous sodium hydroxide solution (128 μl) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt of 4-{2-[(3,5-bis-trifloromethyl)-(4'-fluoro-5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (100 mg). MS (m/z): 738 [M-Na]-.

Examples 143-152

The corresponding starting compound is treated analogously to example 142, while receiving connections, see the s in table 20.

Example 153

The corresponding original connection is treated analogously to example 169, give the compounds shown in table 20.

Examples 154-157

The corresponding starting compound is treated analogously to example 160, thus obtaining the compounds listed in table 20.

Example 158

The corresponding initial connection process as in example 117(1) and example 131, thus obtaining the compound listed in table 21.

Example 159

(1) Tert-butyryl 4-{2-[(2-bromo-4,5-dimethoxybenzyl)-(3-cyano-5-trifloromethyl)amino]pyrimidine-5-yloxy}butyric acid (obtained by treating the corresponding starting compound analogously to example 142(1)-(3)) (1,0 g) dissolved in 1,4-dioxane (10 ml), add complex [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium and dichloromethane (252 mg), bis(pinacolato)LIBOR (782 mg) and potassium acetate (453 mg) and the mixture is stirred under nitrogen atmosphere at 80°C during the night. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography n is a column of silica gel (hexane:ethyl acetate= 80:20→70:30), while receiving tert-butyl 4-(2-{(3-cyano-5-trifloromethyl)-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]amino}pyrimidine-5-yloxy)butyrate (769 mg). MS (m/z): 713 [M+H]+.

(2) Tert-butyryl 4-(2-{(3-cyano-5-trifloromethyl)-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]amino}pyrimidine-5-yloxy)butyrate (60 mg) was dissolved in 1,4-dioxane (1.5 ml), is added 2-bromo-6-Isopropenyl-3-methoxypyridine (38 mg), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (7 mg) and cesium carbonate (55 mg) and the mixture is stirred under nitrogen atmosphere at 80°C during the night. The reaction solution is cooled to room temperature, add ethyl acetate and water, the mixture is separated, the organic layer is filtered through NH-silica gel, the mixture is extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 85:15→70:30), while receiving tert-butyl 4-(2-{(3-cyano-5-trifloromethyl)-[2-(6-Isopropenyl-3-methoxypyridine-2-yl)-4,5-dimethoxybenzyl]amino}pyrimidine-5-yloxy)butyrate (17 mg). MS (m/z): 734 [M+H]+.

(3) Tert-butyl 4-(2-{(3-cyano-5-trifloromethyl)-[2-(6-Isopropenyl-3-methoxypyridine-2-yl)-4,5-dimethoxybenzyl]amino}-pyrimidine-5-yloxy)butyrate (36 mg) is treated analogously to example 142(5), thus obtaining 4-(2-{(3-cyano-5-triptorelin the l)-[2-(6-Isopropenyl-3-methoxypyridine-2-yl)-4,5-dimethoxybenzyl]amino}pyrimidine-5-yloxy)butyric acid (24.5 mg). MS (m/z): 678 [M+H]+.

(4) 4-(2-{(3-Cyano-5-trifloromethyl)-[2-(6-Isopropenyl-3-methoxypyridine-2-yl)-4,5-dimethoxybenzyl]amino}pyrimidine-5-yloxy)butyric acid (24.5 mg) dissolved in methanol (2 ml), add 10% palladium charcoal (10 mg) and the mixture is stirred in hydrogen atmosphere at room temperature for 1 hour. Insoluble matter is removed by filtration and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (chloroform:methanol= 100:0→85:15), while receiving 4-(2-{(3-cyano-5-trifloromethyl)-[2-(6-isopropyl-3-methoxypyridine-2-yl)-4,5-dimethoxybenzyl]amino}pyrimidine-5-yloxy)butyric acid (21 mg). MS (m/z): 680 [M+H]+.

(5) 4-(2-{(3-Cyano-5-trifloromethyl)-[2-(6-isopropyl-3-methoxypyridine-2-yl)-4,5-dimethoxybenzyl]amino}pyrimidine-5-yloxy)butyric acid (21 mg) is treated analogously to example 142(6), while receiving sodium salt of 4-(2-{(3-cyano-5-trifloromethyl)-[2-(6-isopropyl-3-methoxypyridine-2-yl)-4,5-dimethoxybenzyl]amino}pyrimidine-5-yloxy)butyric acid (22 mg). MS (m/z): 678 [M-Na]-.

Example 160

Tert-butyryl 4-(2-{(3-cyano-5-trifloromethyl)-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]amino}-pyrimidine-5-yloxy)butyrate (195 mg) and 1-bromo-5-isopropyl-2-methoxy-4-methylbenzoyl (130 mg) is treated analogously to example 159(2), (3) and (5), obtaining p and this sodium salt of 4-{2-[(3-cyano-5-trifloromethyl)-(5'-isopropyl-4,5,2'-trimetoksi-4'-methylbiphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (66 mg). MS (m/z): 691 [M-Na]-.

Examples 161-162

The corresponding starting compound is treated analogously to example 160, thus obtaining the compounds listed in table 21.

Examples 163-168

The corresponding starting compound is treated analogously to example 142, thus obtaining the compounds listed in table 22.

Example 169

(1) Tert-butyl 4-(2-{(3-cyano-5-trifloromethyl)-[2-(6-Isopropenyl-3-methoxypyridine-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (obtained analogously to example 142(2)-(3) and example 159(1)-(2)) (73 mg) is treated analogously to example 159(4), while receiving tert-butyl 4-(2-{(3-cyano-5-trifloromethyl)-[2-(6-isopropyl-3-methoxypyridine-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyrate (70 mg). MS (m/z): 744 [M+H]+.

(2) Tert-butyl 4-(2-{(3-cyano-5-trifloromethyl)-[2-(6-isopropyl-3-methoxypyridine-2-yl)-5-trifloromethyl]amino}-pyrimidine-5-yloxy)butyrate (70 mg) is treated analogously to example 142(5)-(6), while receiving sodium salt of 4-(2-{(3-cyano-5-trifloromethyl)-[2-(6-isopropyl-3-methoxypyridine-2-yl)-5-trifloromethyl]amino}pyrimidine-5-yloxy)butyric acid (40 mg). MS (m/z): 686 [M-Na]-.

Examples 170-172

The corresponding starting compound is treated analogously to example 160, receiving the ri this connection, shown in table 22.

Examples 173-177

The corresponding starting compound is treated analogously to example 142, thus obtaining the compounds listed in table 23.

Example 178

The corresponding original connection is treated analogously to example 169, thus obtaining the compound listed in table 23.

Example 179

(1) 1-Methoxy-5-methyl-4-nitro-2-triptoreline (10 g) dissolved in methanol (100 ml), add 10% palladium carbon (1 g) and the mixture is stirred in hydrogen atmosphere at room temperature for 1 day. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure, thus obtaining 4-methoxy-2-methyl-5-triptorelin (9,07 g). MS (m/z): 206 [M+H]+.

(2) bromide copper(II) (11.8 g) is added acetonitrile (50 ml), then added dropwise tert-butylnitrite (8.5 ml) under ice cooling and the mixture is stirred under nitrogen atmosphere for 5 minutes. To the reaction mixture is added dropwise a solution of 4-methoxy-5-triptoreline (9,07 g) in acetonitrile (20 ml) under cooling with ice for 20 minutes and the mixture is stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was concentrated, propanganda pressure. To the resulting residue was added 1 n solution of chloride-hydrogen acid and the mixture extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 49:1→0:1) and chromatography on a column with NH-silica gel (hexane:ethyl acetate= 1:0→9:1), while receiving 1-bromo-4-methoxy-2-methyl-5-triptoreline (3,61 g).

(3) 1-Bromo-4-methoxy-2-methyl-5-triptoreline (1.0 g), 2,2'-azo-bis-isobutyronitrile (61 mg) and N-bromosuccinimide (795 mg) dissolved in carbon tetrachloride (15 ml) and the mixture heated under reflux overnight. The reaction solution is cooled to room temperature and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→9:1), while receiving 1-bromo-2-methyl bromide-4-methoxy-5-triptoreline (732 mg).

(4) Tert-butyl 4-[2-(3,5-bis-triphtalocyaninine)pyrimidine-5-yloxy]butyrate (300 mg) is dissolved in N,N-dimethylformamide (4 ml), add sodium hydride (60%) (33 mg) under ice cooling and the mixture is stirred for 15 minutes, then add 1-bromo-2-methyl bromide-4-methoxy-5-triptoreline (327 mg) and the mixture is stirred at room themes is the temperature value during the night. Add water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→17:3), while receiving tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(2-bromo-5-methoxy-4-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (256 mg). MS (m/z): 746/748 [M+H]+.

(5) Tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(2-bromo-5-methoxy-4-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (120 mg) is treated analogously to example 142(4)-(6), while receiving sodium salt of 4-{2-[(3,5-bis-trifloromethyl)-(4'-fluoro-5'-isopropyl-4,2'-dimethoxy-5-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (53 mg). MS (m/z): 776 [M-Na]-.

Example 180

The corresponding original connection is treated analogously to example 179, thus obtaining the compound listed in table 24.

Example 181

The corresponding original connection is treated analogously to example 169, thus obtaining the compound listed in table 24.

Examples 182-184

The corresponding starting compound is treated analogously to example 160, thus obtaining the compounds listed in table 24.

the reamers 185-186

The corresponding starting compound is treated analogously to example 179 to give the compounds listed in table 25.

Example 187

The corresponding original connection is treated analogously to example 169, thus obtaining the compound shown in table 25.

Examples 188-189

The corresponding starting compound is treated analogously to example 160, thus obtaining the compounds listed in table 25.

Example 190

(1) 5-Methoxy-2-nitro-4-triptoreline (5 g) and pyridine (2.6 ml) dissolved in methylene chloride (150 ml), the mixture is cooled to 0°C, add the anhydride triftormetilfullerenov acid (5.3 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate solution and chloroform, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), while receiving 5-methoxy-2-nitro-4-cryptomaterial ether triftormetilfullerenov acid (5.3g).

(2) 5-Methoxy-2-nitro-4-cryptomaterial ether triftormetilfullerenov acid (2.6 g) is dissolved in 1,4-dioxane (20 ml), add 5-isopro the Il-2-methoxybenzeneboronic acid (1.5 g), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (575 mg) and cesium carbonate (3,44 g) and the mixture is stirred under nitrogen atmosphere at 80°C during the night. The reaction solution is cooled to room temperature, add ethyl acetate and saturated aqueous sodium bicarbonate solution, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 49:1→17:3), while receiving 5'-isopropyl-5,2'-dimethoxy-2-nitro-4-triptorelin (2.35 g). MS (m/z): 370 [M+H]+.

(3) 5'-Isopropyl-5,2'-dimethoxy-2-nitro-4-triptorelin (2.35 g) was dissolved in a mixed solvent of tetrahydrofuran (20 ml) and methanol (30 ml), add 10% palladium carbon (500 mg) and the mixture is stirred in hydrogen atmosphere at room temperature for 1 day. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→4:1), while receiving 5'-isopropyl-5,2'-dimethoxy-4-triptorelin-2-ylamine (1.88 g). MS (m/z): 340 [M+H]+.

(4) bromide copper(II) (1,17 g) added acetonitrile (5 ml), then added dropwise tert-butylnitrite (0,835 ml) while cooling Edom and the mixture is stirred under nitrogen atmosphere for 5 minutes. To the reaction mixture is added dropwise a solution of 5'-isopropyl-5,2'-dimethoxy-4-triptorelin-2-ylamine (1.48 g) in acetonitrile (2 ml) under ice cooling and the mixture is stirred under nitrogen atmosphere at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added 1 n solution of chloride-hydrogen acid and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→9:1), while receiving 2-bromo-5'-isopropyl-5,2'-dimethoxy-4-triptorelin (1.29 g).

(5) 2-Bromo-5'-isopropyl-5,2'-dimethoxy-4-triptorelin (1.29 g) was dissolved in dry tetrahydrofuran (30 ml), added dropwise a 1.6 M solution of n-utility in hexane at -78°C and the mixture is stirred for 1 hour, then add N,N-dimethylformamide (1.2 ml) and the mixture is stirred for 1.5 hours. To the reaction solution was added saturated aqueous solution of ammonium chloride and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:is tracecut= 49:1→17:3), while receiving 5'-isopropyl-5,2'-dimethoxy-4-triptorelin-2-carbaldehyde (733 mg). MS (m/z): 353 [M+H]+.

(6) 5'-Isopropyl-5,2'-dimethoxy-4-triptorelin-2-carbaldehyde (692 mg) was dissolved in a mixed solvent of tetrahydrofuran (12 ml), ethanol (3.5 ml) and methylene chloride (1 ml), add sodium borohydride (82 mg) and the mixture is stirred at room temperature for 40 minutes. The reaction solution is concentrated under reduced pressure, add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), while receiving (5'-isopropyl-5,2'-dimethoxy-4-triptorelin-2-yl)methanol (566 mg). MS (m/z): 337 [M+H-H2On]+.

(7) (5'-Isopropyl-5,2'-dimethoxy-4-triptorelin-2-yl)methanol (200 mg) is dissolved in toluene (5 ml), add thionyl chloride (60 μl) under ice cooling and the mixture is stirred for 3 hours. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. Tert-butyl ester 4-[2-(3,5-bis-triphtalocyaninine)pyrimidine-5-yloxy]butyric acid (246 mg) RAS is varaut in N,N-dimethylformamide (5 ml), add sodium hydride (60%) (23 mg) under ice cooling and the mixture is stirred for 20 minutes. Then add a solution of the residue obtained above in N,N-dimethylformamide (3 ml) and the mixture is stirred at room temperature for 3 hours and 20 minutes. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→17:3), while receiving tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-5,2'-dimethoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (74 mg). MS (m/z): 816 [M+H]+.

(8) Tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-5,2'-dimethoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (68 mg) is treated analogously to example 142(5)-(6), while receiving sodium salt of 4-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-5,2'-dimethoxy-4-triptorelin-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (23 mg). MS (m/z): 758 [M-Na]-.

Example 191

The corresponding original connection is treated analogously to example 190, thus obtaining the compounds listed in table 26.

Examples 192-200

Match is their starting compound is treated analogously to example 142, thus the compounds listed in table 27.

Examples 201-205

The corresponding starting compound is treated analogously to example 160, thus obtaining the compounds listed in table 27.

Examples 206-207

The corresponding starting compound is treated similarly to any of the above examples to give the compounds shown in table 27.

Example 208

(1) 2-[(3,5-Bis-trifloromethyl)-(5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-ol (60 mg) dissolved in tetrahydrofuran (1 ml) and added dropwise tert-butyl 3-hydroxypropionate (336 mg), triphenylphosphine (592 mg), and then added dropwise diisopropylethylamine (447 μl) and the mixture was stirred at 60°C over night. To the reaction mixture is added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. To the resulting residue add isopropyl ether, the insoluble substance is filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 9:1→2:1) and chromatography on a column of CNH-silica gel (hexane:ethyl acetate= 9:1→4:1), while receiving tert-butyl-3-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}propionate (43 mg). MS (m/z): 764 [M+H]+.

(2) tert-butyl 3-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}propionate (41 mg) is added 4 n solution of chloride-hydrogen acid in dioxane (4 ml) and the mixture is stirred at room temperature for 9 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, the mixture was doing slightly acidic by adding 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→1:3), the obtained purified product is dissolved in ethanol (0.5 ml), was added 1 M aqueous sodium hydroxide solution (24 μl) and the mixture is concentrated under reduced pressure, thus obtaining the sodium salt of 3-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}propionic acid (18 mg). MS (m/z): 706 [M-Na]-.

Example 209

Methyl 3-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}-2,2-d is methylpropionate (obtained by treating the corresponding starting compound analogously to example 208(1)) (85 mg) is treated analogously to example 103(3), thus the sodium salt of 3-{2-[(3,5-bis-trifloromethyl)-(5'-isopropyl-4,5,2'-trimethoxyphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}-2,2-dimethylpropionic acid (52 mg). MS (m/z): 734 [M-Na]-.

Example 210

The corresponding starting compound is treated analogously to example 139(2)to give the compounds listed in table 28.

Example 211

The corresponding initial connection process similar to example 208, thus obtaining the compound listed in table 29.

Example 212

The corresponding original connection is treated analogously to example 209, thus obtaining the compound listed in table 29.

Example 213

The corresponding original connection is treated analogously to example 139(2), thus obtaining the compound listed in table 29.

Example 214

(1) 5'-Isopropenyl-2'-methoxy-4-triptorelin-2-carbaldehyde (5.0 g) was dissolved in a mixed solvent of tetrahydrofuran (100 ml), ethanol (30 ml) and methylene chloride (10 ml), add sodium borohydride (646 mg) and the mixture is stirred at room temperature for 10 minutes. The reaction solution is concentrated under reduced pressure, we use the t ethyl acetate and water, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 49:1→4:1), while receiving (5'-Isopropenyl-2'-methoxy-4-triptorelin-2-yl)methanol (4,73 g). MS (m/z): 307 [M+H]+.

(2) (5'-Isopropenyl-2'-methoxy-4-triptorelin-2-yl)methanol (500 mg) is dissolved in methylene chloride (3 ml) and added dropwise thionyl chloride (248 μl) under nitrogen atmosphere under ice cooling, the mixture is stirred at room temperature for 15 minutes, the reaction solution is cooled with ice and dropwise added triethylamine (647 μl). To the reaction solution was added diethyl ether and a saturated solution of salt, the mixture is separated, the organic layer is dried over magnesium sulfate and concentrate under reduced pressure. Balance and (3,5-bis-trifloromethyl)-(5-bromopyridin-2-yl)amine (799 mg) dissolved in N,N-dimethylformamide, add sodium hydride (123 mg) and the mixture was stirred at 50°C for 2 hours and 30 minutes. The reaction solution is cooled to room temperature, add diethyl ether and water, the mixture is separated, the organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The remainder of imaut chromatography on a column of silica gel (hexane:ethyl acetate= 49:1→9:1), while receiving (3,5-bis-trifloromethyl)-(5-bromopyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)Amin (481 mg). MS (m/z): 705/707 [M+H]+.

(3) (3,5-Bis-trifloromethyl)-(5-bromopyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)Amin (475 mg), the complex [1,1'-bis(diphenylphosphino)ferrocen]dichloropalladium and methylene chloride (55 mg), potassium acetate (198 mg) and bis(pinacolato)LIBOR (256 mg) was dissolved in dimethyl sulfoxide (2 ml), the mixture is heated to 80°C. in a nitrogen atmosphere and stirred within 1 hour. The reaction solution is cooled to room temperature, add water and ethyl acetate, the mixture is separated, the organic layer is washed twice with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (10 ml) and added dropwise a 30% aqueous hydrogen peroxide solution (0.75 ml) under cooling with ice. The reaction solution was stirred at room temperature over night, add saturated aqueous sodium thiosulfate solution under ice cooling to absorb excess hydrogen peroxide, then add water and diethyl ether and the mixture is separated. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. Forming the camping residue purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:%1), while receiving 6-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyridine-3-ol (141 mg). MS (m/z): 643 [M+H]+.

(4) 6-[(3,5-Bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyridine-3-ol (141 mg) was dissolved in N,N-dimethylformamide (1 ml), added 60% sodium hydride (10 mg) under ice cooling and the mixture is stirred for 5 minutes, then add ethyl 4-bromobutyrate (48 μl) and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added water under ice cooling, the mixture is extracted with methylene chloride and the organic layer concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), thus obtaining the ethyl 4-{6-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyridine-3-yloxy}butyrate (154,1 mg). MS (m/z): 757 [M+H]+.

(5) Ethyl 4-{6-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyridine-3-yloxy}butyrate (150 mg) is dissolved in a mixed solvent of ethanol (1 ml) and tetrahydrofuran (2 ml)is added 2 n aqueous sodium hydroxide solution (0.3 ml) and the mixture was stirred at 50°C for 3 hours and 20 minutes. The reaction solution is cooled to room temperature and neutralized with 2 n p is the target chloride-hydrogen acid (0.3 ml), add methylene chloride and a saturated salt solution, the mixture is separated and the organic layer concentrated under reduced pressure. The resulting residue is purified LC-MS (column: CAPCELPACK MG2 C18, eluate: 10 μm aqueous solution of carboxylic acid/acetonitrile = 55/45→40/60), while receiving 4-{6-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]-pyridine-3-yloxy}butyric acid (31,4 mg). The obtained carboxylic acid is dissolved in ethanol (1 ml)is added 2 n aqueous sodium hydroxide solution (42 ml) and the reaction solution was concentrated under reduced pressure, thus obtaining the sodium salt of 4-{6-[(3,5-bis-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyridine-3-yloxy}butyric acid (30,6 mg). MS (m/z): 727 [M-Na]-.

Example 215

The corresponding original connection is treated analogously to example 214, thus obtaining the compound listed in table 30.

Example 216

(1) 5'-Isopropyl-2'-methoxy-4-triptorelin-2-carbaldehyde (8.0 g), hydroxylamine hydrochloride (3,45 g) and pyridine (28 ml) dissolved in ethanol (140 ml) and the mixture was stirred at 80°C for 1 hour. The reaction solution is cooled to room temperature, add ethyl acetate and 1 n solution of chloride-hydrogen acid, MES share, the organic layer was washed with a saturated solution of sodium carbonate, water and saturated salt solution, the mixture is dried over magnesium sulfate and concentrate under reduced pressure. Then add ethyl acetate and 1 n solution of chloride-hydrogen of the acid, the mixture is separated, the organic layer washed with 1 n NaCl-hydrogen acid, saturated sodium carbonate solution, water and saturated salt solution, the mixture is dried over magnesium sulfate and concentrate under reduced pressure. The residue is dissolved in methanol (100 ml), add Nickel Raney catalyst and the mixture is stirred in hydrogen atmosphere at room temperature for 30 minutes and at 50°C during the night. The reaction solution is cooled to room temperature, the Nickel Raney catalyst is removed by filtration and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→23:2), while receiving S-(5'-isopropyl-2'-methoxy-4-triptorelin-2-yl)methylamine (5.50 g). MS (m/z): 324 [M+H]+.

(2)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-yl)methylamine (107 mg) was dissolved in toluene (3 ml), add Tris(dibenzylideneacetone)dipalladium (30 mg), 1,3-bis(diphenylphosphino)propane (27 mg) and tert-piperonyl sodium (44 mg) and the mixture is stirred under nitrogen atmosphere at 80°C during the night. Reaction the second solution is cooled to room temperature, to the reaction solution was added methylene chloride and saturated aqueous sodium bicarbonate solution, the mixture is separated and the organic layer concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 49:1→4:1), while receiving (5-bromopyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)Amin (41.3 mg). MS (m/z): 479/481 [M+H]+.

(3) (5-Bromopyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amine (700 mg) was dissolved in N,N-dimethylformamide (5 ml), add sodium hydride (60%) (88 mg) in a nitrogen atmosphere at -10°C and the mixture is stirred at the same temperature for 5 minutes, then add 3-methyl bromide-5-cryptomathematical (771 mg) and the mixture is stirred under ice cooling for 1 hour 40 minutes. To the reaction solution was added ethyl acetate and a saturated aqueous solution of citric acid, the mixture is separated, the organic layer is washed twice with a saturated solution of salt, the mixture is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 19:1→17:3 and hexane:ethyl acetate= 49:1→9:1). The residue is dissolved in diethyl ether and filtered. The filtrate is concentrated under reduced pressure, obtained above the rest (630 mg) was dissolved in tetrahydrof is ane (3 ml), add morpholine (119 μl) and triethylamine (190 μl), the mixture was stirred at 50°C for 4 hours, the reaction solution is cooled to room temperature and stirred at the same temperature throughout the night. To the reaction solution was added ethyl acetate and water, the mixture is separated, the organic layer washed with water and saturated salt solution, the mixture is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane: ethyl acetate= 19:1→17:3), while receiving 3-{[(5-bromopyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]-methyl}-5-cryptomathematical (440 mg). MS (m/z): 662/664 [M+H]+.

(4) 3-{[(5-Bromopyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]methyl}-5-cryptomathematical (435 mg) is treated analogously to example 214(3), thus obtaining 3-{[(5-hydroxypyridine-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]methyl}-5-cryptomathematical (251 mg). MS (m/z): 600 [M+H]+.

(5) 3-{[(5-Hydroxypyridine-2-yl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]methyl}-5-cryptomathematical (150 mg) is dissolved in N,N-dimethylformamide (2.5 ml), added 60% sodium hydride (12 mg) under ice cooling and the mixture is stirred for 30 minutes, then added tert-butyl 4-bromobutyrate (85 mg) and the mixture is stirred at room temperature for 6 hours. To the reaction solution was added water under ice cooling, the mixture is extracted with methylene chloride, the organic layer was washed with saturated salt solution, the mixture is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→3:1), while receiving tert-butyl 4-{6-[(3-cyano-5-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyridine-3-yloxy}butyrate (169 mg). MS (m/z): 742 [M+H]+.

(6) Tert-butyl 4-{6-[(3-cyano-5-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyridine-3-yloxy}butyrate (165 mg) is treated analogously to example 142(5)-(6), while receiving sodium salt of 4-{6-[(3-cyano-5-trifloromethyl)-(5'-isopropyl-2'-methoxy-4-triptorelin-2-ylmethyl)amino]pyridine-3-yloxy}butyric acid (113,5 mg). MS (m/z): 684 [M-Na]-.

Example 217

The corresponding initial connection process is similar to any of the above examples, while receiving the connection, shown in table 31.

Examples 218-219

The corresponding starting compound is treated analogously to example 142, thus obtaining the compounds listed in table 32.

Example 220

(1) 5-Benzyloxy-2-bromobenzaldehyde (1.0 g) is dissolved in 1,4-dio the San (30 ml), add complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (280 mg), (5-isopropyl-2-methoxyphenyl)baronova acid (800 mg) and cesium carbonate (1.68 g) and the mixture is stirred under nitrogen atmosphere at 80°C for 6 hours. The reaction mixture is cooled to room temperature, add ethyl acetate and saturated aqueous sodium bicarbonate solution, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→4:1), while receiving 4-benzyloxy-5'-isopropyl-2'-methoxybiphenyl-2-carbaldehyde (1.19 g). MS (m/z): 361 [M+H]+.

(2) 4-Benzyloxy-5'-isopropyl-2'-methoxybiphenyl-2-carbaldehyde (1,16 g) dissolved in ethanol (15 ml), add sodium borohydride (122 mg) and the mixture is stirred at room temperature for 10 minutes. Then add saturated aqueous solution of ammonium chloride and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining (4-benzyloxy-5'-isopropyl-2'-methoxybiphenyl-2-yl)methanol (1.26 g). MS (m/z): 345 [M+H]+.

(3) (4-Benzyloxy-5'-isopropyl-2'-methoxybiphenyl-2-yl)methanol (1.10 g) was dissolved in methylene chloride (10 ml), doba is given in thionyl chloride (332 μl) and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure and the residue purified by chromatography on a column of silica gel (hexane: ethyl acetate= 1:0→9:1), while receiving 4-benzyloxy-2-chloromethyl-5'-isopropyl-2'-methoxybiphenyl (1,15 g). MS (m/z): 345 [M+H]+.

(4) Tert-butyl 4-[2-(3,5-bis-triphtalocyaninine)pyrimidine-5-yloxy]butyrate (1,11 g) and 4-benzyloxy-2-chloromethyl-5'-isopropyl-2'-methoxybiphenyl (805 mg) dissolved in N,N-dimethylformamide (10 ml) and add sodium hydride (60%) (120 mg) under ice cooling, the mixture is stirred under ice cooling for 2 hours and continue to stir at room temperature for 30 minutes. Then add saturated aqueous solution of ammonium chloride and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→4:1), while receiving tert-butyl 4-{2-[(4-benzyloxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)-(3,5-bis-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (1,14 g). MS (m/z): 824 [M+H]+.

(5) Tert-butyl 4-{2-[(4-benzyloxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)-(3,5-bis-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (80 mg) is treated analogously to example 142(5)-(6), while receiving sodium salt of 4-{-[(4-benzyloxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)-(3,5-bis-triptoreline)amino]pyrimidine-5-yloxy}butyric acid (59,5 mg). MS (m/z): 766 [M-Na]-.

Example 221

(1) Tert-butyl 4-{2-[(4-benzyloxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)-(3,5-bis-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (1.0 g) is dissolved in ethanol (20 ml), add 10% palladium carbon (200 mg) and the mixture is stirred in hydrogen atmosphere at room temperature for 4 hours. The catalyst was removed by filtration, the filtrate is concentrated under reduced pressure and add hexane, the resulting crystal was filtered, thus obtaining tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(4-hydroxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (835 mg). MS (m/z): 734 [M+H]+.

(2) Tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(4-hydroxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (70 mg) is treated analogously to example 142(5)-(6), while receiving sodium salt of 4-{2-[(3,5-bis-trifloromethyl)-(4-hydroxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (55,4 mg). MS (m/z): 676 [M-Na]-.

Example 222

(1) Tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(4-hydroxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (70 mg) was dissolved in N,N-dimethylformamide (3 ml), add potassium carbonate (26,4 mg) and Iodate (29,8 mg) and the mixture was stirred at 50°C for 8 hours. Then add atilas the tat and water, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 1:0→9:1), while receiving tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(4-ethoxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (of 60.5 mg). MS (m/z): 762 [M+H]+.

(2) Tert-butyl 4-{2-[(3,5-bis-trifloromethyl)-(4-ethoxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyrate (59 mg) is treated analogously to example 142(5)-(6), while receiving sodium salt of 4-{2-[(3,5-bis-trifloromethyl)-(4-ethoxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)amino]pyrimidine-5-yloxy}butyric acid (48,2 mg). MS (m/z): 704 [M-Na]-.

Example 223

The corresponding initial connection process similar to example 222, thus obtaining the compound listed in table 32.

Examples 224-230

The corresponding starting compound is treated similarly to any of the above examples to give the compounds shown in table 32.

Example 231

(1) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (315 mg) and 4-benzyloxy-2-chloromethyl-5'-isopropyl-'-methoxybiphenyl (300 mg) is dissolved in N,N-dimethylformamide (5 ml), add sodium hydride (60%) (40,9 mg) under ice cooling and the mixture is stirred at room temperature overnight. Then add easymany aqueous solution of ammonium chloride and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→97:3), while receiving (4-benzyloxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)-(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (458 mg). MS (m/z): 744/746 [M+H]+.

(2) (4-Benzyloxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)-(3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (433 mg) dissolved in toluene (5 ml), add Tris(dibenzylideneacetone)dipalladium (107 mg), tert-piperonyl sodium (168 mg), 2-(di-tert-butylphosphino)biphenyl (69,4 mg) and morpholine (152 mg) and the mixture was stirred in nitrogen atmosphere at room temperature during the night. To the reaction solution was added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→2:1), while receiving (4-benzyloxy-5'-isopropyl-2-methoxybiphenyl-2-ylmethyl)-(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amine (384 mg). MS (m/z): 751 [M+H]+.

(3) (4-Benzyloxy-5'-isopropyl-2'-methoxybiphenyl-2-ylmethyl)-(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amine is treated analogously to example 221 and 222, while receiving sodium salt of 4-(2-{[(3,5-bis-trifloromethyl)-(5-morpholine-4-Yeremey-2-yl)amino]methyl}-5'-isopropyl-2'-methoxybiphenyl-4-yloxy)butyric acid. MS (m/z): 745 [M-Na]-.

Example 232

The corresponding initial connection process as in example 231, thus obtaining the compound listed in table 33.

Examples 233-234

The corresponding starting compound is treated similarly to any of the above examples to give the compounds listed in table 33.

Examples 235-238

The corresponding starting compound is treated similarly to any of the above examples to give the compounds listed in table 34.

Example 239

The corresponding original connection is treated analogously to example 142, thus obtaining the compound listed in table 35.

Examples 240-252

The corresponding starting compound is treated similarly to any of the above examples to give the compounds listed in table 36.

Reference example 1

Cyclohexanecarboxaldehyde (38 g), hydrochloride diethylamine (55 g) and acetic acid (29 ml) dissolved in methylene chloride (500 ml), add borohydride createtextarea (71,8 g) at room temperature and the mixture is stirred at room temperature overnight. To the reaction solution was added 2 n aqueous sodium hydroxide solution and methylene chloride, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and the mixture is concentrated under reduced pressure, thus obtaining cyclohexyldimethylamine (40,1 g) as a crude product. MS (m/z): 142 [M+H]+.

Reference example 2

3,5-Bis-triftormetilfosfinov (10 g) and 5-bromo-2-chloropyrimidine (12 g) is dissolved in 1,4-dioxane (50 ml), add N,N-diisopropylethylamine (10,7 ml) and the mixture heated under reflux overnight. The reaction solution is cooled to room temperature and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 9:1 to 7:3)to give (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (10.1 g). MS (m/z): 713 [M+H]+.

Reference the use of the 3

(1) ethylamine Hydrochloride (2 g) dissolved in methylene chloride (20 ml), add pyridine (6 ml) and ethyl 6-(chloroformyl)hexanoate (7.6 g) and the mixture is stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate solution, the mixture is separated, the organic layer is successively washed with 1 n NaCl-hydrogen acid, water and saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining the ethyl 6-ethylcarboxylate (9,29 g) as a crude product. MS (m/z): 216 [M+H]+.

(2) the Crude ethyl 6-ethylcarboxylate (9,29 g) dissolved in tetrahydrofuran (50 ml) and add sodium borohydride (7,35 g). The reaction solution is heated under reflux, is added dropwise acetic acid (11 ml) and the mixture heated under reflux for 1 hour 30 minutes. To the reaction solution was added water under ice cooling and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in ethanol (30 ml), add 4 n solution of chloride-hydrogen acid in ethyl acetate (7,6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution is added 2 n aqueous sodium hydroxide solution and ethyl acetate, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining the ethyl 7-ethylaminoethanol (3.98 g) as a crude product. MS (m/z): 216 [M+H]+.

Reference example 4

(1) Hydrochloride difficult methyl ester 6-aminohexanoic acid (5 g) dissolved in methylene chloride (20 ml), add pyridine (4.5 ml) and acetylchloride (2 ml) and the mixture is stirred at room temperature for 1 hour and 45 minutes. To the reaction solution was added 1 n solution of chloride-hydrogen acid and chloroform, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining methyl 6-acetylaminophenol (5,19 g) as a crude product. MS (m/z): 188 [M+H]+.

(2) the Crude methyl 6-acetylaminophenol (5,19 g) dissolved in tetrahydrofuran (50 ml) and add sodium borohydride (of 5.03 g). The reaction solution is heated under reflux, is added dropwise acetic acid (7,6 ml) and the mixture heated under reflux for 1 hour 30 minutes. To the reaction solution was added water under ice cooling and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and end tryout under reduced pressure. The resulting residue is dissolved in ethanol (30 ml), add 4 n solution of chloride-hydrogen acid in ethyl acetate (7,6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added 2 n aqueous sodium hydroxide solution and ethyl acetate, the mixture is separated, the organic layer was washed with nezamenim salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining the ethyl-6-ethylaminoethanol (1,74 g) as a crude product. MS (m/z): 188 [M+H]+.

Reference example 5

(1) (3,5-Bis-trifloromethyl)-(5-bromopyrimidine-2-yl)amine (10 g) and triethylamine (4,18 ml) dissolved in methylene chloride (100 ml) and add triphosgene (2,97 g) under cooling with ice. The reaction solution was stirred at the same temperature for 30 minutes and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (100 ml), add benzyl alcohol (3,88 ml) and triethylamine (10,45 ml) at room temperature and the mixture is stirred over night. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and 1 n NaCl-hydrogen acid. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue cleaned the Ute chromatography on a column of silica gel (hexane: ethyl acetate= 97:3→9:1), while receiving benzyl (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)carbamate (11,58 g). MS (m/z): 534/536 [M+H]+.

(2) Benzyl (3,5-bis-trifloromethyl)-(5-bromopyrimidine-2-yl)carbamate (11.5g), the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium and dichloromethane (3.51 g), potassium acetate (6,33 g) and bis(pinacolato)LIBOR (10,9 g) dissolved in dimethyl sulfoxide (75 ml), the mixture is heated to 80°C. in a nitrogen atmosphere and stirred for 30 minutes. The reaction solution is cooled to room temperature, add water and ethyl acetate, the insoluble matter is removed by filtration through celite (Celite™), the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (100 ml), added dropwise a 30% aqueous hydrogen peroxide solution (50 ml) under ice cooling and the mixture is stirred for 1 hour. Add saturated aqueous sodium thiosulfate solution under ice cooling to absorb excess hydrogen peroxide, then add water and ethyl acetate and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol= 1:0→9:1), receiving the ri this benzyl (3,5-bis-trifloromethyl)-(5-hydroxypyrimidine-2-yl)carbamate (9,70 g). MS (m/z): 472 [M+H]+.

(3) Benzyl (3,5-bis-trifloromethyl)-(5-hydroxypyrimidine-2-yl)carbamate (9,70 g) and ethyl-4-bromobutyrate (3,53 g) dissolved in N,N-dimethylformamide (50 ml), add potassium carbonate (3,41 g) and the mixture was stirred at 50°C for 1 hour. Then add ethyl acetate and a saturated salt solution, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→1:1), thus obtaining the ethyl 4-{2-[benzyloxycarbonyl-(3,5-bis-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (8,29 g). MS (m/z): 586 [M+H]+.

(4) Ethyl 4-{2-[benzyloxycarbonyl(3,5-bis-trifloromethyl)amino]pyrimidine-5-yloxy}butyrate (3.0 g) dissolved in tetrahydrofuran (20 ml), add 10% palladium carbon (500 mg) and the mixture is stirred in hydrogen atmosphere at room temperature for 2 hours and 30 minutes. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→1:1), thus obtaining the ethyl 4-[2-(3,5-bis-triphtalocyaninine)pyrimidine-5-yloxy]butyrate (2,22 g). MS (m/z): 452 [M+H]+.

Reference example 6

(1) Hydrochloride methyl ester is 6 aminohexanoic acid (2.50 g) was dissolved in tetrahydrofuran (50 ml), add water (50 ml) and sodium bicarbonate (3,44 g), then added dropwise to benzylchloride (2,17 ml) under ice cooling and the mixture is stirred at the same temperature for 2 hours and 30 minutes. To the reaction mixture is added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer is washed twice with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining methyl-6-benzyloxycarbonylglycine (4,16 g). MS (m/z): 280 [M+H]+.

(2) Methyl 6-benzyloxycarbonylglycine (4.15 g) was dissolved in N,N-dimethylformamide (2.5 ml), add sodium hydride (63%) (552 mg) under ice cooling and the mixture is stirred at the same temperature for 1 hour, then add methyliodide (1,72 ml) and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture is added a saturated solution of salt, the mixture is extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 4:1), while receiving methyl 6-(benzyloxycarbonylamino)hexanoic (2.25 g). MS (m/z): 294 [M+H]+.

(3) Methyl 6-(benzyloxycarbonylamino)hexanoic (2.24 g) was dissolved in methanol (35 ml), was added 1% palladium carbon (500 mg) and the mixture is stirred at room temperature in a hydrogen atmosphere for 2 hours. The reaction mixture is filtered and the filtrate concentrated under reduced pressure, thus obtaining methyl-6-methylaminoethanol (1,11 g). MS (m/z): 160 [M+H]+.

Reference example 7

Propylamine (0.65 g) was dissolved in tetrahydrofuran (5 ml), add pyridine (0,89 ml), then under ice cooling are added dropwise methyladipate (1,96 g) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (30 ml), add sodium borohydride (1,93 g) at room temperature and the mixture is heated to 65°C., then added dropwise acetic acid (2,92 ml) for 1 hour and the mixture is stirred at the same temperature for 9 hours. To the reaction mixture cooled with ice, diluted chloride-hydrogen acid, the mixture is stirred for 30 minutes and extracted with ethyl acetate, the organic layer was washed with a mixed solution of saturated aqueous sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in methanol (5 ml), add 4 is a chloride-hydrogen acid in dioxane (7.5 ml) and the mixture is stirred at room temperature overnight. To the reaction mixture is added saturated aqueous sodium bicarbonate solution and a saturated salt solution, the mixture is extracted six times with ethyl acetate, the collected organic layer is dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining methyl-6-propylaminoethyl (914 mg). MS (m/z): 188 [M+H]+.

Reference example 8

(1) Tert-butylpiperazine 4-illecillewaet (2.00 g) was dissolved in tetrahydrofuran (10 ml) and add triethylamine (1,69 ml), then added dropwise to ethylbromoacetate (1,24 ml) on a water bath and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added a saturated salt solution and the mixture extracted with ethyl acetate. The organic layer is washed twice with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, the resulting crystalline residue is added isopropyl ether and the mixture is filtered, thus obtaining the ethyl [4-(tert-butoxycarbonylamino)piperidine-1-yl]acetate (1,87 g). MS (m/z): 301 [M+H]+.

(2) Ethyl [4-(tert-butoxycarbonylamino)piperidine-1-yl]acetate (1.86 g) was dissolved in N,N-dimethylformamide (10 ml), add sodium hydride (63%) (1.19 g) and ethyliodide (6,0 ml) and the mixture is stirred at room temperature for 2 hours. The reaction mixture was doing slightly alkaline by adding 10% aqueous Rast is the PR citric acid and saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 2:1), thus obtaining the ethyl {4-[(tert-butoxycarbonylamino)methyl]piperidine-1-yl}acetate (905 mg). MS (m/z): 329 [M+H]+.

(3) Ethyl {4-[(tert-butoxycarbonylamino)methyl]piperidine-1-yl}acetate (235 mg) is dissolved in methylene chloride (1 ml), add triperoxonane acid (1 ml) and the mixture is stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, thus obtaining salt of bis-triperoxonane acid complex ethyl ester (4-ethylaminomethyl-1-yl)acetic acid (482 mg). MS (m/z): 229 [M+H]+.

Reference example 9

(1) 2-Tert-butoxysilane (2 g) dissolved in methylene chloride (10 ml), add pyridine (940 μl) and ethyl 6-(chloroformyl)hexanoate (1.13 g) under ice cooling and the mixture is stirred at room temperature overnight. To the reaction solution was added 1 n solution of chloride-hydrogen acid and chloroform, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining the ethyl 6-(2-tert-ethylcarbamate)Gex is not in the form of the crude product (2,96 g). MS (m/z): 288 [M+H]+.

(2) the Crude ethyl 6-(2-tert-ethylcarbamate)hexanoate (2,96 g) dissolved in tetrahydrofuran (15 ml) and add sodium borohydride (1.60 g). The reaction solution is heated under reflux, is added dropwise acetic acid (2.4 ml) and the mixture heated under reflux for 1 hour. To the reaction solution was added water under ice cooling and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is dissolved in ethanol (6 ml), add 4 n solution of chloride-hydrogen acid in ethyl acetate (1.5 ml) and the mixture is stirred at room temperature for 3 hours. To the reaction solution was added saturated aqueous sodium bicarbonate solution and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining the ethyl 7-(2-tert-butoxyaniline)heptanoate in the form of the crude product (2.6 g). MS (m/z): 274 [M+H]+.

Reference example 10

(1) 2-Bromopyridin-3-ol (5 g) dissolved in water (150 ml), add sodium carbonate (6,15 g) and iodine (7,65 g) and the mixture is stirred at room temperature for 2 hours. Then add a 1 n solution of chloride of vodorodny the th acid and ethyl acetate, the mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 9:1→3:1), while receiving 2-bromo-6-yodellin-3-ol (4.52 g). MS (m/z): 300/302 [M+H]+.

(2) 2-Bromo-6-yodellin-3-ol (2,98 g) dissolved in N,N-dimethylformamide (140 ml), add cesium carbonate (16.3 g) and methyliodide (1.25 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), while receiving 2-bromo-6-iodine-3-methoxypyridine (2,45 g). MS (m/z): 314/316 [M+H]+.

(3) To a 0.5 M solution of bromide isopropanolamine in tetrahydrofuran add trimethylboron (3,3 ml) and the mixture is stirred under nitrogen atmosphere at room temperature for 30 minutes. To the reaction solution was added 6 n solution of chloride-hydrogen acid and diethyl ether and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining isopropenylbenzene KIS the GTC in the form of the crude product (818 mg). Untreated isopropenylbenzene acid (287 mg) and 2-bromo-6-iodine-3-methoxypyridine (800 mg) was dissolved in a mixed solvent of 1,2-dimethoxyethane (8 ml) and ethanol (3.2 ml), was added 1 M aqueous sodium carbonate solution (6.4 ml) and tetrakis(triphenylphosphine)palladium (240 mg) and the mixture is stirred under nitrogen atmosphere at 80°C for 5 hours. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 49:1→9:1) and then by chromatography on a column with NH-silica gel (hexane:ethyl acetate= 49:1→9:1), while receiving 2-bromo-6-Isopropenyl-3-methoxypyridine (138 mg). MS (m/z): 228/230 [M+H]+.

Reference example 11

5-Methoxy-2-methylsulfonylamino-4-ol (250 mg) was dissolved in acetonitrile (7 ml), added phosphorus oxychloride (0.7 ml) and diethylaniline (460 μl) and the mixture heated under reflux for 5.5 hours. The reaction solution is evaporated three times with toluene to azeotrope conditions, to the residue add an aqueous solution of citric acid and chloroform and the mixture is separated. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified chromatog what afia on a column of silica gel (hexane:ethyl acetate= 19:1→17:3), while receiving 4-chloro-5-methoxy-2-methylsulfonylamino (260 mg). MS (m/z): 191/193 [M+H]+.

Reference example 12

(1) 3-Nitro-5-(trifluoromethyl)benzoic acid (50 g) dissolved in tetrahydrofuran (300 ml), added dropwise 1.0 M solution of boron complex and tetrahydrofuran in tetrahydrofuran (300 ml) at 0°C under nitrogen atmosphere for 2 hours and the mixture is stirred at 75°C for 1 hour and 30 minutes. The reaction solution is allowed to cool to room temperature and concentrated under reduced pressure, was added 1 n solution of chloride-hydrogen acid and the mixture extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining the crude (3-nitro-5-triptoreline)methanol. The obtained product is dissolved in methanol (500 ml), add 10% palladium charcoal (5 g) and the mixture is stirred in hydrogen atmosphere at room temperature overnight. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure, thus obtaining neojidannyi (3-amino-5-triptoreline)methanol. The copper bromide (II) (53,6 g) added acetonitrile (500 ml), then added dropwise tert-butylnitrite (35,7 ml) under ice cooling and the mixture is stirred under nitrogen atmosphere for 5 min is so To the reaction mixture is added dropwise a solution of the above crude (3-amino-5-triptoreline)methanol in acetonitrile (200 ml) under cooling with ice for 1 hour and 15 minutes and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction mixture was added 1 n solution of chloride-hydrogen acid and the mixture extracted with ethyl acetate. The organic layer is successively washed with 1 n NaCl-hydrogen acid, water and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. Obrazovaniya the residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 7:1→4:1), while receiving (3-bromo-5-triptoreline)methanol (40,7 g).

NMR (CDCl3): 1,90 (1H, t), was 4.76 (2H, d), 7,56 (1H, s), to 7.68 (1H, s), 7,72 (1H, s).

(2) (3-Bromo-5-triptoreline)methanol (33,9 g) dissolved in N,N-dimethylformamide (400 ml), add cyanide zinc(II) (16,39 g) and tetrakis(triphenylphosphine)palladium (of 7.68 g) and the mixture is heated in a nitrogen atmosphere at 120°C for 2 hours. The reaction solution is allowed to cool to room temperature, filtered through celite (Celite™and the filtrate concentrated under reduced pressure. Then water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrate the ri reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane: ethyl acetate = 2:1), thus obtaining 3-hydroxymethyl-5-cryptomathematical (23,4 g).

NMR (CDCl3): of 2.09 (1H, t), is 4.85 (2H, d), 7,83 (1H, s), 7,87 (2H, s).

(3) 3-Hydroxymethyl-5-cryptomathematical (23,4 g) dissolved in methylene chloride (230 ml), add tetrabromide carbon (42,4 g) and triphenylphosphine (32,0 g) under ice cooling and the mixture is stirred at the same temperature for 30 minutes. The reaction solution is concentrated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate = 10:1), thus obtaining 3-methyl bromide-5-cryptomathematical (25,5 g).

NMR (CDCl3): 4,51 (2H, s), 7,86 (1H, s), 7,88 (2H, s).

Reference example 13

2-Chloropyrimidine-5-ol (3,89 g) dissolved in N,N-dimethylformamide (50 ml), add potassium carbonate (498 g) and tert-butyl 4-bromo-butyrate (of 7.36 g) and the mixture is stirred at room temperature overnight. To the reaction solution was added ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 24:1→4:1), while receiving tert-butyl-4-(2-chloropyrimidine-5-yloxy)bromobutyrate (6,22 g). M is (m/z): 273 [M+H] +.

Reference example 14

2.5-Dibromopyridine (4,74 g) dissolved in toluene (100 ml), add 3,5-bis-triftormetilfosfinov (of 5.84 g), palladium acetate (449,0 mg), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1,25 g) and tert-piperonyl sodium (to 4.23 g) and the mixture is stirred under nitrogen atmosphere at 80°C for 12 hours. The reaction solution is cooled to room temperature, add saturated aqueous sodium bicarbonate solution, the mixture is extracted twice with ethyl acetate, the organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 19:1→4:1), while receiving (3,5-bis-trifloromethyl)-(5-bromopyridin-2-yl)amine (2,08 g). MS (m/z): 399/401 [M+H]+.

Reference example 15

3-methyl bromide-5-cryptomathematical (obtained in reference example 12) (15.9 g) was dissolved in 7 M ammonia solution in methanol (550 ml) and the mixture was stirred at 50-60°C for 30 minutes. The reaction solution is concentrated under reduced pressure. To the resulting residue add saturated aqueous sodium bicarbonate solution and chloroform, the mixture is separated, the organic layer dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is purified of chromatogr is via on a column of silica gel (chloroform:methanol = 1:0→19:1 → chloroform:methanol:ammonium hydroxide solution = 19:1:0,1), while receiving 3-aminomethyl-5-cryptomathematical (10.4 g). MS (m/z): 201 [M+H]+.

Reference example 16

This connection receiving, processing corresponding to the original connection analogously to example 142(1).

Reference example 17

(1) 3-Bromo-4-methoxybenzoic acid (2.00 g) was dissolved in tetrahydrofuran (50 ml), the mixture is cooled to -78°C and added dropwise 1.1 M solution metallice in diethyl ether (7.7 ml). The mixture was stirred at -78°C for 5 minutes and added dropwise 1.6 M solution of tert-utility in n-pentane (13,2 ml), the mixture was stirred at -78°C for 15 minutes and allowed to warm to -45°C., then stirred for 45 minutes and again cooled to -78°C. and Then added dropwise to triisopropylsilyl, the mixture was stirred at -78°C for 15 minutes and allowed to warm to room temperature. The mixture is stirred at room temperature for 1.5 hours, concentrated under reduced pressure and add water and hexane. The aqueous layer was brought to pH 4 by adding 6 n solution of chloride-hydrogen acid and saturated aqueous sodium bicarbonate solution, and the mixture is extracted twice with ethyl acetate and methanol. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. To the resulting residue, add diethyl ether and the solid matter is collected by filtration, while receiving 2-methoxy-5-carboxybenzeneboronic acid (1,37 g) as a crude product.

(2) the Crude 2-methoxy-5-carboxybenzeneboronic acid (370 mg) was dissolved in N,N-dimethylformamide (10 ml) and added 2.0 M solution of dimethylamine in tetrahydrofuran (1.9 ml), dihydrate 1-hydroxybenzotriazole (725 mg) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (579 mg). The mixture is stirred at room temperature for 3 hours, add saturated aqueous solution of sodium bicarbonate and the mixture extracted twice with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (chloroform:methanol = 19:1), thus obtaining 2-methoxy-5-dimethylcarbamodithioato acid (210 mg). MS (m/z): 224 [M+H]+.

Reference example 18

This connection receiving, processing corresponding to the original connection similar to reference example 17.

Reference example 19

4-sec-butylphenol (3.0 g) is dissolved in chloroform, add bromine (1,02 ml) and the mixture is stirred at room temperature for 30 minutes. Then add saturated aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and ethyl acetate and the mixture is separated. The organic layer is washed with nasyscennosti salt, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining 2-bromo-4-sec-butylphenol (of 4.57 g).

NMR (CDCl3): 0,81 (3H, t)to 1.19 (3H, d), and 1.56 (2H, m), of 2.51 (1H, m), 5,33 (1H, s), 6,93 (1H, d), 7,02 (1H, d), 7,26 (1H, s).

(2) 2-Bromo-4-sec-butylphenol (1.50 g) was dissolved in N,N-dimethylformamide (10 ml), add potassium carbonate (1.18 g) and jodean (1.12 g) and the mixture is stirred at room temperature overnight. Then add ethyl acetate and water, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 1:0→20:1), while receiving 2-bromo-4-sec-butyl-1-methoxybenzo (1,58 g).

NMR (CDCl3): to 0.80 (3H, t), of 1.20 (3H, d), of 1.55 (2H, m), of 2.51 (1H, m), a 3.87 (3H, s), PC 6.82 (1H, d), 7,07 (1H, d), 7,35 (1H, s).

(3) 2-Bromo-4-sec-butyl-1-methoxybenzo (1,15 g) dissolved in tetrahydrofuran (17 ml) and the mixture is cooled to -78°C., added dropwise 1.6 M n-utility in hexano and the mixture was stirred at -78°C for 15 minutes. To the reaction solution add trimethylboron (1.47 g), the reaction mixture was stirred at -78°C for 30 minutes and add saturated aqueous solution of ammonium chloride and ethyl acetate. The mixture was separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate the Ute under reduced pressure, while receiving 5-sec-butyl-1-methoxybenzeneboronic acid (950 mg).

NMR (CDCl3): 0,81 (3H, t)to 1.22 (3H, d), was 1.58 (2H, m), 2,58 (1H, m), 3,90 (3H, s), and 6.25 (2H, s), 6.85 (2H, d), 7,25 (1H, d), the 7.65 (1H, s).

Reference examples 20-23

Connection data receiving, processing corresponding starting compound similar to reference example 19.

Reference example 24

2-Bromo-6-iodine-3-methoxypyridine (500 mg) is dissolved in dry toluene (5 ml), added dropwise a 1.6 M solution of n-utility in hexano (1 ml) at -78°C under nitrogen atmosphere and the mixture is stirred for 1 hour, then add acetone (0,23 ml) and the mixture is stirred over night. To the reaction solution was added water and ethyl acetate, the mixture is separated, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate= 4:1→3:2), thus obtaining 2-(6-bromo-5-methoxypyridine-2-yl)propan-2-ol (197 mg). MS (m/z): 246/248 [M+H]+.

Industrial applicability

The compound of formula (1) according to the present invention or its pharmaceutically acceptable derivative has the activity of inhibiting SETR, increasing the level of the I of HDL cholesterol and reduce LDL cholesterol. Thus, the compounds of the present invention can be used for the prevention and/or treatment arteriosclerotic diseases, hyperlipemia or dyslipidemia, and the like.

1. The compound of General formula (1):

where ZAmeans N or CH;
A21Ameans CNS group, optionally substituted by 1-2 groups selected from carboxyl group, halogen atom, alkoxycarbonyl group, CNS group, hydroxyl group, mono - or dialkylamino, alkylsulfonyl group, ceanography, tetrazolyl group, alkylsulfonyl group and alkylsulfonyl group; alkyl group, optionally substituted by 1-2 groups selected from carboxyl group, halogen atom, alkoxycarbonyl group, CNS group, hydroxyl group, mono - or dialkylamino, alkylsulfonyl group, ceanography, tetrazolyl group, alkylsulfonyl group and alkylsulfonyl group; morpholinyl group; carboxyl group or carboxypeptidases group;
R1Ameans cyano or alkyl group, optionally substituted by 1 to 3 halogen atoms;
In' means a group independently selected from halogen atom, alkyl group, optionally substituted by 1-3 halogen atoms, or alkoxyl the th group, optionally substituted by 1 to 3 halogen atoms;
pAmeans an integer from 0 to 3;
D means pyrimidinyl group, pyridyloxy group, phenyl group, pyrimidinylidene, tetrazolyl group or oxazolidinyl group;
D' means a group independently selected from CNS group, optionally substituted by 1 to 3 halogen atoms, halogen atom, ceanography, alkylsulfonyl group, mono - or dialkylamino, alkenylphenol groups, alkyl groups, optionally substituted by 1-3 halogen atoms, carboxyl group, hydroxyl group, carboxylcontaining group, carboxialkilnuyu group, alkoxycarbonyl group, carbonyl group, cycloalkyl group, hydroxyalkyl group, alkoxyalkyl group, carbamoyl group, mono - or dialkylanilines group, alkylcarboxylic, morpholinyl group or carboxylcontaining group;
qAmeans an integer from 0 to 3;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which ZAmeans N, or its pharmaceutically acceptable salt.

3. The compound according to claim 1, in which R1Ameans alkyl group, optionally substituted by 1-3 halogen atoms, or its pharmaceutically acceptable salt.

4. The compound according to claim 1, in which D is phenyl group, or f is matemticas acceptable salt.

5. The compound according to claim 1, in which D' is a group independently selected from a halogen atom, CNS group or alkyl group, or its pharmaceutically acceptable salt.

6. The connection of claim 1, wherein A21Ameans morpholinyl group or CNS group, substituted carboxyl group, or its pharmaceutically acceptable salt.

7. The connection according to claim 1, in which And21Ameans CNS group, substituted carboxyl group, or carboxypeptidases group;
D means pyridyloxy group or phenyl group;
D' means a group independently selected from CNS group, halogen atom, alkenylphenol groups, alkyl groups, optionally substituted by 1 to 3 halogen atoms, and a hydroxyalkyl group, or its pharmaceutically acceptable salt.

8. The compound according to claim 1, which is selected from:






























or its pharmaceutically acceptable salt.

9. The compound according to claim 1, chosen from:



or its pharmaceutically acceptable salt.

10. The compound according to claim 1, which is represented by the following chemical formula:

or its pharmaceutically acceptable salt.

11. The compound according to claim 1, which is represented by the following chemical formula:

or its pharmaceutically acceptable salt.

12. The compound according to claim 1, which is represented by the following chemical formula:

or its pharmaceutically acceptable salt.

13. Pharmaceutical composition having inhibitory activity against protein transfer cholesterolemia ether containing as active ingredient a compound according to any one of claims 1 to 12 or agopermalink acceptable salt.

14. The method of prevention or treatment of arteriosclerosis such as atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, ischemia of the heart, stroke, myocardial infarction, impaired reperfusion injury, restenosis after reconstruction of blood vessels, hypertension, heart attack, brain damage, strokes, diabetes, vascular complication of diabetes, thrombotic disorders, obesity, endotoxicosis, metabolic syndrome, ischemic stroke, coronary artery disease, dysfunction of the ventricle, cardiac arrhythmia, vascular disease of the lung, vascular disease of the kidney (renovaskulyarnoy), vascular disease of the internal organs, hemostatic vascular disease, fatty infiltration of the liver or steatohepatitis, which includes an introduction to the needy to the subject an effective amount of a compound according to any one of claims 1 to 12 or its pharmaceutically acceptable salt.

15. The use of compounds according to any one of claims 1 to 12 or its pharmaceutically acceptable salts for the preparation of drugs for the treatment of subjects suffering from arteriosclerosis such as atherosclerosis, peripheral vascular disease, DISL pideme, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, ischemia, ischemia of the heart, stroke, myocardial infarction, impaired reperfusion injury, restenosis after reconstruction of blood vessels, hypertension, heart attack, brain damage, strokes, diabetes, vascular complication of diabetes, thrombotic disorders, obesity, endotoxicosis, metabolic syndrome, ischemic stroke, coronary artery disease, dysfunction of the ventricle, cardiac arrhythmia, vascular disease of the lung, vascular disease of the kidney, vascular disease of the internal organs, hemostatic vascular disease, fatty infiltration of the liver or steatohepatitis.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula 2 and 3

, synthesis methods thereof, pharmaceutical compositions, as well as use thereof to prepare a medicinal agent, having antagonistic activity towards D2-receptors and modulating activity towards 5HT reuptake.

EFFECT: present invention provides salt forms used as modulators of one or more GPCR.

20 cl, 3 tbl, 5 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidinium derivatives of formula I

in enantiomer form or pharmaceutically acceptable salt thereof, where R1 and R3 each independently denotes cyclopentyl, cyclohexyl, phenyl; R2 denotes OH; R4 denotes C1-C4alkyl; R5 denotes C1alkyl, substituted with a CO-NH-R6 group; R6 denotes a 5-member unsaturated heterocyclic group containing one N atom and one O atom in the ring, a 6-member heterocyclic group containing two N atoms in the ring.

EFFECT: compounds can inhibit binding of aceylcholine with M3 muscarinic receptors, which facilitates their use in a pharmaceutical composition.

6 cl, 3 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of cis-2,4,5-triarylimidazoline of general formula I and pharmaceutically acceptable salts thereof, where X1 is selected from a group comprising lower alkoxy; X2 and X3 are independently selected from a group comprising hydrogen, halogen, cyano, lower alkyl, lower alkoxy, piperidinyl, -NX4X5, -SO2NX4X5, -C(O)NX4X5, -C(O)X6, -SOX6, -SO2X6, -NC(O)-lower alkoxy, -C≡C-X7, provided that both X2 and X3 do not denote hydrogen, lower alkyl or lower alkoxy, provided that when X2 or X3 denote hydrogen, the other does not denote lower alkyl, lower alkoxy or halogen, provided that when X2 denotes -HX4X5, X3 does not denote hydrogen, X2 and X3 together can form a ring selected from 5-7-member unsaturated rings which can contain three heteroatoms selected from S, N and O, X4 and X5 are independently selected from a group comprising hydrogen, lower alkyl, lower alkoxy, lower alkyl, substituted by a lower alkoxy, -SO2-lower alkyl, -C(O)piperazinyl-3-one; X6 is selected from a group comprising lower alkyl, morpholine, piperidine, pyrrolidine; X7 is selected from a group comprising hydrogen, lower alkyl, trifluoromethyl; Y1 and Y2 are independently selected from a group comprising halogen; R is selected from a group comprising lower alkoxy, piperidinyl substituted with a five-member heterocyclic ring which contains one nitrogen heteroatom, piperidinyl substituted with a hydroxy, -CH2OH or -C(O)NH2, piperazinyl substituted with one or two R1 [1,4]diazepanyl, substituted R1, R1 can denote one or two substitutes selected from a group comprising oxo, lower alkyl substituted with one R2, -C(O)R3, -SO2-lower alkyl, -SO2-five-memer heterocyclyl, which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl; R2 is selected from a group comprising -SO2-lower alkyl, hydroxy, lower alkoxy, -NH-SO2-lower alkyl, -cyano, -C(O)R4; R3 is selected from a group comprising a five-member heterocyclyl which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl, lower alkyl, lower alkenyl, lower alkyl substituted with a six-member heterocyclyl selected from piperidinyl, piperazinyl, 3-oxopiperazinyl, morpholinyl, C3-cycloalkyl; R4 is selected from a group comprising hydroxy, morpholine, piperidine, 4-acetylpiperazinyl, -NR5R6; R5 and R6 are independently selected from a group comprising hydrogen, lower alkyl, lower alkyl substituted with lower alkoxy or cyano, lower alkoxy and C3-cycloalkyl. The invention also relates to a pharmaceutical composition based on the formula I compound, use of the formula I compound in preparing a medicinal agent and a method for synthesis of the formula I compound.

EFFECT: novel derivatives of cis-2,4,5-triarylimidazoline of general formula I are obtained, which can be used to treat diseases, based on reaction of the MDM2 protein with p53-like protein, particularly as anticancer agent.

54 cl, 412 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts, tautomers, or N-oxides, for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases. In formula (Ia) X stands for group R1-A-NR4; A stands for link, C=O, or NRg(C=O, where R8 stands for hydrogen or C1-3 alkyl; Y stands for link or alkylene chain, made of 1, 2 or 3 atoms of carbon; R1 stands for carbocyclic or heterocyclic group, containing from 3 to 12 circular units; or saturated C1-8hydrocarbyl group, optionally substituted with one or more substituents selected from halogen (for instance, fluorine), hydroxygroups, C1.4alkoxygroups, and carbocyclic or heterocyclic groups, and where 1 or 2 atoms of hydrocarbyl group carbon may be optionally substituted with atom or group selected from O, S, NH, SO, SO2; R2 stands for hydrogen or methyl; R3 is selected from hydrogen and carbocyclic or heterocyclic groups, containing from 3 to 6 circular units; and R4 stands for hydrogen or methyl. Specified carbocyclic and heterocyclic groups are determined in formula of invention and may be optionally substituted with groups specified in invention formula. Objects of invention are also a pharmaceutical composition based on proposed compounds, their application to produce medicinal agents and methods of their application.

EFFECT: production of pharmaceutical composition based on proposed compounds for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases.

48 cl, 6 tbl, 254 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I):

where A denotes -CONH-CH2-, -CO-CH=CH-, -CO-CH2CH2-, -CO-CH2-O-, -CO-CH2-NH-, or ; R1 denotes hydrogen, C1-5-alkyl or C1-5-alkoxy; R2 denotes hydrogen, C1-2-alkyl, C1-5-alkoxy, trifluoromethyl or halogen, R3, R31, R32, R33, R34, R4, R5, R6, R7, k, m, n are described in claim 1. The invention also relates to a pharmaceutical composition for preventing or treating diseases and disorders associated with an activated immune system, based on said compounds and to use thereof as therapeutically active compounds for preventing or treating diseases or disorders such as graft rejection, graft versus host reaction and autoimmune syndromes.

EFFECT: improved properties of the compound.

27 cl, 2 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent which modulates PPARδ (peroxisome proliferator-activated receptor δ). In formula I

, p is equal to 1; L2 is selected from a group which includes -XOX- and -XSX-, where X is independently selected from a group which includes a bond and C1-C4alkylene; R13 is selected from a group which includes halogen, C1-C6alkyl; R14 is selected from a group which includes -XOXC(O)OR17 and -XC(O)OR17, where X denotes a bond or C1-C4alkylene and R17 denotes hydrogen; R15 and R16 are independently selected from a group which includes -R18 and -YR18, where Y is selected from a group which includes C2-C6alkenylene, and R18 is selected from a group which includes C6-C10aryl, pyridinyl, pyrimidinyl, quinolinyl, benzo[b]furanyl, benzoxazolyl, 1,5-benzodioxanyl, 1,4-benzodioxanyl and 3,4-dihydro-2H-benzo[b][1,4]dioxepin; where any of phenyl, pyridinyl, pyrimidinyl, benzoxazolyl in R18 is independently substituted with 1-2 radicals, independently selected from a group which includes halogen, C1-C6alkyl, C2-C7alkenyl, C1-C6alkoxy group, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy group, C3-C12cycloalkyl, phenyl, morpholinyl, pyrrolidinyl, piperidinyl, -XNR17R17, -XC(O)NR17R17, -XC(O)R19 and -XOXR19, where X denotes a bond or C1-C4alkylene; R17 is selected from a group which includes C1-C6alkyl, and R19 is selected from a group which includes C3-C12cycloalkyl, piperidinyl and phenyl. The invention also relates to use of the disclosed compounds to prepare a medicinal agent which modulates PPARδ activity, a pharmaceutical composition having PPARδ activity modulating properties, which contains a therapeutically effective amount of the disclosed compound and to use of the pharmaceutical composition in preparing a medicinal agent which modulates PPARδ activity.

EFFECT: improved properties of compounds.

10 cl, 1 tbl, 69 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of compounds of formula (A), where R1 denotes halogen, C1-C6halogenalkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2 denotes halogen, C1-C4alkyl or C1-C4alkoxy; R3 and R4 independently denote a branched C3-C6alkyl; and R5 denotes C3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanoylamino(C1-C6)alkyl, HO(O)C-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl, or their pharmaceutically acceptable salts which have renin inhibiting activity, as well as to basic intermediate compounds obtained during steps for synthesis of the desired compounds and to methods for synthesis of said intermediate compounds.

EFFECT: alternative synthesis method.

43 cl, 8 dwg, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new derivatives of piperidine of formula I: , in which: R1 and R2 are selected from group, including alkyl, halogenalkyl, alkyl substituted with one or more hydroxy groups, -CN, alkynyl, -N(R6)2, - N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2 and group , , , ,

provided that at least one of R1 and R2 stands for -CN or group , , , ,

W stands for =C(R8)- or =N-; X stands for -C(O)- or -S(O2)-; Y is selected from group, including -CH2-, -O- and -N(R6)-C(O)-, provided that: (a) atom of nitrogen of group -N(R6)-C(O)- is linked with X, and (b) if R1 and/or R2 stands for and Y stands for -O-, then X does not stand for -S(O2)-; Z stands for -C(R7)2-, -N(R6)-, or -O-; R3 is selected from group, including H and non-substituted alkyl; R4 stands for H; R5 stands for H or alkyl; R6 is selected from group, including H, alkyl, cycloalkyl and aryl; each R7 independently stands for H or alkyl; or each R7 together with circular atom of carbon, to which they are linked, as indicated, forms cycloalkylene ring; R8 is selected from group including H, alkyl, alkyl substituted with one or large number of hydroxygroups, -N(R6)2, -N(R6)-S(O2)- alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -CN; R9 is selected from group including H, alkyl and aryl, or each R9 jointly with atom of nitrogen, to which, as indicated, they are linked, forms heterocycloalkyl ring; Ar1 stands for non-substituted phenyl; Ar2 stands for phenyll substituted with 0-3 substituents, selected from group including halogenalkyl; n equals 0, 1 or 2; and m equals 1, 2 or 3, and to their pharmaceutically acceptance salts and hydrates.

EFFECT: production of new biologically active compounds, having properties of antagonist of neurokinin receptor NK1.

35 cl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I and to its pharmaceutically acceptable salts. In formula I R1 is selected from C1-6alkyl, C3-12cycloalkyl, phenyl, furanyl, thienyl, pyridyl, where phenyl of radical R1, is optionally substituted with radical, which is selected from halogen, nitro, C1-6alkyl, C1-6alkoxy, substituted with halogen of C1-6alkyl and -XC(O)YR5; where X represents C1-4alkylene, Y represents O, and R5 represents hydrogen; R2 represents -C(O)NR4XOR5, where X represents C1-4alkylene; R4 is selected from hydrogen and C1-6alkyl; R5 represents phenyl; where any phenyl of radical R2, is optionally substituted with two radicals, which are independently selected from halogen, nitro and halogen-substituted C1-6alkyl; R3 represents phenyl, which is optionally substituted with radicals in number from 1 to 2, which are independently selected from halogen, C1-6alkyl, C1-6alkoxy, -XOXC(O)OR5, -XC(O)OR5, where X is independently selected from simple link and C1-4alkylene; and R5 is selected from hydrogen and C1-6alkyl. Invention also relates to compounds selected from 2-(2-nitro-4-trifluoromethylphenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 2-(2,4-dichlorophenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 3-(2,6-dichlorophenyl)-5-methyl-4-[2-(2-nitro-4-trifluoromethylphenoxy)ethoxymethyl]isoxazole, other compounds are specified in invention formula.

EFFECT: compounds of present invention may find application as medicinal agent that modulates activity of receptors activated by PPARδ.

7 cl, 2 tbl, 65 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidinium derivatives of formula I

in enantiomer form or pharmaceutically acceptable salt thereof, where R1 and R3 each independently denotes cyclopentyl, cyclohexyl, phenyl; R2 denotes OH; R4 denotes C1-C4alkyl; R5 denotes C1alkyl, substituted with a CO-NH-R6 group; R6 denotes a 5-member unsaturated heterocyclic group containing one N atom and one O atom in the ring, a 6-member heterocyclic group containing two N atoms in the ring.

EFFECT: compounds can inhibit binding of aceylcholine with M3 muscarinic receptors, which facilitates their use in a pharmaceutical composition.

6 cl, 3 tbl, 8 ex

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