Aryloxy-substituted benzimidazole derivative

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

EFFECT: novel compounds which can be useful in treating and preventing diabetes and obesity are obtained and described.

29 cl, 227 ex, 6 tbl

 

Technical area

The present invention relates to a glucokinase activator comprising as an active ingredient arylacetamide derivative of benzimidazole and suitable in the field of medicines. Further, it relates to a new arylacetamide derivative of benzimidazole.

The level of technology

Glucokinase (GK) (ATP: D-hexoses-6-phosphotransferase, EC 2,7.1,1) is one (glucokinase (IV) of the four hexokinase mammals. Glucokinase is an enzyme in the first step of glycolysis and catalyzes the reaction from glucose to hexaphosphate glucose. In relation to the expression of glucokinase is limited essentially by beta cells of the liver and pancreas and controls limiting the speed stage of glucose metabolism in these cells, thus playing an important role in the system of sugar metabolism. Glucokinase in beta cells and liver glucokinase in the beta cells of the pancreas differ from each other in regard to the N-terminal sequence of 15 amino acids due to differences in splicing, but they are the same in relation to enzymatic properties. The enzymatic activity of the other three hexokinase (I, II, III) except glucokinase is saturated when the concentration of glucose at most 1 mm, but the Km of glucokinase to glucose is 8 mm and close to the physiologist the economic level of sugar in the blood. Therefore, in accordance with changes in the level of blood sugar normal blood sugar levels (5 mm) to increased blood sugar levels after the introduction of food (10-15 mm) extracellular glucose metabolism accelerated by glucokinase.

Ten years ago was the hypothesis that glucokinase may act as a glucose sensor in the beta cells of the pancreas and liver (for example, see D. Garfinkel et al. Computer modeling identifies glucokinase as glucose sensor of pancreatic beta-cells; American Journal discrimination, Vol.247 (3Pt2), 1984, pp.527-536).

The result of recent research glucokinase managed glucokinase gene in mice confirmed that glucokinase plays an important role in systemic glucose homeostasis. The mouse, which was torn glucokinase gene die shortly after birth (for example, see Grupe A. et al. Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis, Cell, Vol.83, 1995, pp.69-78); but, on the other hand, normal mice or mice with diabetes, the body glucokinase is expressed excessively, have low blood sugar levels (for example, see T. Ferre et al., Correction of diabetic alterations by glucokinase; Proceedings of the National Academy of Sciences of the USA, Vol.93, 1996, pp.7225-7230).

With increasing concentration of glucose response of beta-cells of the pancreas and liver cells leads in both cases to reduce blood sugar levels, but it varies. Beta-glue the key of the pancreas secrete more insulin, and the liver raises the sugar to keep it in the form of glycogen, and simultaneously reduces the release of sugar.

In the framework of this effect a change in the enzymatic activity of glucokinase plays an important role in glucose homeostasis mammal through the beta cells of the liver and pancreas. In cases of juvenile diabetes, which is referred to as MODY2 (maturity-onset diabetes of the young), was found mutation of the glucokinase gene, and the reduction glucokinase activity causes an increase in blood sugar levels (for example, see Vionnet N. et al., Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus; Nature Genetics, Vol.356, 1992, pp.721-722).

On the other hand, was discovered genealogy, having a mutation that increases glucokinase activity and show symptoms of low blood sugar levels (for example, see B. Glaser et al. Familial hyperinsulinism caused by an activating glucokinase mutation; New England Journal Medicine, Vol.338, 1998, pp.226-230).

Thus, glucokinase acts as a glucose sensor and plays an important role in glucose homeostasis also in humans. On the other hand, the regulation of blood sugar levels using glucokinase sensor systems may be possible in many patients with diabetes type II. We can assume that glucokinase-activating substance has a stimulating effect on insulin secretion in beta-cells of p is zheludochno gland activity in relation to expedite the capture of sugar and inhibiting the release of sugar in the liver and therefore may be useful in the treatment of patients with diabetes type II.

Recently it has become clear that glucokinase pancreatic beta-cell type is expressed exclusively locally in the rat brain, especially in ventromedial hypothalamus (VMH). Approximately 20% of neurons in the VMH are referred to as sensitive to glucose neurons, and therefore it is considered that they can play an important role in the regulation of body weight. When glucose is injected into the rat brain, it reduces the amount of food consumed; but when glucose metabolism is slowed down through vnutricerepnae introduction of glucosamine, an analogue of glucose, it causes hyperphagia. On the basis of the electrophysiological experiment, the assumption was made that sensitive to glucose neurons are activated in accordance with changes in physiological glucose concentrations (5-20 mm), but when glucose metabolism is inhibited by glucosamine or similar drugs, then their activity slows down. In sensitive to the concentration of glucose system in VHM expected to be mediated glucose mechanism, such as the secretion of insulin in the beta cells of the pancreas. Accordingly, it may be possible that the substance to activate glucokinase in VHM, in addition to the beta-cells of the liver and pancreas, can be effective not only for correction of blood sugar levels, but also for the treatment of obesity, which is a is a roblem for many patients with diabetes type II.

This indicates that compounds with glucokinase-activating effect, suitable as a therapeutic and/or prophylactic agent for the prevention and/or treatment of diabetes, a therapeutic and/or prophylactic agent for the prevention and/or treatment of diabetic complications such as retinopathy, nephropathy, neurosis, coronary heart disease, arteriosclerosis and the like, and as therapeutic and/or prophylactic agent for the prevention and/or treatment of obesity.

In respect of derivatives of benzimidazole, for example, described compound of the following formula (for example, WO 2002/032872):

The connection of the specified formula like the connection according to the present invention in that they have 2-pyridinyl group in position 6 of them 7H-pyrrolo[2,3-d]pyrimidinyl skeleton, a group of phenoxy in position 4, but differ structurally in that the first has one Deputy on 7H-pyrrolo[2,3-d]pyrimidinyl group, and the fact that the first Deputy on fenoxaprop is an amino group.

Next, this compound is an intermediate compound to obtain a compound that inhibits angiogenesis, and is not described and it is not expected that this compound may be useful for the treatment and/or prevention of a particular diabetes and obesity.

The opening image is etenia

The problem solved by the invention

The object of the present invention is a new arylacetamide derivative of imidazole and including its activator of glucokinase, especially as a therapeutic and/or prophylactic agent for the treatment and/or prevention of diabetes and obesity.

The authors conducted in-depth research to develop a new drug for the treatment of diabetes, which has pharmaceutical potential, exceeding the capacity of existing medicines for the treatment of diabetes due to effects other than the effects of existing medicines, and which has the additional pharmaceutical potential, and as a result discovered that the new arylacetamides benzimidazole derivative has a glucokinase-activating effect, and accomplished the present invention.

In particular, the invention relates to the following:

(1) compound of formula (I):

or its pharmaceutically acceptable salt, in which:

R1and R2each independently represent a hydrogen atom, halogen atom, lower alkyl, hydroxyl group, cyano or lower alkoxy;

R3independently denotes a hydrogen atom, halogen atom, lower alkyl, lower alkoxy, hydroxyalkyl, trifluoromethyl, lower alkenyl is whether the cyano;

R4independently denotes a hydrogen atom, lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, hydroxyalkyl, optionally substituted lower alkyl, aminoalkyl, optionally substituted lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano;

Q denotes the carbon atom, nitrogen atom or sulfur atom, optionally substituted by one or two exography;

R5and R6each independently represent a hydrogen atom, lower alkyl, halogen atom, lower alkyl, lower alkylsulfonyl, lower alkylsulfonyl, alkanoyl, formyl, aryl, mono - or di-(lower) allylcarbamate or mono - or di-(lower) alkylsulfonyl; or Q, R5and R6together can form the following:

(A) 5 - or 6-membered aliphatic nitrogen-containing heterocyclic group which may have a ring from 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, and having at least one nitrogen atom in addition to the heteroatoms; specified heterocyclic group may have one or two double bonds;

(B) a 5 - or 6-membered aromatic nitrogen-containing heterocyclic group which may have a ring from 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, and having at meredin the nitrogen atom in addition to the heteroatoms; or

(C) phenyl,

and aliphatic nitrogen-containing heterocyclic group, an aromatic nitrogen-containing heterocyclic group or phenyl can have from 1 to 3 groups selected from the following group of substituents α, and/or may have, as a substituent, (3-6)-membered ring formed by the connection with each other associated groups selected from the group of substituents α, and/or may be condensed with a group of the formula (A):

in whichrepresents a simple bond or double bond;

X1X2X3and X4each independently represent a carbon atom or a nitrogen atom;

Z represents an oxygen atom, a sulfur atom or a nitrogen atom;

Ar denotes an aryl or heteroaryl, optionally substituted groups a number from 1 to 3, selected from the following group of substituents β;

ring A represents a 5 - or 6-membered nitrogen-containing heteroaromatic group of formula (III):

in which X represents a carbon atom;

m denotes an integer from 1 to 6;

n denotes an integer from 0 to 3;

p denotes an integer from 0 to 2; provided that at least two of X1-X4denote hydrogen atoms;

q represents 0 or 1;

the group of substituents α:

oxoprop, tocograph, lower alkyl, lower and is coxi, alkanoyl, formyl, hydroxyl group, carboxyl group, trifluoromethyl, hydroxyalkyl, optionally substituted lower alkyl, cyano, mono - or di-(lower) allylcarbamate, lower alkylsulfonyl, lower alkylsulfonyl and halogen atom;

the group of substituents β:

lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, hydroxyalkyl, optionally substituted lower alkyl, lower alkylsulfonyl, lower alkylsulfanyl, lower alkylsulfonyl, aminoalkyl, optionally substituted lower alkyl, alkanoyl, carboxyl group, mono - or di-(lower) allylcarbamate, mono - or di-(lower) alkylsulfonyl, lower alkoxycarbonyl, cyano, aryl and heteroaryl having in the ring 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom;

specified aryl and heteroaryl can have one or two groups selected from the following group of substituents γ;

the group of substituents γ:

lower alkyl, lower alkoxy, halogen atom, hydroxyl group, lower alkylsulfonyl, lower alkylsulfonyl, alkanoyl, cyano, mono - or di-(lower) allylcarbamate;

(2) the Compound or pharmaceutically acceptable salt according to (1), in which ring A represents thiazolyl, imidazolyl, isothiazolin, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl,pyridyl, pyridazinyl, pyrazolyl or pyrimidinyl;

(3) the Compound or pharmaceutically acceptable salt according to paragraphs in which ring A represents thiazolyl, imidazolyl, isothiazolin, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl or pyrimidinyl, and the formula (I) represented by the following formula (I-1):

in which the symbols have the same meanings as defined above;

(4) the Compound or pharmaceutically acceptable salt according to (1), in which ring A represents thiazolyl, imidazolyl, isothiazolin, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl or pyrimidinyl, and the formula (I) represented by formula (I-2):

in which the symbols have the same meanings as defined above;

(5) the Compound or pharmaceutically acceptable salt according to (1), in which ring A represents thiazolyl, imidazolyl, isothiazolin, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl or pyrimidinyl, and the formula (I) represented by formula (I-3):

in which the symbols have the same meanings as defined above;

(6) the Compound or pharmaceutically acceptable salt according to (3)in which m ranges from to 4;

(7) the Compound or pharmaceutically acceptable salt according to (3), in which Z denotes an oxygen atom or a sulfur atom;

(8) the Compound or pharmaceutically acceptable salt according to (3), in which Ar denotes phenyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, which may be substituted by a group selected from the group of substituents β;

(9) the Compound or pharmaceutically acceptable salt according to (3), in which R5and R6each independently represent a hydrogen atom, lower alkyl, halogen atom, lower alkyl, lower alkylsulfonyl, lower alkylsulfonyl, alkanoyl or formyl;

(10) the Compound or pharmaceutically acceptable salt according to (3), in which Q denotes a nitrogen atom;

(11) the Compound or pharmaceutically acceptable salt according to (3)in which Q represents a carbon atom;

(12) the Compound or pharmaceutically acceptable salt according to (3), in which a group of the formula (I-A):

in the formula (I-1) represents a group of the following formula:

in which R11denotes a hydrogen atom or lower alkyl; and the other symbols have the same meanings as defined above;

(13) the Compound or pharmaceutically p is Jemima salt according to (3), where:

Q denotes a nitrogen atom;

R5and R6together with the nitrogen atom form a 5 - or 6-membered aliphatic nitrogen-containing heterocyclic group which may have a ring from 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, and having at least one nitrogen atom in addition to the heteroatoms;

the specified 5 - or 6-membered aliphatic nitrogen-containing heterocyclic group may have one or two double bonds and may be mono - or disubstituted by identical or different groups selected from the following group of substituents α1;

m=1;

Z represents an oxygen atom;

Ar denotes phenyl or pyridyl, optionally mono - or disubstituted by identical or different groups selected from the following group of substituents β1;

R1and R2denote independently a hydrogen atom or lower alkyl;

the group of substituents α1:

oxoprop, tocograph, lower alkyl, lower alkoxy, alkanoyl, halogen atom, cyano, mono - or di-(lower) allylcarbamate;

the group of substituents β1:

lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, hydroxyalkyl, optionally substituted lower alkyl, lower alkylsulfonyl, alkanoyl, carboxyl group, mono - or di-(lower) allylcarbamate, mono - or di-(lower) alkyls efamol, lowest alkoxycarbonyl, cyano, aryl or heteroaryl with the ring 2, or 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom;

specified aryl and heteroaryl can have one or two groups selected from the group of substituents γ;

(14) the Compound or pharmaceutically acceptable salt according to (3)in which Q, R5and R6together form a 5 - or 6-membered aromatic nitrogen-containing heterocyclic group having at least one nitrogen atom, optionally having in the ring 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, in addition to the nitrogen atom, or phenyl;

specified aromatic heterocyclic group or phenyl can have from 1 to 3 groups selected from the following group of substituents α2;

Z represents an oxygen atom;

Ar denotes phenyl or pyridyl, optionally mono - or disubstituted by identical or different groups selected from the following group of substituents β1;

R1and R2denote independently a hydrogen atom or lower alkyl;

the group of substituents α2:

hydroxyl group, lower alkyl, lower alkoxy, alkanoyl, halogen atom, cyano or mono - or di-(lower) allylcarbamate;

the group of substituents β1:

lower alkyl, lower alkoxy, halogen atom, three is tormentil, hydroxyalkyl, optionally substituted lower alkyl, lower alkylsulfonyl, alkanoyl, carboxyl group, mono - or di-(lower) allylcarbamate, mono - or di-(lower) alkylsulfonyl, lower alkoxycarbonyl, cyano, aryl or heteroaryl with the ring 2, or 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom;

specified aryl and heteroaryl can have one or two groups selected from the group of substituents γ;

(15) the Compound or its pharmaceutically acceptable salt according to (1)where: formula (I) represents one of the following connections:

1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-5-thioxo-2-pyrrolidinone,

4-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}morpholine-3,5-dione,

3-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-thiazolane-2,4-dione,

3-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-thiazolin-2-it,

1-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione,

1-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-3-methylimidazolidine-2,5-dione,

2-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}isothiazolin-1,1-dioxide,

3-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyrazinyl)-N-benzimidazole-6-yl]methyl}-2-oxazolidinone,

1-{[5-{[6-(ethylsulfonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione,

1-[(5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl)methyl]-2-pyrrolidinone,

N-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)-N-methylacetamide,

3-{[5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-oxazolidin-2,4-dione,

5-[4-(ethylsulfonyl)phenoxy]-6-((2-methyl-2H-tetrazol-5-yl)methyl)-2-(2-pyridinyl)-1H-benzimidazole,

5-[4-(ethylsulfonyl)phenoxy]-6-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-2-(2-pyridinyl)-1H-benzimidazole,

1-[(6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]pyrrolidin-2-he

or

4-(2,6-diferensial)-6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1H-benzimidazole;

(16) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-5-thioxo-2-pyrrolidinone;

(17) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 4-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}morpholine-3,5-dione;

(18) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 3-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzoni the azole-6-yl]methyl}-1,3-thiazolane-2,4-dione;

(19) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 3-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-thiazolin-2-he;

(20) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 1-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione;

(21) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 1-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-3-methylimidazolidine-2,5-dione;

(22) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) represents 2-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}isothiazolin-1,1-dioxide;

(23) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 3-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyrazinyl)-1H-benzimidazole-6-yl]methyl}-2-oxazolidinone;

(24) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 1-{[5-{[6-(ethylsulfonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione;

(25) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 1-[(5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-Ben is imidazol-6-yl)methyl]-2-pyrrolidinone;

(26) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes N-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)-N-methylacetamide;

(27) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 3-{[5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-oxazolidin-2,4-dione;

(28) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 5-[4-(ethylsulfonyl)phenoxy]-6-((2-methyl-2H-tetrazol-5-yl)methyl)-2-(2-pyridinyl)-1H-benzimidazole;

(29) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 5-[4-(ethylsulfonyl)phenoxy]-6-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-2-(2-pyridinyl)-1H-benzimidazole;

(30) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) denotes 1-[(6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]pyrrolidin-2-he;

(31) the Compound or pharmaceutically acceptable salt according to (1), in which formula (I) refers to 4-(2,6-diferensial)-6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1H-benzimidazole;

(32) a Pharmaceutical composition containing the following (1) to (3), which is used for the treatment, prevention and/or delay the development of type II diabetes:

(1) the connection is whether its pharmaceutically acceptable salt, specified in(1)-(31),

(2) one or more compounds selected from the following groups (a)-(h):

(a) any other activator of glucokinase,

(b) bis-guanin,

(c) a PPAR agonist,

(d) insulin,

(e) somatostatin,

(f) an inhibitor of α-glucosidase,

(g) the promoter of insulin secretion and

(h) an inhibitor of DP-IV inhibitor dipeptidylpeptidase IV)

(3) a pharmaceutically acceptable carrier;

(33) a glucokinase Activator comprising a compound or pharmaceutically acceptable salt of any of the above (1)to(31) as an active ingredient;

(34) therapeutic and/or prophylactic agent for the treatment and/or prevention of diabetes, containing the compound or pharmaceutically acceptable salt of any of the above (1)to(31) as an active ingredient;

(35) therapeutic and/or prophylactic agent for the treatment and/or prevention of obesity, containing the compound or pharmaceutically acceptable salt of any of the above (1)to(31) as an active ingredient.

The best way of carrying out the invention

The meaning of the terms used in this description, described below, and the compounds according to the invention is described in more detail below.

Unless specifically stated otherwise, the following groups have the meanings described below.

"Halogen atom" includes, for example, fluorine atom, chlorine atom, bromine atom, iodine atom.

"And lower the keel" denotes a straight or branched alkyl, having from 1 to 6 carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, isopentyl, 1,1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl.

"Lower alkoxy" denotes a hydroxyl group in which a hydrogen atom is substituted by the above lower alkyl and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine, hexyloxy, etexilate.

"Hydroxyalkyl" means the above lower alkyl, substituted hydroxyl group, and includes, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl.

"Lower alkenyl" denotes a straight or branched lower alkenyl having from 2 to 6 carbon atoms, and includes, for example, vinyl, allyl, 1-butenyl, 2-butenyl, 1-pentenyl.

"Aminoalkyl" denotes the above alkyl, in which the hydrogen atom is substituted by an amino group, and includes, for example, aminomethyl, aminoethyl, aminopropyl.

"Alkanoyl" denotes the above alkyl, associated with the carbonyl group, and includes, for example, methyl shall arbonyl, ethylcarboxyl, propylmalonic, isopropylcarbonate.

"Lower alkoxycarbonyl" denotes a carboxyl group in which a hydrogen atom is substituted by the above lower alkyl and includes, for example, methoxycarbonyl, etoxycarbonyl, propylmalonic, isopropylcarbonate.

"Lower alkylsulfonyl" means the above lower alkyl associated with sulfonyloxy group, and includes, for example, methylsulphonyl, ethylsulfonyl, isopropylphenyl, n-propylsulfonyl.

"Lower alkylsulfonyl" means the above lower alkyl associated with sulfanilic group, and includes, for example, methylsulfinyl, ethylsulfinyl, isopropylphenyl.

"The lowest alkylsulfanyl" means the above lower alkyl associated with sulfanilic group, and includes, for example, methylsulfonyl, ethylsulfonyl, isopropylphenyl.

Mono-(lower) allylcarbamate" means karbamoilnuyu group, once substituted by the above lower alkyl and includes, for example, methylcarbamoyl, ethylcarbitol, propellerblades, isopropylcarbamate, butylcarbamoyl, second-butylcarbamoyl, tert-butylcarbamoyl.

"Di-(lower) allylcarbamate" means carbamoyl group disubstituted by identical or different lower alkyl groups of the above, and includes, for example, dimethylcarbamoyl, diethylcarbamoyl, Adilet carbamoyl, dipropylamino, methylpropylketone, diisopropylamino.

Mono-(lower) alkylsulfonyl" means sulfamoyl group, once substituted by the above lower alkyl and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylphenol.

"Di-(lower) alkylsulfonyl" means sulfamoyl group disubstituted by identical or different lower alkyl groups of the above, and includes, for example, dimethylsulphamoyl, diethylcarbamoyl, ethylmethylamino, isopropylalcohol.

For more specific disclosure of the compounds according to the invention the following formula (I):

(in which the symbols have the same meanings as defined above), the symbols used in this formula (I)described with reference to specific examples.

R1and R2each independently represent a hydrogen atom, halogen atom, lower alkyl, hydroxyl group, cyano or lower alkoxy.

"Halogen atom", the "lower alkyl" and "lower alkoxy" for R1and R2have the same meanings as defined above.

Preferably one of R1and R2denotes the hydrogen atom and the other represents lower alkyl, or both denote hydrogen atoms. More preferably both denote hydrogen atoms.

R3not avisio denotes a hydrogen atom, halogen atom, lower alkyl, lower alkoxy, hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano.

"Halogen atom", the "lower alkyl", "lower alkoxy", "hydroxyalkyl" and "lower alkenyl for R3have the same meanings as defined above.

Preferably R3denotes a hydrogen atom.

R4independently denotes a hydrogen atom, lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, hydroxyalkyl (the hydrogen atom of hydroxyl group in hydroxyalkyl may be substituted by lower alkyl), aminoalkyl (the amino group may be substituted by lower alkyl), alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano.

"Lower alkyl", "lower alkoxy", the "halogen atom", "alkanoyl" and "lower alkoxycarbonyl for R4have the same meanings as defined above.

"Hydroxyalkyl for R4includes, in addition to some higher "hydroxyalkyl such group, where the hydrogen atom in the hydroxyl group substituted lower alkyl.

"Hydroxyalkyl for R4includes, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methoxymethyl, methoxyethyl, ethoxyethyl.

R4preferably denotes a hydrogen atom, lower alkyl, halogen atom, trifluoromethyl or hydroxyalkyl (the hydrogen atom of hydroxyl group in the hydroxyalkyl group may be C the substituted lower alkyl); more preferably a hydrogen atom, lower alkyl, halogen atom or trifluoromethyl.

Q denotes a carbon atom, a nitrogen atom or a sulfur atom (the sulfur atom may be substituted by one or two oxopropyl). Q preferably represents a carbon atom or a nitrogen atom.

R5and R6each independently represent a hydrogen atom, lower alkyl, halogen atom, lower alkyl, lower alkylsulfonyl, lower alkylsulfonyl, alkanoyl, formyl, aryl, mono - or di-(lower) allylcarbamate or mono - or di-(lower) alkylsulfonyl; or Q, R5and R6in the following formula (II):

may together form a 5 - or 6-membered aliphatic nitrogen-containing heterocyclic group (this group may have one or two double bonds, or aromatic nitrogen-containing heterocyclic group which may have a ring from 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, or phenyl.

Aliphatic nitrogen-containing heterocyclic group, an aromatic nitrogen-containing heterocyclic group or phenyl can have from 1 to 3 groups selected from the following group of substituents α, and/or may have, as a substituent, (3-6)-membered ring formed by the connection with each other associated groups selected from the group of substituents α, and is and can be condensed with a group of the formula (A):

(whererepresents a simple bond or double bond).

"Lower alkyl", the "halogen atom", the "lower alkyl", "lower alkylsulfonyl", "lower alkylsulfonyl and alkanoyl for R5and R6can have the same values as defined above.

A group of the following formula (II):

in which Q is a carbon atom, nitrogen atom or sulfur atom and R5and R6denote independently a hydrogen atom, lower alkyl, halogen atom, lower alkyl, lower alkylsulfonyl, lower alkylsulfonyl, alkanoyl, formyl, aryl, mono - or di-(lower) allylcarbamate or mono - or di-(lower) alkylsulfonyl includes, for example, acetylamino, methanesulfonamido, benzazolyl, benzosulfimide, methanesulfonyl. Of them, preferred are acetylamino, acetamidomethyl, methanesulfonamido.

5 - or 6-membered aliphatic nitrogen-containing heterocyclic group (this group may have one or two double bonds, or aromatic nitrogen-containing heterocyclic group which may have a ring from 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, or phenyl, which together form Q, R5and R6is preferably 5 - or 6-membered aliphatic and odderade heterocyclic group (this group may have one or two double bonds), containing in the ring one or two heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, or a 5 - or 6-membered aromatic nitrogen-containing heterocyclic group which may contain 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, or a phenyl formed along Q, R5and R6.

The Deputy, who may be 5 - or 6-membered aliphatic nitrogen-containing heterocyclic group (this group may have one or two double bonds), preferably is oxoprop, tocograph, lower alkyl, lower alkoxy, alkanoyl, halogen atom, cyano, mono - or di-(lower) allylcarbamate selected from the group of substituents α.

The Deputy, who may be 5 - or 6-membered aromatic nitrogen-containing heterocyclic group, or phenyl, preferably is hydroxyl group, lower alkyl, lower alkoxy, alkanoyl, halogen atom, cyano, mono - or di-(lower) allylcarbamate selected from the group of substituents α.

Specifically, 5 - or 6-membered aliphatic nitrogen-containing heterocyclic group of the formula (II) includes, for example, the following groups (II-1):

Of them, preferred are groups of the following formula (II-2):

Specifically, 5 - or 6-membered aromatic nitrogen-containing heterocyclic group, and the phenyl of the formula (II) include, for example, groups of the following formula (II-2):

X1X2X3and X4each independently represent a carbon atom or a nitrogen atom. Preferably X1-X4all represent the carbon atoms.

Z represents an oxygen atom, a sulfur atom or nitrogen atom, preferably an oxygen atom or a sulfur atom, more preferably an oxygen atom.

Ar denotes an aryl or heteroaryl, optionally substituted groups a number from 1 to 3, selected from the group of substituents β.

"Aryl" for Ar include phenyl and naphthyl, and preferably denotes phenyl.

"Heteroaryl" for Ar represents 5 - or 6-membered monocyclic ring containing in the ring 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom.

Specifically, heteroaryl includes, for example, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrazinyl. Of them, preferred is pyridyl.

The Deputy, who may be Ar include groups selected from the above group of substituents β. Of them, preferred is Vlada lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, hydroxyalkyl (the hydrogen atom of hydroxyl group in the hydroxyalkyl group may be substituted by lower alkyl), lower alkylsulfonyl, alkanoyl, carboxyl group, mono - or di-(lower) allylcarbamate, mono - or di-(lower) alkylsulfonyl, lower alkoxycarbonyl, cyano, aryl and heteroaryl containing ring 2 or 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom (aryl and heteroaryl can have one or two groups selected from the group of substituents γ).

The group of substituents γ includes lower alkyl, lower alkoxy, halogen atom, hydroxyl group, lower alkylsulfonyl, lower alkylsulfonyl, alkanoyl, cyano or mono - or di-(lower) allylcarbamate. Of them, preferred are lower alkylsulfonyl, cyano and halogen atom.

Ring And denotes a nitrogen-containing heteroaryl formula (III):

(in which the symbols have the same meanings as defined above). The ring A can be in the ring one or two heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom in addition to at least one nitrogen atom.

A group of the formula (III) specifically includes, for example, thiazolyl, imidazolyl, isothiazolin, thiadiazolyl, triazolyl, oxa is alil, isoxazolyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl and pyrimidinyl. Of them, preferred are pyridyl, thiazolyl, pyrazolyl, pyrazinyl and thiadiazolyl.

n denotes an integer from 0 to 3, preferably from 0 to 2.

The lower alkyl for R4means, for example, preferably methyl, ethyl, propyl.

Lower alkoxy for R4means, for example, preferably methoxy, ethoxy, propoxy, isopropoxy.

The halogen atom for R4means, for example, preferably fluorine atom, chlorine atom, bromine atom.

Hydroxyalkyl for R4means, for example, preferably hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxy-1-methylethyl. The hydrogen atom of hydroxyl group in the hydroxyalkyl group may be substituted by lower alkyl. Substituted lower alkyl hydroxyalkyl includes, for example, methoxymethyl, ethoxymethyl.

Aminoalkyl for R4includes, for example, methylamino, ethylamino, isopropylamino.

The amino aminoalkyl may be substituted by lower alkyl.

Aminoalkanoic for R4includes, for example, acetylamino, ethylcarbodiimide, propylnitrosamine, isopropylcarbodiimide.

Lowest alkoxycarbonyl for R4includes, for example, methoxycarbonyl, etoxycarbonyl, isopropylcarbonate.

From the above group of formula (III-1):

(in which the symbols have the same meanings as defined above) specifically includes, for example, thiazole-2-yl, 5-chlorothiazole-2-yl, 4-methylthiazole-2-yl, 5-methylthiazole-2-yl, 4-hydroxymethylimidazole-2-yl, 4-methoxycarbonylmethyl-2-yl, 4-methoxymethanol-2-yl, 4-cenotesa-2-yl, 4-cortisol-2-yl, imidazol-2-yl, 4-Mei-2-yl, 4-methoxycarbonylamino-2-yl, 4-acetylimidazole-2-yl, 5-hydroxymethylimidazole-2-yl, isothiazol-3-yl, 4-hydroxymethylimidazole-3-yl, 5-acetyl-[1,3,4]thiadiazole-2-yl, [1,3,4]thiadiazole-2-yl, 5-methyl-[1,3,4]thiadiazole-2-yl, 5-fluoro-[1,3,4]thiadiazole-2-yl, [1,2,4]thiadiazole-5-yl, 3-methyl-[1,2,4]thiadiazole-5-yl, [1,2,4]triazole-3-yl, 5-hydroxymethyl-[1,2,4]triazole-3-yl, 5-acetyl-[1,2,4]triazole-3-yl, oxazol-2-yl, isoxazol-3-yl, pyrazin-2-yl, 5-methylpyridin-2-yl, pyridin-2-yl, 4-methylpyridin-2-yl, pyridazin-3-yl, 6-methylpyridazin-3-yl, 1H-pyrazole-3-yl, 1-methyl-1H-pyrazole-3-yl, pyrimidine-2-yl, pyrimidine-4-yl.

m denotes an integer from 1 to 6, preferably from 1 to 4, more preferably 1 or 2, more preferably 1.

p denotes an integer from 0 to 2, preferably 0 or 1.

q denotes 0 or 1, preferably q=1.

Of the compounds of formula (I) according to the invention preferred are compounds and their pharmaceutically acceptable salts of formula (I-11):

or of the formula (I-1):

(which chars the crystals have the same values, as defined above); and from compounds of the formula (I-1) is more preferred compounds of formula (I-2):

(in which the symbols have the same meanings as defined above), and the compounds of formula (I-3):

In the formula (I-1), the following formula (I-A):

is preferably a group of the following formula:

(in which R11denotes a hydrogen atom or lower alkyl; and the other symbols have the same meanings as defined above).

The compounds of formula (I) include, for example, the following compounds and their pharmaceutically acceptable salts:

1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-5-thioxo-2-pyrrolidinone,

4-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}morpholine-3,5-dione,

3-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-thiazolane-2,4-dione,

3-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-thiazolin-2-it,

1-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione,

1-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-3-methylimidazolidine-2,5-dione,

2-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}isothiazolin-1,1-is ioxid,

3-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyrazinyl)-1H-benzimidazole-6-yl]methyl}-2-oxazolidinone,

1-{[5-{[6-(ethylsulfonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione,

1-[(5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl)methyl]-2-pyrrolidinone,

N-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)-N-methylacetamide,

3-{[5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-oxazolidin-2,4-dione,

5-[4-(ethylsulfonyl)phenoxy]-6-((2-methyl-2H-tetrazol-5-yl)methyl)-2-(2-pyridinyl)-1H-benzimidazole,

5-[4-(ethylsulfonyl)phenoxy]-6-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-2-(2-pyridinyl)-1H-benzimidazole,

1-[(6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]pyrrolidin-2-he

or

4-(2,6-diferensial)-6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1H-benzimidazole.

Describes how to get to compounds according to the invention.

Of the compounds of formula (I) according to the invention the compounds of formula (I-11):

or of the formula (I-21):

(in which Ar1has the same meaning as defined above for Ar; and other symbols have the same meanings as defined above) can be obtained, for example, according to the following method:

(R stands for lower alkyl; Rprodenotes a protective group, aromatic group; L1and L2each represents a leaving group; Met represents a metal; and other symbols have the same meanings as defined above).

Stage 1

This stage is a way of interaction of the compound (1) with compound (2) in the presence of an acid catalyst to obtain compound (3).

L1can be any group that can be used to produce compound (8) by reaction of compound (7) with Ar-ZH in stage 4, including, for example, fluorine atom, chlorine atom and bromine atom. Of them, preferred is a fluorine atom.

The acid catalyst is used at this stage include, for example, sulfuric acid, p-toluensulfonate acid, methanesulfonate acid, hydrochloric acid, thionyl chloride.

The amount of acid catalyst may be generally from 0.01 to 10 equivalents to one equivalent of the compound (1), preferably from 0.1 to 1 equivalent.

The compound (1) includes, for example, 2-fluoro-4-nitrobenzoic acid, 2-fluoro-5-nitrobenzoic acid, 5-fluoro-2-nitrobenzoic acid, 3-fluoro-5-nitrobenzoic acid.

The lower alkyl for R denotes the same group, as defined above lower alkyl.

Compound (2) can also serve as rest is rites reaction, including, for example, methanol, ethanol.

The amount used of the compound (2) can usually be the number for dissolving one equivalent of the compound (1).

The reaction temperature may generally be in the range of from room temperature to the boiling point of the reaction solvent, preferably from 60°C to the boiling point of the solvent of the reaction. The reaction time may usually be from 1 to 120 hours, preferably from 24 to 72 hours.

The reaction solvent for use in this stage includes, for example, methanol, ethanol, toluene, tetrahydrofuran, dimethylformamide.

Thus obtained compound (3) may be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 2

This stage is a way to restore the nitro group of the compound (3)obtained above in stage 1, obtaining thus the compounds (4).

For recovery at this stage can be used a method known to the expert.

Recovery at this stage specifically includes, for example, catalytic reduction using bodoro is a, formic acid, ammonium formate or hydrazine hydrate, and a catalyst based on palladium, platinum or Nickel; recovery using hydrochloric acid or ammonium chloride, and iron; and recovery using methanol and chloride of tin.

The amount of reducing agent that is used for recovery varies depending on the type of compound and solvent used, but may typically be from 1 to 50 equivalents, preferably from 2 to 20 equivalents per one equivalent of the compound (3).

The reaction temperature may usually range from -10 to 100°C, preferably from 0 to 5°C.

The reaction time may usually be from 1 to 20 hours, preferably from 1 to 5 hours.

Solvent used in the reaction is not specifically defined, if it does not hinder the reaction. As such, for example, there may be used methanol, N,N-dimethylformamide, ethyl acetate, tetrahydrofuran and mixtures thereof.

Thus obtained compound (4) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 3

This stage is the Wallpaper the way of interaction of the compound (4), obtained in stage 2, with the compound (5) obtaining thus the compounds (6).

Reaction of amide bond formation at this stage can be carried out using a carboxylic acid compound (5) or its reactive derivative.

The connection (5) includes, for example, pyridine-2-carboxylic acid, pyrazin-2-carboxylic acid, pyrimidine-4-carboxylic acid, pyrimidine-2-carboxylic acid, thiazole-2-carboxylic acid isoxazol-3-carboxylic acid, 5-methyl-isoxazol-3-carboxylic acid, 1-methyl-1H-imidazole-4-carboxylic acid, imidazole-2-carboxylic acid, 1-methyl-1H-imidazole-2-carboxylic acid, imidazole-1-carboxylic acid, [1,2,4]triazole-1-carboxylic acid [1,2,4]triazole-3-carboxylic acid [1,2,3]triazole-4-carboxylic acid, 3-methyl-[1,2,4]thiadiazole-5-carboxylic acid, [1,2,5]thiadiazole-3-carboxylic acid [1,2,3]oxadiazol-3-carboxylic acid, pyrazole-3-carboxylic acid.

The amount used of the compound (5) or its reactive derivative may typically be from 0.1 to 100 equivalents, preferably from 0.1 to 20 equivalents, more preferably from 0.1 to 3 equivalents to one equivalent of the compound (4).

Reactive derivative of compound (5) includes, for example, mixed acid anhydrides, active esters, active amides. They can the be obtained, for example, according to the method described in WO 98/05641.

In this reaction when using carboxylic acid compound (5), then, for example, the reaction is preferably carried out in the presence of a condensing agent, such as carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, diphenylphosphoryl, dipyridyl disculfidlifederfpan, more preferably carbonyldiimidazole.

While not strictly defined, the amount of the condensing agent may be from 0.1 to 100 equivalents, preferably from 1 to 10 equivalents relative to compound (5).

The reaction can be conducted usually in an inert solvent. The inert solvent includes, for example, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, benzene, toluene, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, pyridine and mixtures thereof.

The reaction temperature may usually range from 0°C to the boiling point of the reaction solvent, preferably from room temperature to the boiling point of the solvent of the reaction.

The reaction time may usually be from 0.1 hours to 72 hours, preferably from 0.5 hours to 24 hours.

For soft promotion reaction can be carried out in the presence of a base and promoter of condensation.

The base includes 4-dimethy the aminopyridine, the triethylamine.

The amount of base may typically be from 0.1 to 100 equivalents, preferably from 0.1 to 1 equivalent per one mole of the carboxylic acid compound (5) or its reactive derivative.

The condensation promoter includes, hydrate, N-hydroxybenzotriazole, N-hydroxysuccinimide.

The amount of the condensation promoter may typically be from 1 to 100 equivalents, preferably 1 to 5 equivalents to one mole of the carboxylic acid compound (5) or its reactive derivative.

In the above reaction, when the reagent is an amino group or aminogroup, not participating in the reaction, it is desirable that these amino group or aminogroups were respectively protected by a protective group for amino group or aminogroup, and the protective group is removed after the reaction.

Thus obtained compound (6) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 3-1

This stage is a way of interaction of the compound (6)obtained at the specified stage 3, with fuming nitric acid with receipt is m thus the compound (6-1).

The amount of fuming nitric acid, used at this stage may typically be from 1 to 100 equivalents, preferably from 2 to 20 equivalents per one equivalent of the compound (6).

The reaction temperature may usually range from 0 to 100°C, preferably from 10 to 50°C.

The reaction time may usually be from 0.1 to 48 hours, preferably from 0.5 to 12 hours.

The compound (6-1) can also be obtained by the interaction of the compound (6) with potassium nitrate in the presence of acid.

The amount of potassium nitrate may typically be from 1 to 100 equivalents, preferably 1 to 5 equivalents to one equivalent of the compound (6).

Used acid includes, for example, triperoxonane acid, hydrochloric acid, sulfuric acid, nitric acid.

The amount of acid used may typically range from about 1 equivalent to the solvent amount, preferably from 1 to 100 equivalents to one equivalent of the compound (6).

The reaction temperature may usually range from 0°C to the boiling point of the solvent, preferably from room temperature to 100°C.

The reaction time may usually be from 0.1 to 72 hours, preferably from 0.5 to 12 hours.

The reaction solvent may be any one not interfering with the reaction, including, for example, chloroform, dichloromethane.

Thus obtained compound (7) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 4

This stage is a way of interacting compounds (6-1)obtained in the above stage 3-1, with compound (7) in the presence of a base with obtaining thus the compounds (8).

The amount used of the compound (7) may typically be from 0.1 to 20 equivalents, preferably from 0.5 to 5 equivalents per 1 equivalent of compound (6-1).

The connection (7) includes, for example, 4-methanesulfonyl, 4-acanaloniidae, 3-chloro-4-methanesulfonyl, 6-methanesulfonamido-3-ol, 6-acanaloniidae-3-ol, 4-cyanophenyl, 6-(5-methyl-[1,2,4]thiadiazole-3-yl)pyridine-3-ol, 6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinol, 4-(5-methyl-1,2,4-oxadiazol-3-yl)phenol. These compounds may be commercially available or can be obtained by a method known to the specialist, or according to a similar method, or according to combined with the method proceeding from commercially available compounds.

The number of used grounds can usually costal shall be from 0.1 to 20 equivalents, preferably from 0.5 to 5 equivalents per 1 equivalent of compound (6-1).

Used the base may be any suitable to obtain compound (8) by reaction of the compound (6-1) with compound (7) at this stage, including, for example, sodium hydride, cesium carbonate, sodium carbonate, potassium carbonate, potassium phosphate, potassium acetate, tert-butyrate, potassium, triethylamine. Of them, preferred are potassium carbonate, cesium carbonate. When the compound (7) is a primary or secondary amine, the reaction then at this stage can be carried out in the absence of base.

The reaction temperature may usually range from 0°C to the boiling point of the reaction solvent, preferably from room temperature to the boiling point of the solvent of the reaction.

The reaction time may usually be from 0.1 to 72 hours, preferably from 0.5 to 5 hours.

While not specifically defined, the reaction solvent may be any inert solvent which does not impede the reaction, and specifically includes, for example, pyridine, toluene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone.

Thus obtained compound (8) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 5

This stage is a way to restore the nitro group of compound (8)obtained above in stage 4, and at the same time dehydrogenation and cyclization of the compound in the presence of an acid catalyst with obtaining thus the compounds (9).

Reaction conditions for this stage can be the same as in stage 2, or may be similar, or may be a combination with them the usual way.

Thus obtained compound (9) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 6

This stage is a way of interaction of the compound (9)obtained in the above stage 8, with the compound (10) in the presence of a base with obtaining thus the compounds (11).

The reaction at this stage is a way of introducing a protective group into aromatic amino group, and it can be carried out according to the method described in references (for example the EP, Protective Groups in Organic Synthesis, T.W.Green, 2nd Ed., John Wiley & Sons, 1991), or according to such method, or according to the method, combined with him.

L2in the compound (10) indicates, for example, a halogen atom, preferably a chlorine atom or a bromine atom.

The connection (10) includes a 2-(trimethylsilyl)ethoxymethylene (SEMCl), methoxymethane (MOMCl).

The amount used of the compound (10) may typically be from 1 to 10 equivalents, preferably 1 to 3 equivalents per 1 equivalent of compound (9).

Used the base is, for example, sodium hydride.

The amount of base may usually be from 1 to 10 equivalents, preferably 1 to 3 equivalents.

The reaction temperature may usually range from -20 to 50°C, preferably from 0°C to room temperature.

The reaction time may usually be from 0.1 to 12 hours, preferably from 0.1 to 3 hours.

The reaction solvent may be any one not interfering with the reaction, including, for example, N,N-dimethylformamide, tetrahydrofuran, methylene chloride.

Thus obtained compound (11) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, extraction is rastvoritele, repeated precipitation, chromatography, or extraction and purification.

Stage 7

This stage is a way to recover the ester group of compound (11)obtained above in stage 6, obtaining thus the compounds (12).

The reducing agent that is used at this stage include alumoweld lithium (LiAlH4), lithium borohydride, sodium borohydride. After hydrolysis of the ester form of the compound (11) in the carboxylic acid, it can be processed into compound (12) according to the method described in references (for example, SYNLETT, 1995, Vol.8, pp.839-840), or according to such method, or according to the method, combined with him.

The amount of reducing agent may typically be from 1 to 20 equivalents, preferably 1 to 3 equivalents to 1 equivalent of the compound (11).

The reaction temperature may usually range from 0 to 80°C, preferably from 0.1°C to room temperature.

The reaction time may usually be from 0.1 to 24 hours, preferably from 0.1 to 3 hours.

While not specifically defined, the reaction solvent may be any one not interfering with the reaction, and includes, for example, methanol, N,N-dimethylformamide, ethyl acetate, tetrahydrofuran, and mixtures thereof.

Thus obtained compound (12) can be subjected to the next stage, after you the population and cleaning any known isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 8

This stage is a way of interaction of the compound (12)obtained in the previous stage 7, with the compound (13) obtaining thus the connection 13.

The reaction at this stage may represent a stage (8-1) Mitsunobu reaction or phase (8-2) the formation of the germ, which is carried out in the presence of a base.

Stage 8-1

The reaction at this stage is a so-called Mitsunobu reaction, which may be carried out in the presence of phosphine compounds and azo compounds, according to the method described in references (for example, The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products, Mitsunobu O.; Synthesis, Vol.1, 1981, pp.1-28), or according to such method, or according to the usual method, combined with this method.

The connection (13) includes, for example, succinimide, morpholine-3,5-dione, phthalic acid imide, 1-methylhydantoin, 1-methyluracil.

The amount used of the compound (13) may usually be from 0.5 to 10 equivalents, preferably 1 to 3 equivalents to 1 equivalent of the compound (12).

Used phosphine compound usually represents, e.g. the measures triphenylphosphine, triethylphosphine.

The amount of phosphine compounds may usually be from 0.5 to 10 equivalents, preferably 1 to 3 equivalents to 1 equivalent of the compound (12).

Used uzasadnienie includes, for example, diethylazodicarboxylate, diisopropylsalicylic.

The amount of azo compounds may usually be from 0.5 to 10 equivalents, preferably 1 to 3 equivalents to 1 equivalent of the compound (12).

The reaction time at this stage can usually be from 1 to 48 hours, preferably from 4 to 12 hours.

The reaction temperature at this stage may typically be from 0°C to the boiling point of the reaction solvent, preferably from 15 to 30°C.

While not specifically defined, the reaction solvent used at this stage may be any which does not impede the reaction, and includes, for example, tetrahydrofuran, toluene.

Thus obtained compound (14) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 8-2

This stage represents the manual interaction of the compound (12) compound (13) in the presence of a base with obtaining thus the compounds (14).

Used the base includes, for example, sodium hydride, utility, diisopropylamide lithium.

The amount of base may usually be from 0.5 to 10 equivalents, preferably 1 to 3 equivalents to 1 equivalent of the compound (12).

The connection (13) concretely includes, for example, compounds listed in the specified stage 8-1, and pyrrolidone, oxazolidone, 3-methyluracil, 1-methylimidazolidine.

The reaction temperature may usually range from -78 to 50°C, preferably from 0°C to room temperature.

The reaction time may usually be from 0.1 to 24 hours, preferably from 0.1 to 6 hours.

The reaction solvent may be any one not interfering with the reaction, including, for example, N,N-dimethylformamide, tetrahydrofuran, methylene chloride.

Thus obtained compound (14) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 8-3

This stage is a way of oxidation of the hydroxyl group of compound (12)obtained in the above stage 7, obtaining thus connected to the I (15).

The reaction at this stage can be carried out according to the method described in references (for example, Journal of the American Chemical Society, 1967, Vol.89, pp.5505-5507), or according to such method, or according to the usual method, combined with this method.

Thus obtained compound (15) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 9

This stage is a way to remove aminosidine group, Rprofrom the compound (14)obtained in the above stage 8-1 or 8-2, obtaining thus the compound (I-1) according to the invention.

The removal of the protective group can be achieved in the same manner as in the method described in references (for example, Protective Groups in Organic Synthesis, by T.W.Green, 2nd Ed., John Wiley & Sons, 1991), or in accordance with it, or combining it with an ordinary method. For example, when the protective group is a SEM, then the connection (14) can be introduced into reaction with triperoxonane acid to remove the group SEM.

Thus obtained compound (I-1) can be isolated and purified by any known means of separation and purification such as the p concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography.

Stage 10

This stage is a way of interaction of the compound (15)obtained in the above stage 8-3, with compound (16) obtaining thus the connection (17).

Ar1in the connection (16) and the compound (17) has the same meaning as indicated above for the Ar.

The connection (16) includes, for example, 4-performancebased, 2-performancebased, 3-Li-2-herperidin.

The amount used of the compound (16) may typically be from 1 to 5 equivalents, preferably 1 to 10 equivalents per 1 equivalent of compound (15).

The reaction temperature may usually range from -78 to 50°C, preferably from -78°C to room temperature.

The reaction time may usually be from 0.1 to 24 hours, preferably from 0.1 to 12 hours.

The reaction solvent may be any one not interfering with the reaction, and includes, for example, tetrahydrofuran, diethyl ether.

Thus obtained compound (17) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re the deposition, chromatography, or to isolation and purification.

Stage 11

This stage is a method of removing the protective group from the compound (17)obtained in the above stage 10, obtaining thus the compound (I-2) according to the invention.

The reaction at this stage can be carried out in the same manner as in the above stage 9, or in accordance with it, or its combination with a customary method.

Thus obtained compound (1-2) according to the invention can be isolated and purified by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography.

The compound (12) can also be obtained according to the following method:

(where R7denotes lower alkyl; M represents a metal atom; and other symbols have the same meanings as defined above).

Stage 12

This stage is a way of interaction of the compound (18) with the above-mentioned compound (5) obtaining thus the compounds (19).

The reaction at this stage can be carried out in the same manner as in the above stage 3, or in accordance with it, or its combination with a customary method.

The connection (18) including the AET, for example, 4-bromo-3-ftoranila, 3-bromo-5-ftoranila.

Thus obtained compound (19) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 13

This stage is a way of interaction of the compound (19)obtained in the above stage 12, with potassium nitrate in the presence of acid, obtaining thus the compounds (20).

The amount of potassium nitrate may typically be from 1 to 100 equivalents, preferably 1 to 5 equivalents, per 1 equivalent of compound (19).

Used acid includes, for example, triperoxonane acid, hydrochloric acid, sulfuric acid, nitric acid.

The amount of acid used may typically range from about 1 equivalent to the solvent amount, preferably from 1 to 100 equivalents per 1 equivalent of compound (19).

The reaction temperature may usually range from 0°C to the boiling point of the reaction solvent, preferably from room temperature to 100°C.

The reaction time may usually be from 0.1 to 72 hours, preferably from 0.5 to 12 hours.

Dissolve the al reaction can be any, not impede the reaction, including, for example, chloroform, dichloromethane.

Thus obtained compound (20) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 14

This stage is a way of interaction of the compound (20)obtained in the above stage 13, with the compound (7) obtaining thus the connection (21).

The reaction at this stage can be carried out in the same manner as in the above stage 4, or in accordance with it, or its combination with a customary method.

Thus obtained compound (21) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 15

This stage is a way to restore the nitro group of the compound (21)obtained above in stage 14, obtaining thus the connection (22).

The reaction at this stage which may be carried out in the same manner, as mentioned above stage 2 or 5, or in accordance with it, or its combination with a customary method.

Thus obtained compound (22) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 16

This stage is a way of interaction of the compound (22)obtained in the above stage 15, with the compound (10) obtaining thus the connection (23).

The reaction at this stage can be carried out in the same manner as in the above stage 6, or in accordance with it, or its combination with a customary method.

Thus obtained compound (23) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 17

This stage is a way of interaction of the compound (23)obtained in the above stage 16, with compound (24) in the presence of metal kata is Isadora obtaining thus the connection (25).

The connection (24) includes, for example, tributyl(vinyl)tin or vinyltrifluoroborate potassium, described in reference (Organic Letters, 2002, Vol.4, No.1, pp.107-109).

The amount used of the compound (24) can typically be from 1 to 10 equivalents, preferably 1 to 3 equivalents to 1 equivalent of the compound (23).

The metal catalyst used includes, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium.

The amount of metal catalyst may usually be from 0.01 to 10 equivalents, preferably from 0.05 to 5 equivalents.

The reaction solvent used at this stage may be any which does not impede the reaction, and is not specifically defined. For example, it includes a simple dimethyl ether of ethylene glycol, water, toluene, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, benzene, acetone, isopropanol.

The reaction temperature at this stage may typically be from 0°C to the boiling point of the reaction solvent, preferably from room temperature to 150°C.

The reaction time at this stage may typically be from 0.1 hours to 72 hours, preferably from 0.5 hours to 12 hours.

Thus obtained compound (25) can be subjected to following the stage, after extraction and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 18

This stage is a way for the oxidation of compound (25)obtained in the above stage 17, obtaining thus delovogo compounds (26).

The reaction at this stage involves reacting the compound (25) with osmium oxide.

The reaction system may contain 4-methylmorpholin-N-oxide.

The amount of osmium oxide may typically be from 0.001 to 3 equivalents, preferably from 0.01 to 0.5 equivalents per 1 equivalent of compound (25).

The number 4 methylmorpholin-N-oxide may typically be from 1 to 50 equivalents, preferably 1 to 5 equivalents, per 1 equivalent of compound (25).

The reaction temperature may usually range from 0 to 70°C, preferably from 0°C to room temperature.

The reaction time may usually be from 0.5 to 72 hours, preferably from 6 to 48 hours.

The reaction solvent may be any one not interfering with the reaction, including, for example, tetrahydrofuran, water, acetone, simple, dimethyl ether of ethylene glycol, N,N-dimethylformamide, 1,4-dioxane, and propanol.

Thus obtained compound (26) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 19

This stage is a way for the oxidation of compound (26)obtained in the above stage 18, obtaining thus the connection (27).

The reaction at this stage involves reacting the compound (26) with periodate sodium.

The number of periodate sodium may generally be from 1 to 100 equivalents, preferably from 1 to 10 equivalents per 1 equivalent of compound (26).

The reaction temperature may usually range from 0 to 80°C, preferably from room temperature to 50°C.

The reaction time may usually be from 0.5 to 72 hours, preferably from 12 to 48 hours.

The reaction solvent may be any one not interfering with the reaction, including, for example, water, tetrahydrofuran, acetone, simple, dimethyl ether of ethylene glycol, N,N-dimethylformamide, 1,4-dioxane, isopropanol.

Thus obtained compound (27) can be subjected to the next stage, after isolation and purification by any known method from the texts and cleaning, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 20

This stage is a way to recover the compound (27)obtained in the above stage 19, obtaining thus the compounds (12).

The reaction at this stage involves reacting the compound (27) with a reducing agent.

Used the reducing agent includes, for example, sodium borohydride, triacetoxyborohydride sodium.

The amount of reducing agent may typically be from 1 to 50 equivalents, preferably from 1 to 10 equivalents per 1 equivalent of compound (27).

The reaction temperature may usually range from 0 to 100°C, preferably from 0 to 50°C.

The reaction time may usually be from 0.1 to 72 hours, preferably from 0.5 to 24 hours.

The reaction solvent may be any one not interfering with the reaction, including, for example, methanol, tetrahydrofuran, 1,4-dioxane, isopropanol.

Thus obtained compound (12) can be used on the specified stage 8, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, popcorn the m deposition, chromatography, or to isolation and purification.

The compound (12-1), which is included in the scope of the definition of compound (12)can also be obtained according to the following method:

(where L3denotes a leaving group; Rprodenotes a protective group of an aromatic amino group; and other symbols have the same meanings as defined above).

Stage 22

This stage is a way of interaction of the compound (29) with compound (2) in the presence of an acid catalyst with obtaining thus the connection (30).

Used by the connection (29) can be, for example, 5-fluoro-2-nitrobenzoic acid.

The reaction at this stage can be carried out in the same manner as in the above stage 1, or in accordance with it, or its combination with a customary method.

Thus obtained compound (30) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 23

This stage is a way of interaction of the compound (30)obtained in the above stage 22, with the compound (7) with the floor is the group of so coupling (31).

The reaction at this stage can be carried out in the same manner as in the above stage 4, or in accordance with it, or its combination with a customary method.

Thus obtained compound (31) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 24

This stage is a way to restore the nitro group of the compound (31)obtained in the above stage 23, obtaining thus the connection (32).

The reaction at this stage can be carried out in the same manner as in the above stage 2, or in accordance with it, or its combination with a customary method.

Thus obtained compound (32) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 25

This stage is a way of interacting compounds (32)obtained in the above stud and 24, with compound (5) obtaining thus the compound (33).

The reaction at this stage can be carried out in the same manner as in the above stage 3, or in accordance with it, or its combination with a customary method.

Thus obtained compound (33) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 26

This stage is a way of interacting compounds (33)obtained in the above stage 25, with potassium nitrite in the presence of acid to obtain thus compounds (34).

The reaction at this stage can be carried out in the same manner as in the above stage 13, or in accordance with it, or its combination with a customary method.

Thus obtained compound (34) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 27

This stage before the hat is way nitrogroup reduction of compound (34), obtained in the above stage 26, obtaining thus the compound (35).

The reaction at this stage can be carried out in the same manner as in the above stage 5, or in accordance with it, or its combination with a customary method.

Thus obtained compound (35) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 28

This stage is a way of interacting compounds (35)obtained in the above stage 27, with compound (10) obtaining thus the compound (36).

The reaction at this stage can be carried out in the same manner as in the above stage 6, or in accordance with it, or its combination with a customary method.

Thus obtained compound (36) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 29

This stage before the hat is way to restore the connection (36), obtained in the above stage 28, obtaining thus the compound (37).

The reaction at this stage can be carried out in the same manner as in the above stage 7, or in accordance with it, or its combination with a customary method.

Thus obtained compound (37) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 30

This stage is a way to remove aromatic aminosidine group, Rprofrom the compound (37)obtained in the above stage 29, obtaining thus the compound (12-1).

The reaction at this stage can be carried out in the same manner as in the above stage 9, or in accordance with it, or its combination with a customary method.

Thus obtained compound (12-1) may be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Connection of the tell (I-1-1) or its pharmaceutically acceptable salt according to the invention is of the formula:

(in which the symbols have the same meanings as defined above) can be obtained, for example, according to the following method:

(where the symbols have the same meanings as defined above).

Stage 31

This stage is a way of interaction of the compound (38) with compound (7) in the presence of a base to obtain thus compounds (39).

Compound (38)used at this stage may be commercially available or can be obtained by a method known to the specialist, or according to such method, or according to the method, combined with this way of proceeding from commercially available compounds. Specifically, it is, for example, 2-chloro-5-nitrobenzaldehyde.

The amount of compound (7)used at this stage may typically be from 0.1 to 20 equivalents, preferably from 0.5 to 5 equivalents per 1 equivalent of compound (38).

The connection (7) includes the compounds referred to above stage 4.

The amount of base may typically be from 0.1 to 20 equivalents, preferably from 0.5 to 5 equivalents per 1 equivalent of compound (38).

Used the base can be any suitable for obtaining compounds (39) at this stage, including collaboration is their connection (38) with compound (7), and includes, for example, sodium hydride, cesium carbonate, sodium carbonate, potassium carbonate, potassium phosphate, potassium acetate, tert-butyrate, potassium, triethylamine. Of them, preferred are potassium carbonate, cesium carbonate.

The reaction temperature may usually range from 0°C to the boiling point of the reaction solvent, preferably from room temperature to the boiling point of the solvent of the reaction.

The reaction time may usually be from 0.1 to 72 hours, preferably from 0.5 to 5 hours.

The reaction solvent may be inert solvent and is not specifically defined provided that it does not hinder the reaction. Specifically, it includes, for example, pyridine, toluene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone.

Thus obtained compound (39) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 32

This stage is a way of interaction of the compound (39) with compound (40) to obtain thus compounds (41).

Used at this stage is EDINENIE (40) represents for example, the compound where R denotes methyl or ethyl.

The compound (40) can also be in the form of an acid additive salt such as hydrochloride. If you use an acid additive salt of compound (40), then to the reaction system may be added to the base, such as triethylamine.

The amount used of the compound (40) can usually be from 0.5 to 20 equivalents, preferably 1 to 5 equivalents, per 1 equivalent of compound (39).

The amount used can be almost equimolar amount relative to 1 equivalent of compound (40).

The reducing agent that is used at this stage include, for example, triacetoxyborohydride, cyanoborohydride sodium, triacetoxyborohydride sodium.

The amount of hydride reagent may typically be from 1 to 10 equivalents, preferably 1 to 3 equivalents to 1 equivalent of the compound (39).

Not interfering with the reaction, the reaction solvent is not specifically defined, and it includes, for example, methanol, ethanol, acetic acid, tetrahydrofuran, dichloromethane and mixtures thereof. Of them, preferred are, for example, methanol, ethanol, tetrahydrofuran and mixtures thereof.

The reaction time may usually be from 1 hour to 8 hours, preferably from 1 hour to 24 hours.

The reaction temperature may be the usual range from 0 to 100°C, preferably from 0 to 40°C.

Thus obtained compound (41) according to the invention can be isolated and purified by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography.

Stage 33

This stage is a way to restore the nitro group of the compound (41) to obtain the so coupling (42).

Recovery at this stage can be, for example, by catalytic regeneration with a catalyst, such as Raney Nickel, in an atmosphere of hydrogen.

The number of Raney Nickel, which is used at this stage may be from 0.001 to 5 equivalents, preferably from 0.01 to 1 equivalent per 1 equivalent of compound (41).

The reaction temperature may usually range from 0 to 80°C, preferably from 20 to 50°C.

The reaction time may usually be from 1 to 24 hours, preferably from 1 to 10 hours.

Thus obtained compound (42) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 34

This stage is a way of interacting carboxylic acid derivative (5) or its reactive derivative with the compound (42) obtaining thus the compound (3).

This reaction may be a conventional amidation, which is carried out according to the method described in references (for example, Bases and Experiments of Peptide Synthesis. Nobuo Izumiya, et al. Maruzen, 1983; Comprehensive Organic Synthesis, Fol.6, Pergamon Press, 1991), or according to such method, or according to the usual method, combined with this method. In particular, use of the condensing agent known to the specialist; or you can use the activation method of ester, the method of the mixed acid anhydride, acid chloride method, the acid or the way carbodiimide, well-known specialist. The amidation reagent includes, for example, thionyl chloride, oxalicacid, N,N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridine, N,N'-carbonyldiimidazole, diphenylphosphoryl, diphenylphosphoryl, N,N'-disuccinimidyl, N,N'-disuccinimidyl, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, ethylchloride, isobutylparaben, hexaflurophosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium. Of them, for example, preferred are thionyl chloride, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N-dicyclohexylcarbodiimide, sexafter the SFAT benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium. In the amidation base and a condensation promoter can be used along with the specified reagent amidation.

Used the base includes, for example, tertiary aliphatic amines, such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5,4 .0]undec-7-ene (DBU), 1,5-azabicyclo[4,3 .0]non-5-ene (DBN); aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine (dimethylpyridin), quinoline, and isoquinoline. Of them, for example, preferred are tertiary aliphatic amines, and more preferred is, for example, triethylamine, N,N-diisopropylethylamine.

Used the condensation promoter includes, for example, hydrate, N-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide, 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazol. Of them, for example, preferred is N-hydroxybenzotriazole.

The amount used of the compound (42) can vary, depending on the type of these compounds and the used solvent and other reaction conditions, and, for example, may typically be from 0.1 to 10 equivalents, preferably from 0.5 to 3 equivalents per 1 equivalent of the carboxylic acid derivative (5) or its reactive derivative.

The number of reaction is willow amidation may also be varied, depending on the connection type and the used solvent and other reaction conditions, and, for example, may typically be from 1 to 10 equivalents, preferably 1 to 3 equivalents to 1 equivalent of the carboxylic acid derivative (5) or its reactive derivative.

The amount of the condensation promoter may also vary, depending on the connection type and the used solvent and other reaction conditions, and, for example, can be from 1 to 10 equivalents, preferably 1 to 3 equivalents to 1 equivalent of the carboxylic acid derivative (5) or its reactive derivative.

The amount of base may vary, depending on the connection type and the used solvent and other reaction conditions, and, for example, may be from 0.1 to 10 equivalents, preferably 1 to 5 equivalents, per 1 equivalent of compound (42).

The reaction solvent used at this stage, represents, for example, an inert solvent which is not specifically defined provided that it does not hinder the reaction. Specifically, for example, it includes methylene chloride, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, ethyl acetate, methyl acetate, acetonitrile, benzene, xylene, toluene, 1,4-dioxane, tetrahydrofuran is, dimethoxyethane and mixtures thereof. To ensure that the preferred reaction temperature, for example, preferred are methylene chloride, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide.

The reaction temperature at this stage may normally be from -78°C to the boiling point of the solvent, preferably from 0 to 30°C.

The reaction time at this stage can usually be from 0.5 to 96 hours, preferably from 3 to 24 hours.

Base, the amidation reagent and the condensation promoter, which are used at this stage, can be one or more different types of compounds individually or in combination.

Thus obtained compound (43) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography, or extraction and purification.

Stage 35

This stage is a way of interaction of the compound (43) with fuming nitric acid with obtaining thus the connection (44).

The amount of fuming nitric acid, which is used at this stage may typically be from 1 to 100 equivalents, preferably from 2 to 20 equivalents, per 1 equivalent compounds the Oia (43).

The reaction temperature may usually range from 0 to 100°C, preferably from 10 to 50°C.

The reaction time may usually be from 0.1 to 48 hours, preferably from 0.5 to 12 hours.

Compound (44) can also be obtained by reacting compound (43) with potassium nitrate in the presence of acid.

The amount of potassium nitrate may typically be from 1 to 100 equivalents, preferably 1 to 5 equivalents, per 1 equivalent of compound (6).

Used acid includes, for example, triperoxonane acid, hydrochloric acid, sulfuric acid, nitric acid.

The amount of acid used may typically range from about 1 equivalent to the solvent amount, preferably from 1 to 100 equivalents per 1 equivalent of compound (6).

The reaction temperature may usually range from 0°C to the boiling point of the solvent, preferably from room temperature to 100°C.

The reaction time may usually be from 0.1 to 72 hours, preferably from 0.5 to 12 hours.

The reaction solvent may be any one not interfering with the reaction, including, for example, chloroform, dichloromethane.

Thus obtained compound (44) can be subjected to the next stage, after isolation and purification by any known means of separation and purification such as concentration, concentric is she under reduced pressure, crystallization, extraction with solvent, re-precipitation, chromatography, or extraction and purification.

Stage 45

This stage is a way to restore the nitro group of the compound (44), followed by cyclization with obtaining thus the compound (I-1-1) according to the invention.

The reducing agent that is used at this stage, represents, for example, tin chloride (SnCl2). The reducing agent may also be a hydrate.

The amount of reducing agent that is used at this stage may typically be from 1 to 20 equivalents, preferably 1 to 10 equivalents per 1 equivalent of compound (44).

The base, which is used at this stage may represent, for example, triethylamine.

The amount of base may range from 1 to 10 equivalents, preferably 1 to 5 equivalents, per 1 equivalent of compound (44).

The reaction temperature may usually range from 0 to 100°C, preferably from 20 to 80°C.

The reaction time may usually be from 0.5 to 20 hours, preferably from 1 to 5 hours.

While not specifically defined, the reaction solvent may be any one not interfering with the reaction, and includes, for example, methanol, chloroform, N,N-dimethylformamide, ethyl acetate, tetrahydrofuran and mixtures thereof.

Obtained the them, the compound (I-1-1) can be isolated and purified by any known means of separation and purification, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, re-precipitation, chromatography.

Arylacetamides benzimidazole derivatives according to the invention can be in the form of their pharmaceutically acceptable salts. Salts can be obtained by any conventional method, compounds of the above formulas (I-1) and (I-2), which are within the scope of the definition of the compounds (I) according to the invention.

Specifically, when the compounds of formula (I-1) or (I-2) have in the molecule a core group, which is derived, for example, an amino group or peredelnoj group, then the compounds may be treated with acid to convert them into the corresponding pharmaceutically acceptable salt. Acid additive salts include, for example, hydrogenogenic, such as hydrochloride, hydrohloride, hydrobromide, hydroiodide; salts of inorganic acids such as nitrates, perchlorates, sulfates, phosphates, carbonates; lower alkyl sulphonates, such as methanesulfonate, triftoratsetata, econsultancy; arylsulfonate, such as benzosulfimide, p-toluensulfonate; salts of organic acids, such as fumarate, succinate, citrates, tartratami, oxalates, maleate; other organic acid additive salts formed with amino acids, such as glutamate, aspartate. When the connection is about the invention have an acid group in the molecule, for example when they have a carboxyl group, then the compounds may be treated with base to convert them into the corresponding pharmaceutically acceptable salt. Additive salt includes, for example, salts of alkali metal, formed with sodium or potassium; salts of alkaline earth metal formed with calcium or magnesium; ammonium salts; additive salts of organic bases derived from guanidine, triethylamine, dicyclohexylamine etc. in Addition, the compounds according to the invention can also be in any other form of hydrate or solvate their free compounds or their salts.

When getting medicines for the prevention and treatment of type II diabetes or disorders or symptoms associated therewith, the compounds of formula (I) according to the invention can be combined with the media.

The dose of the compounds of formula (I) according to the invention for the prevention or treatment of diseases naturally varies depending on the properties subject to the treatment of the symptom, the specific compound and route of administration.

In addition, the dose varies depending on age, body weight and sensitivity of patients. In General, the daily dose for single or repeated administration may be from about 0.001 mg/kg body weight to about 100 mg/kg of body weight, before occhialino from about 0.01 mg/kg body weight to about 50 mg/kg of body weight, even more preferably from about 0.1 mg/kg body weight to about 10 mg/kg of body weight. Depending on the circumstances may require the introduction of a higher dose.

An example of a suitable dose for oral administration is described next. Daily dose for single or two-to fourfold introduction may be at least from about 0.01 mg to at most to 2.0, Preferably daily frequency is several times a day, and the daily dose is from about 1.0 mg to about 200, More preferably the daily dose is from about 10 mg to 100 mg for administration once a day.

For intravenous or oral administration of a typical dose of compound (I) can be from about 0.001 mg/day/kg body weight to about 100 mg/day/kg body weight (preferably from 0.01 mg/day/kg body weight to about 10 mg/day/kg body weight), more preferably from about 0.1 mg/day/kg body weight to 10 mg/day/kg body weight.

As mentioned above, the pharmaceutical composition according to the invention includes a compound of formula (I) and a pharmaceutically acceptable carrier. The term "composition" includes not only the product obtained directly or indirectly combination, hybridization or aggregation of 2 or more ingredients, the product, resulting from dissociation of one or more ingredients, or compound resulting from the reaction or interaction of different types of ingredients, but also active and inactive ingredient forming media (pharmaceutically acceptable carrier).

Being combined with a pharmaceutically acceptable carrier, the composition according to the invention preferably contains a compound of the formula (I) in an amount effective for the treatment and prevention of type II diabetes and to delay the onset of the disease.

To Institute an effective dose of the compounds according to the invention is a mammal, especially humans, can be used by any suitable route of administration. For example, this path may be by oral administration, rectal introduction, local introduction, intravenous, ocular introduction, introduction through the lung or nazalnam introduction. Examples of forms for administration include tablets, lozenges, powders, suspensions, solutions, capsules, creams, aerosols. Preferred are oral tablets.

To obtain oral compositions is any suitable conventional pharmaceutical environment. Examples are water, glycol, oil, alcohol, flavoring agents, preservatives, dyes. To obtain liquid compositions for oral administration, for example, can be specified suspense and, elixirs and solutions. Their carriers are, for example, starch, sugar, microcrystalline cellulose, diluent, the promoter granulation, lubricant, binder, disintegrator. For solid compositions for oral administration can be specified, for example, powders, capsules and tablets. Above all, preferred such solid compositions for oral administration.

Because of the ease of their administration tablets and capsules are the most preferred forms for oral administration. If necessary, the tablets may be coated by standard aqueous or nonaqueous techniques covering.

In addition to the above conventional methods of introducing the compounds of formula (I) can be also introduced in the systems controlled release and/or controlled delivery systems, for example, as in U.S. patents 3845770, 3916899, 3536809, 3598123, 3630200 and 4008719.

The pharmaceutical composition according to the invention suitable for oral administration include capsules, pills and tablets, which contain a predetermined amount of the active ingredient in the form of powders or granules or in the form of water-soluble liquids, water-insoluble liquids, emulsions of the type oil-in-water or emulsions water in oil". These compositions can be obtained by any pharmaceutical method, and all methods include the up the process of combining the active ingredient with a carrier of one or more necessary ingredients.

In General, the active ingredient uniformly and completely mixed with the liquid medium, or well-separated solid carrier, or both and then, if desirable, the product is formed into a suitable shape, to obtain a composition. For example, the tablets obtained by compressing and molding, optionally along with one or more side components. Using a suitable mechanism, pressed tablets can be obtained by mixing the active ingredient optionally with a binder, lubricant, inert carrier, a surface-active agent or a dispersant, and extruding the resulting mixture in any desired way in powders or granules.

Molded tablets can be obtained by forming a mixture of powdered wet compound and an inert liquid diluent, using a suitable mechanism.

Preferably, each tablet contains from about 1 mg to 1 g of the active ingredient; and each wafer and the capsule contains from about 1 mg to 500 mg of active ingredient.

Examples of routes of administration of the compounds of formula (I) for pharmaceutical applications are as follows.

Table 1
Suspension for injection (intramuscular)mg/ml
The compound of formula (I)10
The methylcellulose5,0
Tween 800,5
Benzyl alcohol : 9,0
The benzalkonium chloride1,0
Water for injection to volume of 1.0 ml

Table 2
Tabletsmg tablet
The compound of formula (I)25
The methylcellulose415
Tween 8014,0
Benzyl alcohol : 43,5
Magnesium stearate2,5
Only500

Table 3
Capsulesmg/capsule
With the Association of the formula (I) 25
The lactose powder573,5
Magnesium stearate1,5
Only600

Table 4
AerosolOne container
The compound of formula (I)24 mg
Lecithin, NF fluid. conc.1.2 mg
Trichlorofluoromethane, NF4,025 g
DICHLORODIFLUOROMETHANE, NF12,15 g

The compounds of formula (I) can be used in combination with any other drugs for diabetes-related type II diseases or symptoms, but also for the treatment/prevention/delay of type II diabetes. Additional medicines may be introduced by any route of administration and the dose normally used in this field, simultaneously with or separately from the compounds of formula (I).

If the compound of formula (I) is used along with one or the more other drugs, preferred pharmaceutical composition comprising a compound of formula (I) and complementary medicines. Accordingly, the pharmaceutical composition according to the invention may include not only the compound of formula (I), but also one or more of these active ingredients. Examples of active ingredients that can be combined with compounds of formula (I)below, but they are not restrictive. They may be introduced separately or may be executed simultaneously in one and the same pharmaceutical composition.

(a) other activators of glucokinase,

(b) bis-guandi (for example, buformin, Metformin, phenformin),

(c) PPAR agonists (for example, troglitazone, pioglitazone, rosiglitazone),

(d) insulin,

(e) somatostatin,

(f) inhibitors of α-glucosidase (e.g., voglibose, miglitol, acarbose),

(g) the promoters of insulin secretion (for example, acetohexamide, carbutamide, hlorpropamid, globalid, gliclazide, glimepiride, glipizide, gliadin, glisoxepide, gliburid, glyhexamide, pipename, fenbutatin, trashed, tolbutamide, tolciclate, nateglinide, Repaglinide), and

(h) inhibitors of DPP-IV (dipeptidyl peptidase IV).

The weight ratio of the compounds of formula (I) to the second active ingredient may be varied within a wide range and depends on the effective number of indiv the dual active ingredients.

Accordingly, for example, when the compound of formula (I) combined with a PPAR agonist, then the weight ratio of the compounds of formula (I) PPAR agonist may typically be from about 1000/1 to 1/1000, preferably from about 200/1 to 1/200. The combination of the compounds of formula (I) and the other active ingredient may be within a specified range. In any case, in combination, should be effective amount of the individual ingredients.

Glucokinase-activating potential of the compounds of formula (I) according to the invention and the method of testing described below.

Excellent glucokinase-activating effect of the compounds of formula (I) can be determined by the method described in references (for example, Diabetes, Vol.45, pp.1671-1677, 1996), or in accordance with this method.

Glucokinase activity can not be determined directly by measuring glucose-6-phosphate, but by measuring the level of thio-NADH, which is produced when a reporter enzyme, glucose-6-phosphatedehydrogenase produces phosphogluconolactonase of glucose-6-phosphate, and based on this level can be determined by the degree glucokinase activity of the tested compounds.

This test was used recombinant human GK liver, which expressives E. coli in the form of a fused protein FLAG and which was purified ANTIFLAG M2 AFFINITY GEL (Sigma).

And who uses a flat-bottomed plate with 96 holes, the test was carried out at 30°C. 69 ál buffer (25 mm Hepes buffer /pH to 7.2, 2 mm MgCl2, 1 mm ATP, 0.5 mm TNAD, 1 mm dithiothreitol) were placed in the tablet and added 1 μl of a solution of the compound in DMSO or only DMSO as a control. Then add 20 ál chilled on ice enzyme mixture (FLAG-GK, 20 Ed./ml G6PDH) and 10 μl of substrate, 25 mm glucose, and initiated the reaction (final glucose concentration = 2.5 mm).

After start of the reaction, the increase of absorption at 405 nm was measured for 12 minutes at intervals of 30 seconds and increase within the first 5 minutes was used for the evaluation of the tested compounds. FLAG-GK was added to increase absorption after 5 minutes in the presence of 1% DMSO could be from 0.04 to 0.06.

The optical density (OD) DMSO control was taken as 100%; and determined the level OD of test compounds in varying concentrations. On the basis of the level OD at each concentration Emax (%) EC50 (μm) was calculated and used as an indicator of GK-activating potential of the connection.

GK-activating potential of the compounds according to the invention was measured in accordance with the method described above, and the results are shown below in table 5.

Table 5
GK-activating potential of soedineniya invention
The connection numberEmax (%)EC50 (μm)
Example 110900,12
Example 319820,49
Example 658050,36

Accordingly, the compounds according to the invention have an excellent GK-activating potential, at which point Emax and EC50 values.

EXAMPLES

The invention is described more specifically in the following examples, which, however, the invention is in no case should not be limited.

Example obtain 1

10 parts of the compound of example product 1, 15 parts of heavy magnesium oxide and 75 parts of lactose were uniformly mixed, receiving powdered drug or preparation in the form of particles with a size of at most 350 μm. The drug was encapsulated to obtain capsules.

Example of getting 2

45 parts of the compound of example product 1, 15 parts of starch, 16 parts of lactose, 21 parts of crystalline cellulose, 3 parts of polyvinyl alcohol and 30 parts of distilled water were uniformly mixed, and then grinded, was granulated and dried, and then sieved, receiving the edge of the s, with sizes from 1410 to 177 μm in diameter.

Example of getting 3

Pellets were obtained in the same manner as in example getting 2. 3 parts of calcium stearate were added to 96 parts of pellets and molded under compression, obtaining tablets with a diameter of 10 mm

Example 4

10 parts of crystalline cellulose and 3 parts of calcium stearate were added to 90 parts of the granules obtained according to the method of example getting 2, and molded under compression, obtaining tablets with a diameter of 8 mm were coated with a slurry mixture of gelatin syrup and precipitated calcium carbonate, getting pills with sugar coating.

In the next part of the invention is described more specifically in relation to the examples of the preparation, examples of the product and reference examples, which, however, the invention is in no way intended to be limited.

In thin-layer chromatography in examples Silicagel 60F245(Merck) was used for the tablet and a UV detector was used for detection. For columns used silica gel Wakogel™ C-300 (Wako Pure Chemical) and a column for reverse phase used silica gel LC-SORB™ SP-B-ODS (Chemco) or YMC-GEL™ ODS-AQ 120-S50 (Yamamura Chemical Laboratory).

Acronyms the following examples is shown below.

i-Bu: isobutyl

n-Bu: n-butyl

t-Bu: tert-butyl

Me: methyl

Et: ethyl

Ph: phenyl

i-Pr: isopropyl

n-Pr: n-propyl

CDCl3: heavy is hloroform

CD3OD: heavy methanol

DMSO-d6: heavy dimethyl sulfoxide

Acronyms the following spectra nuclear magnetic resonance is shown below.

s: singlet

d: doublet

DD: double doublet

t: triplet

m: multiplet

ush.: extended

kV: Quartet

J: constant interaction

Hz: Hertz

Example 1

1-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione

Stage 1. Obtaining N-(4-bromo-3-forfinal)-2-pyridinecarboxamide:

of 2.9 ml of triethylamine and of 1.87 g of the hydrochloride of the acid chloride pikolinos acid was added to a solution of 1 g of 4-bromo-3-foronline in chloroform (30 ml) and stirred at room temperature for 4 hours. The reaction liquid was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 4/1)to give 1.44 g of the target compound in the form of crystal light yellow color.

Stage 2. Obtaining N-(4-bromo-5-fluoro-2-nitrophenyl)-2-pyridinecarboxamide:

1,71 g of potassium sulfite was added to 10 ml of N-(4-bromo-3-forfinal)-2-pyridinecarboxamide and was stirred overnight at 70°C. Rast ritel evaporated, the residue was diluted with chloroform and washed with saturated aqueous sodium bicarbonate and saturated saline solution. Wednesday was dried over anhydrous magnesium sulfate and the solvent evaporated, getting 1,17 g of target compound in the form of crystal yellow color.

Stage 3. Obtain N-{4-bromo-5-(4-(methylsulphonyl)phenoxy]-2-nitrophenyl}-2-pyridinecarboxamide:

100 ml of N-(4-bromo-5-fluoro-2-nitrophenyl)-2-pyridinecarboxamide, 55 mg of 4-(methylsulphonyl)phenol obtained in reference example 1, and 88 mg of potassium carbonate suspended in 2 ml of dimethylformamide and stirred at 70°C for 30 minutes. The reaction liquid was allowed to cool to room temperature, then added water and the resulting crystal was separated by filtration, getting 145 mg of the target compound in the form of crystal light yellow color.

Stage 4. Obtain 6-bromo-5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole:

145 ml of N-{4-bromo-5-(4-(methylsulphonyl)phenoxy]-2-nitrophenyl}-2-pyridinecarboxamide suspended in 1 ml of dimethylformamide, 1 ml of methanol and 0.5 ml of concentrated hydrochloric acid was added 327 mg of the dihydrate of tin chloride(II) and stirred at 70°C for 30 minutes. The reaction liquid was neutralized with an aqueous solution of sodium bicarbonate and diluted with chloroform. The insoluble substance was separated by filtration, the filtrate industry is Ali saturated saline solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting 121 mg of the target compound in the form of crystal light yellow color.

Stage 5. Obtain 6-bromo-5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole and 5-bromo-6-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole:

6.50 g of 6-bromo-5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole was dissolved in 65 ml of dimethylformamide and, while cooling on ice, was added 0.71 g of sodium hydride (with the addition of 30% liquid paraffin). The mixture was stirred for 15 minutes and then was added to 3.9 ml of 2-trimethylsilylamodimethicone and was additionally stirred for 30 minutes. Was added a saturated aqueous solution of ammonium chloride, diluted with ethyl acetate, then the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent is evaporated and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 6/4)to give 7,39 g of target compound in the form of crystal light yellow color.

Stage 6. Getting 5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-6-vinyl-1H-benzimidazole and 6-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-5-vinyl-1H-benzimidazole:

1 the crystal, received at stage 5, was dissolved in 10 ml of toluene and added 0,83 g tributyl(vinyl)tin and 0.1 g of tetrakis(triphenylphosphine)palladium was purified nitrogen and stirred at 110°C for 3 hours. Wednesday was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 3/1)to give 0,69 g of target compound in the form of an amorphous substance of white color.

Stage 7. Obtaining 1-(5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)-1,2-ethanediol and 1-(6-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)-1,2-ethanediol:

0,69 g vinyl compounds obtained in stage 6, was dissolved in 7 ml of tetrahydrofuran and 1 ml of water was added to 0.23 g of 4-methylmorpholin-N-oxide and 17 mg of oxide of osmium(VIII) and was stirred over night at room temperature. Was added an aqueous solution of sodium thiosulfate, diluted with ethyl acetate and the organic layer was washed with saturated saline solution. Wednesday was dried over anhydrous magnesium sulfate, the solvent evaporated and the residue was purified by chromatography on a column of silica gel (manifesting the solvent from chloroform to the mixture chloroform/methanol = 98/2)to give 0,57 g of target compound in the form of an amorphous substance of white color.

Stage 8. Getting 5-[4-(methylsulphonyl)phenoxy]-2-(2-PI is idini)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-carbaldehyde and 6-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-carbaldehyde :

1.7 g of diol obtained in stage 7, was dissolved in 16 ml of chloroform, was added 11 ml of water and 0.84 g of periodate sodium and stirred at room temperature for 3 hours. The reaction liquid was diluted with chloroform and washed with a saturated saline solution. Wednesday was dried over anhydrous magnesium sulfate, the solvent evaporated and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1-3/1-1/1)to give 1.2 g of the target compound in the form of an amorphous substance of white color.

Stage 9. Receive (5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol or (6-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanol:

100 mg of the aldehyde obtained in stage 8, was dissolved in 1 ml of methanol was added 15 mg of sodium borohydride and stirred at room temperature for 1 hour. The reaction liquid was diluted with ethyl acetate and washed with saturated saline solution. Wednesday was dried over anhydrous magnesium sulfate, the solvent evaporated and the residue was purified by chromatography on a column of silica gel (manifesting the solvent from chloroform to the mixture chloroform/methanol = 98/2)to give 94 mg of the target compound in the form of an amorphous substance of white color.

Stage 10. Poluchenie-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione :

50 mg of the alcohol compound obtained in stage 9, and 47.5 mg succinimide and 127 mg of triphenylphosphine was dissolved in 1 ml of tetrahydrofuran, while cooling on ice was added to 0.21 ml of diethylazodicarboxylate (40% solution in toluene) and stirred at room temperature for 2 hours. The reaction solvent is evaporated and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1-5/5-8/2), receiving 52,3 mg of yellow oil.

52,3 mg of the obtained oil was dissolved in 1 ml triperoxonane acid and stirred at room temperature for 2 hours. The solvent is evaporated, the residue was neutralized with triethylamine and then separating purified by thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 11.2 mg of the target compound in a solid white color.

1H-NMR (CDCl3) δ: 2,56 (2H, m)to 2.66 (2H, m), 3,06 (3H, c), 4,79 (2H, c), 7,02-7,20 (2H+1/2H, m), 7,40 (1H, m), 7,44 (1/2H, m), 7,65 (1/2H, m), 7,76 (1/2H, m), a 7.85-of 7.90 (3H, m), 8,35 (m, 1H), 8,64 (m, 1H), 10,5 (ush., 1H).

ESI-MASS (m/e): 477 [M+H].

Example 2

1-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

While cooling on ice, 22 μl of methanesulfonamide was added to the solution in tetrahydrofuran (0.75 ml) 75 mg alcohol compound obtained in example 1 (stage 9), and 40 μl of triethylamine and displaced ivali within 30 minutes. Added ice water, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. It was dried and the solvent evaporated under reduced pressure, receiving 62 mg of amorphous material, light yellow color.

While cooling on ice, 22 mg of sodium hydride (with the addition of 30% liquid paraffin) was added to a solution of 62 mg of the amorphous substance and 46 mg of 2-pyrrolidone in dimethylformamide (0.5 ml) and stirred at room temperature for 40 minutes. When cooled on ice was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1), getting to 22.1 mg of colorless oil.

to 22.1 mg of the obtained colorless oil was dissolved in 1 ml triperoxonane acid and stirred at room temperature for 1 hour. The solvent is evaporated, the residue was neutralized with triethylamine and purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1), getting to 9.3 mg of target compound in the form of amorphous material, light yellow color.

1H-NMR (CDCl3) δ: 1.85 to a 2.00 (2H, m), 2,30-of 2.38 (2H, m), 3,06 (3H, c), of 3.25 to 3.35 (2H, m),of 4.54 (2H, m),? 7.04 baby mortality-7,10 (2H, m), 7,19 (1/2N, c), 7,40 (1H, m), 7,49 (1/2N, c), EUR 7.57 (1/2N, c), to 7.77 (1/2N, c), a 7.85-a 7.92 (3H, m), 8,40 (1H, m), 8,65 (1H, m), 10,7 (1/2H, USS), 10,8 (1/2H, USS).

ESI-MS (m/e): 463 [M+H].

Example 3

3-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-oxazolidinone

Using 2-oxazolidone, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 3,06 (3H, c), 3,42-of 3.60 (2H, m), 4,22-to 4.28 (2H, m)to 4.52 (2H, m), to 7.09 (2H, m), 7,21 (1/2N, c), 7,41 (1H, m), 7,51 (1/2N, c), 7,65 (1/2N, c), 7,82-of 7.95 (3H+1/2H, m), 8,40 (1H, m), to 6.67 (1H, m)10,7 (ush., 1H).

ESI-MS (m/e): 465 [M+H].

Example 4

1-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}piperidine-2,6-dione

Using glutarimide, the target compound was obtained in the same manner as in example 1 (stage 10), or in accordance with this method, or its combination with a customary method.

1H-NMR (CD3OD) δ: 0,93 (1H, m)of 1.29 (1H, c), 1,85-of 1.92 (2H, m)to 2.66 (2H, m), 3,11 (3H, c), 5,02 (2H, c), 7,14 (m, 2H), 7,29 (s, 1H), 7,49 (m, 2H), 7,87-7,98 (3H, m), compared to 8.26 (1H, m), 8,71 (1H, m).

ESI-MASS (m/e): 491 (M+H).

Example 5

1-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2(1H)pyridinone

Using 2-hydroxypyridine, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1 H-NMR (CDCl3) δ: 3,05 (3H, c), a total of 5.21 (2H, c), between 6.08 (1H, m), 6,56 (1H, m), 7,07 (2H, m), 7,26 (1H, m), 7,37 (2H, m), 7,42 (1H, c), 7,74 (1H, c), 7,87 (3H, m), 8,35 (1H, m), to 8.62 (1H, m).

ESI-MASS (m/e): 473 (M+H).

Example 6

1-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}piperidine

Using δ-valerolactone, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 0,91 (2H, m)of 1.75 (2H, m), is 2.37 (2H, m), 3.04 from (3H, c), 3,24 (2H, m), of 4.66 (2H, c), 7,06 (2H, m), 7,37-7,40 (1H, m), 7,53 (1H, m), 7,68 (1H, m), 7,86 (3H, m), scored 8.38 (1H, m)8,64 (1H, m).

ESI-MASS (m/e): 477.

Example 7

2-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1H-isoindole-1,3(2H)dione

Using the phthalic acid imide, the target compound was obtained in the same manner as in example 1 (stage 10), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 3,03 (3H, c), 4,99 (2H, c), 7,05 (3H, m), 7,40 (1H, m), 7,80 (8H, m), scored 8.38 (1H, d, J=7.8 Hz), 8,64 (1H, d, J=3,9 Hz), 10,79 (1H, USS).

ESI-MASS (m/e): 525 (M+H).

Example 8

2-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-CIS-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)dione

Using CIS-1,2,3,6-tetrahydrophthalic, the target compound was obtained in the same manner as in example 1 (stage 10), or in accordance with this method, or comb the nation with a customary method.

1H-NMR (CDCl3) δ: of 2.21 (2H, m), 2,59 (2H, m), 2,99 (2H, m), 3,05 (3H, m), to 4.73 (2H, c), 5,91 (2H, m), to 7.09 (2H, m), 7,29 (1H, m), 7,39 (1H, m), 7,51 (1H, m), 7,86 (3H, m), of 8.37 (1H, m), to 8.62 (1H, m).

ESI-MASS (m/e): 529 (M+H).

Example 9

5-Methyl-1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using 5-methyl-2-pyrrolidinone, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 0,89 (1H, m)of 1.16 (3H, m), 2,11 (1H, m), 2,25 is 2.33 (1H, m), 2,46 (1H, m), of 3.07 (3H, d, J=3.5 Hz), 3,62 (1H, m), 4,17 (1H, d, J=15.2 Hz), of 4.95 (2H, d, J=15.2 Hz), was 7.08 (2H, m), 7,35 (1H, c), 7,42 (1H, m), 7,69 (1H, c), 7,89 (3H, m), to 8.41 (1H, m), 8,66 (1H, m).

ESI-MASS (m/e): 477 (M+H).

Example 10

3-Methyl-1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using 3-methyl-2-pyrrolidinone, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 0,87 (1H, c), 1,10-1,15 (3H, m)and 1.51 (1H, m), is 2.41 (1H, m), 3.04 from (3H, m), 3,21 (2H, m), of 4.44-br4.61 (2H, m), 7,01-7,06 (2H, m), 7,38-7,40 (1H, m)to 7.50 (1H, d, J=19.2 Hz), 7,74 (1H, c), a 7.85-of 7.90 (3H, m), at 8.36-to 8.41 (1H, m), 8,63-8,64 (1H, m), 10,91 (1H, USS).

ESI-MASS (m/e): 477 (M+H).

Example 11

Methyl 1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-5-oxo-2-pyrrolidinecarboxylic

Stage . Getting methyleneglutarate:

1 g dl-pyroglutamic acid was dissolved in a mixture of 25 ml methanol and 15 ml of chloroform, was added at room temperature of 7.7 ml trimethylsilyldiazomethane (2M solution in hexane) and then was stirred for 20 minutes. The solvent is evaporated under reduced pressure, the residue was dissolved in chloroform and washed with a saturated saline solution. After drying the solvent was removed, receiving of 1.03 g of target compound in the form of oil is light yellow in color.

Stage 2. Obtain methyl 1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-5-oxo-2-pyrrolidinecarboxylic:

Using methyleneglutarate, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,01 (1H, m)to 2.13 (1H, m), 2,24 (1H, m), of 2.44-2.50 (1H, m), 3.04 from (3H, m)to 3.67 (3H, m), a 4.03-4,16 (2H, m), 5,01 (1/2H, m), 5,12 (1/2H, m), 7,01-to 7.09 (2H, m), 7,16 (1/2H, d, J=2.0 Hz), 7,40 (1H, DD, J=5,5, 6,7 Hz), of 7.48 (1/2H, d, J=a 21.5 Hz), 7,60 (1/2N, c), to 7.77 (1/2H, d, J=2.3 Hz), 7,87 (3H, m), at 8.36-8,39 (1H, m), 8,64-8,65 (1H, m), 10,65 (1H, d, J=13,7 Hz).

ESI-MASS (m/e): 521 (M+H).

Example 12

1-(1-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1H-pyrrol-2-yl)-1-alanon

Using 2-acetylpyrrole, the target compound was obtained in the same manner as in example 2 or in accordance with this method, Riego combination with a customary method.

1H-NMR (CDCl3) δ: 2,29-2,39 (3H, m), 3,05 (3H, m), 5,64 (2H, c), 6,17 (1H, m)6,91 (1H, m), 6,98 (1H, m),? 7.04 baby mortality-7,20 (3H, m), 7,34-7,37 (2H, m), a 7.85 (3H, m), 8,53 (1H, d, J=7.8 Hz), 8,59 (1H, d, J=4,7 Hz).

ESI-MASS (m/e): 487 (M+H).

Example 13

1-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-5-thioxo-2-pyrrolidinone

Stage 1. Getting 5-thioxo-2-pyrrolidinone:

300 mg succinimide was dissolved in 3 ml of tetrahydrofuran at 60°C and added 606 mg Lawson reagent (Aldrich). The mixture was stirred at 60°C for 1.5 hours and the solvent evaporated. Added ice water, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. It was dried over anhydrous magnesium sulfate, the solvent evaporated and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 20/1-7/3-1/1)to give 255 mg of the target compound in the form of a solid of light yellow color.

Stage 2. Obtain 1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-5-thioxo-2-pyrrolidinone:

Using 5-thioxo-2-pyrrolidinone, the target compound was obtained in the same manner as in example 1 (stage 10), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,62 (1H, m), of 2.72 (1H, m), 3,05 (1H, m), of 3.07 (3H, c), of 3.12 (1H, m), is 5.18 (2H, c), 7,00-7,20 (2H+1/2H, m), 7,39-the 7.43 (1H, m), 7,44 (1/2H, ush.is), 7,49 (1/2H, USS), 7,60 (1/2H, USS), 7,82-of 7.90 (3H, m), at 8.36 (1H, d, J=8.0 Hz), 8,63 (1H, USS), or 10.6 (1H, ush.).

ESI-MS (m/e): 493 [M+H].

Example 14

5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-6-(1H-1,2,4-triazole-1-ylmethyl)-1H-benzimidazole

Using 1,2,4-triazole, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 3,05-3,10 (3H, m), 5,46 (2H, c), 7,06 (2H, m), of 7.36-7,44 (2H, m), 7,83-to 7.93 (5H, m), with 8.05 (1H, c), to 8.41 (1H, d, J=7.8 Hz), 8,66 (1H, d, J=4.3 Hz).

ESI-MASS (m/e): 447 (M+H).

Example 15

CIS-3,4-Dimethyl-1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl]-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione

Stage 1. Obtaining CIS-3,4-dimethylpyrrole-2,5-dione:

2,3 ml acetylchloride and 0.24 ml of thionyl chloride were added to 500 mg of meso-2,3-dimethylethanol acid and heated under reflux for 2 hours. The reaction liquid was allowed to cool to room temperature and the solvent evaporated under reduced pressure. The residue was recrystallized from toluene and hexane, obtaining 398 mg anhydride meso-2,3-dimethylethanol acid in a solid white color.

On cooling bath gaseous ammonia was introduced into a solution of 390 mg anhydride CIS-2,3-dimethylethanol acid in toluene (5 ml) for 30 minutes. The solvent is evaporated under reduced pressure, getting the e substance of white color. It was dissolved in 10 ml of DMF at -78°C was added 0.5 ml of thionyl chloride and stirred at 0°C for 2 hours. The reaction liquid was allowed to cool to room temperature, the solvent evaporated under reduced pressure, to the residue was added ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. After drying the solvent was removed and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 7/3 to 0/1)to give 269 mg of the target compound in a solid white color.

Stage 2. Obtaining CIS-3,4-dimethyl-1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione:

Using CIS-3,4-dimethylpyrrole-2,5-dione, the target compound was obtained in the same manner as in example 1 (stage 10), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,19 (6H, m), 2,84 (2H, m), 3.04 from (3H, m), 4,74 (2N, c), was 7.08 (3H, m), 7,38-7,42 (2H, m), 7,84-7,86 (3H, m), of 8.37 (1H, d, J=7,4 Hz), 8,61 (1H, c), 10,88 (1H, s).

ESI-MASS (m/e): 505 (M+H).

Example 16

4-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}morpholine-3,5-dione

Using morpholine-3,5-dione, the target compound was obtained in the same manner as in example 1 (stage 10), or in accordance with this method, or its combination with a customary method.

<> 1H-NMR (CDCl3) δ: 3,05 (3/2H, c), 3,06 (3/2H, c), 4,27 (2H, c), 4,34 (2H, c), 5,07 (2H, c), 7,05-7,10 (2H+1/2H, m), 7,35-7,42 (1H, m), 7,44 (1/2H, m), 7,53 (1/2H, m), 7,74 (1/2H, m), a 7.85-a 7.92 (3H, m), scored 8.38 (1H, m), 8,61 (1H, m), or 10.9 (1H, ush.).

ESI-MS (m/e): 493 [M+H].

Example 17

3-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-thiazolane-2,4-dione

Using 2,4-thiazolidinedione, the target compound was obtained in the same manner as in example 1 (stage 10), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 3,06 (3/2N, c)3,07 (3/2H, c), of 3.77 (1H, c), a 3.87 (1H, c), 4,89 (1H, c), 4,91 (1H, c), 7,02 for 7.12 (2H+1/2H, m), 7,35-7,44 (1H, m), 7,45 (1/2N, c), 7.62mm (1/2N, c), 7,81 (1/2N, c), a 7.85-a 7.92 (3H, m), of 8.37 (1H, m), 8,63 (1H, m), 10,7 (1/2H, ush.), 10,8 (1/2H, ush.).

ESI-MS (m/e): 495 [M+H].

Example 18

3-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-thiazolin-2-he

Using 2-oxothiazolidine obtained according to the method described in Synthetic communications, 1987, Vol.17, No.13, pp.1577-1785, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 3,06 (3H, c), and 3.16 (2H, m), 3,55 (2H, m), 4,55 (1H, c), of 4.57 (1H, c), 7,03-to 7.09 (2H, m), 7,17 (1/2N, c), 7,41 (1H, m), 7,49 (1/2N, c), 7,58 (1/2N, c), 7,83-a 7.92 (3H+1/2H, m), to 8.41 (1H, m), 8,65 (1H, m), 10,95 (1/2H, ush.), 10,91 (1/2H, ush.).

ESI-MS (m/e): 481 [M+H].

Example 19

1-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazol-yl]methyl}pyrrolidin-2,5-dione

Stage 1. Obtain methyl 2-fluoro-4-nitrobenzoate:

5 ml of concentrated sulfuric acid was added to a solution of 140 g of 2-fluoro-4-nitrobenzoic acid in methanol (1300 ml) and was heated under reflux for 48 hours. The solvent is evaporated under reduced pressure, to the residue was added water and the formed solid substance was separated by filtration. It was dried under reduced pressure, getting 141 mg of the target compound in a solid yellow color.

Stage 2. Obtain methyl 4-amino-2-perbenzoate:

141 g of methyl 2-fluoro-4-nitrobenzoate was dissolved in 1000 ml of methanol and 400 ml of tetrahydrofuran, was added 20 g of Raney Nickel and was stirred overnight in a hydrogen atmosphere. The catalyst was removed by filtration and the solvent evaporated under reduced pressure, getting 119 g of methyl 4-amino-2-perbenzoate.

Stage 3. Obtain methyl 2-fluoro-4-[(2-pyridylcarbonyl)amino]benzoate:

Hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added to a solution of 18.9 g of methyl 4-amino-2-perbenzoate and 16.5 g pikolinos acid in pyridine (500 ml) and stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure, was added to the residue 600 ml of ethyl acetate, the organic layer was washed water of 0.25 N. hydrochloric acid, water of 0.25 N. the solution of hydro is sid sodium and saturated saline solution, was dried, concentrated under reduced pressure, utverjdali from a solvent mixture of hexane/ethyl acetate and the solid product was separated by filtration. It was dried under reduced pressure, getting to 28.3 g of target compound in a solid white color.

Stage 4. Obtain methyl 2-fluoro-5-nitro-4-[(2-pyridylcarbonyl)amino]benzoate:

While cooling on ice 110 ml of fuming nitric acid was gradually added to 27.7 g of methyl 2-fluoro-4-[(2-pyridylcarbonyl)amino]benzoate and stirred at room temperature for 1.5 hours. While cooling on ice, the reaction liquid was gradually added to a solution of sodium carbonate (138 g) in water (2000 ml) and the formed solid product was separated by filtration. It was dried under reduced pressure, obtaining 27.5 g of target compound in a solid yellow color.

Stage 5. Obtain methyl 2-[4-(ethylsulfonyl)phenoxy]-5-nitro-4-[(2-pyridylcarbonyl)amino]benzoate:

3.5 g of potassium carbonate was added to the solution in dimethylformamide (110 ml), 6 g of methyl 2-fluoro-5-nitro-4-[(2-pyridylcarbonyl)amino]benzoate and of 3.48 g of 4-(ethylsulfonyl)phenol obtained in reference example 2, and stirred under heating at a temperature of 80°C for 30 minutes. The reaction liquid was allowed to cool to room temperature, poured into 300 ml of water and the resulting solid product is CT was separated by filtration. It was dried under reduced pressure, getting 7,46 g of target compound in a solid yellow color.

Stage 6. Obtain methyl 5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-carboxylate and methyl 6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-carboxylate:

7,46 g of methyl 2-[4-(ethylsulfonyl)phenoxy]-5-nitro-4-[(2-pyridylcarbonyl)amino]benzoate suspended in 37 ml of dimethylformamide and 37 ml of methanol, was added 17.3 g of dihydrate of tin chloride(II) and 15 ml of concentrated hydrochloric acid and stirred under heating at a temperature of 80°C for 40 minutes. The reaction liquid was allowed to cool to room temperature, then was gradually added an aqueous sodium hydrogen carbonate solution and neutralized. Added ethyl acetate was stirred at room temperature for 30 minutes and the formed salt was removed by filtration. The filtrate was washed with water and saturated salt solution. After drying, the solvent is evaporated, receiving of 6.9 g of a crude product of methyl 5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-carboxylate in the form of a solid yellow color.

While cooling on ice, 4 ml of 2-(trimethylsilyl)ethoxymethylene and 0.92 g of sodium hydride (with the addition of 30% liquid paraffin) was added the solution of 6.9 g of crude product in dimethylformamide (70 ml) and stirred at room temperature for 30 minutes. When cooled on ice was added a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 3/2), getting to 6.43 g of target compound in the form of a yellow oil.

Stage 7. Receive (5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol and (6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanol:

While cooling on ice, a solution of 0.99 g of lithium aluminum hydride and 5.9 g of the specified complex ester in tetrahydrofuran (50 ml) was gradually added to 60 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes and cooled on ice was gradually added 10-hydrate of sodium sulfate to stop the foaming. Then added ethyl acetate and stirred at room temperature for 1 hour. The formed salt was removed by filtration and the solvent evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 3/2)to give 4.5 g of the target connect the deposits in the form of a yellow oil.

Stage 8. Obtain 1-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione:

1.3 g of succinimide and 3.5 g of triphenylphosphine were added to a solution of 2.4 g of the obtained alcohol compound in tetrahydrofuran (24 ml), cooled on ice was added 5.8 ml of diethylazodicarboxylate (40% solution in toluene) and stirred at room temperature for 1 hour. The reaction solvent evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 8/2-1/1-1/9)to give 2.3 g of a yellow oil.

15 ml triperoxonane acid was added to the resulting oil was stirred for 2 hours. The solvent is evaporated under reduced pressure, the residue was purified by chromatography on a column of silica gel (manifesting the solvent from chloroform to the mixture chloroform/methanol = 99/1) and recrystallized (ethyl acetate), obtaining of 1.02 g of target compound in the form of crystal white.

1H-NMR (CDCl3) δ: of 1.30 (3H, m), of 2.54 (2H, c), to 2.65 (2H, c), of 3.12 (2H, m), 4,79 (1H, m), 4,80 (1H, c), 7,05 for 7.12 (2H+1/2H, m), 7,39 (1H, m), 7,44 (1/2N, c)of 7.64 (1/2N, c), 7,76 (1/2N, c), 7,81-of 7.90 (3H, m), scored 8.38 (1H, m), 8,65 (1H, m), 10,5 (1/2H, ush.), 10,6 (1/2H, ush.).

ESI-MASS (m/e): 491 (M+H).

Example 20

1-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using spirtovodocnoje, obtained in example 19 (step 7), the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,24-of 1.30 (3H, m), at 1.91 (2H, dt, J=23,7, and 7.8 Hz), 2,32 (2H, m), 3,06-3,13 (2H, m), 3,26 (2H, q, J=10.4 Hz), a 4.53 (2H, c), 7,05 (2H, m), 7,39 (2H, m), 7,79-7,89 (4H, m), scored 8.38 (1H, d, J=8,2 Hz), 8,63 (1H, d, J=4,7 Hz).

ESI-MASS (m/e): 477 (M+H).

Example 21

3-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl]-1H-benzimidazole-6-yl]methyl}-2-oxazolidinone

Using the alcohol compound obtained in example 19 (step 7), and 2-oxazolidone, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=7.4 Hz), 3,11 (2H, q, J=7.4 Hz), of 3.46 (2H, m)to 4.23 (2H, t, J=8,2 Hz), 4,51 (2H, c), was 7.08 (2H, q, J=9.0 Hz), 7,40 (1H, t, J=6.3 Hz), 7,50 (1H, m), 7,65-to 7.68 (1H, m), 7,83-7,86 (3H, m), at 8.36 is 8.38 (1H, m)8,64 (1H, c), as 10.63 (1H, s).

ESI-MASS (m/e): 479 (M+H).

Example 22

1-({2-(5-Bromo-2-pyridinyl)-[5-[4-(ethylsulfonyl)phenoxy]-1H-benzimidazole-6-yl}methyl)pyrrolidin-2,5-dione

Using a 5-bromopicolinic acid in example 19 (step 3), the target compound was obtained in the same manner as in example 19, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,29 (3H, m)to 2.55 (2H, c), to 2.65 (2H, c), of 3.12 (2H, c), 4,79 (1H, c), 4,80 (1H, c), 7,05-to 7.15 (2H+1/2H, m), 7,44 (1/2N, c), 7,65 (/2N, c)7,76 (1/2N, c), 7,82-of 7.90 (2H, m), 8,00 (1H, m), compared to 8.26 (1H, m), to 8.70 (1H, m), 10,3 (1/2H, ush.), 10,4 (1/2H, ush.).

ESI-MS (m/e): 569, 571 [M+H].

Example 23

1-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-imidazolidinone

Using the alcohol compound obtained in example 19 (step 7), and etilenmocevina, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3one drop CD3OD) δ: of 1.28 (3H, t, J=7.2 Hz), 3,11 (2H, q, J=7.2 Hz), 3.25 to or 3.28 (4H, m)to 4.41 (2H×1/2, c), of 4.44 (2H×1/2, c), 4,63 (1H×1/2, c)and 4.65 (1H×1/2, c), 7,05 (2H, d, J=8,2 Hz), 7,20 (1H×1/2, c), 7,37-7,41 (1H, m), 7,45 (1H×1/2, c), to 7.59 (1H×1/2, c), to 7.77 (1H×1/2, c)of 7.82 (2H, d, J=8,2 Hz), the 7.85-of 7.90 (1H, m), of 8.37 (1H, d, J=7,4 Hz), 8,61-8,65 (1H, m).

ESI-MASS (m/e): ND.

Example 24

1-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}imidazolidine-2,5-dione

Using the alcohol compound obtained in example 19 (step 7), and as the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: is 1.31 (3H, t, J=7.4 Hz), of 3.13 (2H, q, J=7.4 Hz), 3,70-4,00 (2H, m), 4,77-4,89 (3H, m), 7,05-of 7.90 (8H, m), of 8.37-8,42 (1H, m), 8,62-8,67 (1H, m), at 10.64-10,95 (1H, m).

ESI-MASS (m/e): 492 (M+H).

Example 25

1-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1H-pyrimidine-2,4-dione

IP is by using an alcohol compound, obtained in example 19 (step 7), and uracil, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.12 (3H, t, J=7.4 Hz), 3,24 (2H, q, J=7.4 Hz), 4,94 (2H, c), vs. 5.47 (1H, d, J=8,2 Hz), 7,10 (2H, d, J=8,2 Hz), 7,55 (1H, DD, J=7,8, and 5.5 Hz), EUR 7.57 (1H, c), to 7.59 (1H, c), 7,83 (2H, d, J=8,2 Hz), 8,02 (1H, DD, J=7,8, and 7.8 Hz), 8,31 (1H, d, J=7.8 Hz), the rate of 8.75 (1H, d, J=5.5 Hz), 11,18 (1H, USS).

ESI-MASS (m/e): 504 (M+H).

Example 26

1-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-3-methylimidazolidine-2,5-dione

Using 1-methylhydantoin, the target compound was obtained in the same manner as in example 19 (step 8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.0 Hz), 2,85 (3H×1/2, c), of 2.92 (3H×1/2, c), the 3.11 (2H, q, J=7,0 Hz)and 3.59 (2H×1/2, c), 3,74 (2H×1/2, c), of 4.77 (2H×1/2, c), 4,78 (2H×1/2, c), 7,06 (2H, d, J=9.0 Hz), 7,10 (1H×1/2, c), was 7.36-7,40 (1H, m), 7,45 (1H×1/2, c), 7,66 (1H×1/2, c), 7,79-7,89 (3H, m), 7,79-7,89 (1H×1/2, m)of 8.37 (1H×1/2, d, J=8,2 Hz), 8,40 (1H×1/2, d, J=8,2 Hz), 8,60-8,65 (1H, m), 10,63 (1H×1/2, USS), 10,67 (1H×1/2, USS).

ESI-MASS (m/e): 506 (M+H).

Example 27

3-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl]-1H-benzimidazole-6-yl]methyl}-1-methyl-1H-pyrimidine-2,4-dione

Using 1-methyluracil, the target compound was obtained in the same manner as in example 19 (step 8), or in accordance with this method, or its combination with the usual way

1H-NMR (CDCl3) δ: 1.28 (in 3H×1/2, t, J=7.4 Hz), 1.28 (in 3H×1/2, t, J=7.4 Hz), 3,10 (2H×1/2, kV, J=7,4 Hz), 3,10 (2H×1/2, kV, J=7,4 Hz)at 3.25 (3H×1/2, c)to 3.33 (3H×1/2, c), 5,23 (2H×1/2, c), of 5.24 (2H×1/2, c), 5,63 (1H×1/2, d, J=7.8 Hz), 5,72 (1H×1/2, d, J=7.8 Hz), 6,99 (1H×1/2, d, J=7.8 Hz),? 7.04 baby mortality (2H×1/2, d, J=9.0 Hz), to 7.09 (1H×1/2, c), 7,10 (2H×1/2, d, J=9.0 Hz), 7,10 (1H×1/2, d, J=7.8 Hz), 7,34-7,38 (1H, m), the 7.43 (1H×1/2, c), 7,52 (1H×1/2, c), 7,63 (1H×1/2, c), 7,78 (2H×1/2, d, J=9.0 Hz), 7,81-7,87 (1H, m), 7,82 (2H×1/2, d, J=9.0 Hz), 8,35 (1H, d, J=7.8 Hz), at 8.60 (1H×1/2, d, J=5,1 Hz), 8,61 (1H×1/2, d, J=5,1 Hz), 10,65 (1H, USS).

ESI-MASS (m/e): 518 (M+H).

Example 28

1-{[5-[4-Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-3-methyl-1H-pyrimidine-2,4-dione

Using the alcohol compound obtained in example 19 (step 7), and 3-methyluracil, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: is 1.31 (3H, t, J=7.4 Hz), of 3.12 (2H, q, J=7.4 Hz), 3,26 (3H×1/2, c), 3,29 (3H×1/2, c)5,00 (2H×1/2, c)of 5.03 (2H×1/2, c), the 5.65 (1H×1/2, d, J=7.8 Hz), the 5.65 (1H×1/2, d, J=7.8 Hz), 7,05 (2H×1/2, d, J=8.6 Hz), to 7.09 (2H×1/2, d, J=8.6 Hz), 7,13 (1H×1/2, c), 7,19 (1H×1/2, d, J=7.8 Hz), 7,27 (1H×1/2, c), 7,38-7,42 (1H, m), the 7.43 (1H×1/2, c), of 7.70 (1H×1/2, c), 7,83-of 7.90 (3H, m), 7,83-of 7.90 (1H×1/2, m), at 8.36 (1H, d, J=7.8 Hz), 8,39 (1H, d, J=7.8 Hz), 8,61-8,65 (1H, m), 10,80 (1H, USS).

ESI-MASS (m/e): 518 (M+H).

Example 29

1-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-3-methyl-2-imidazolidinone

Using the alcohol compound obtained in example 19 (studies is 7), and 1 methylimidazolidine, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=7.4 Hz), 2,73 (3H×1/2, c)of 2.75 (3H×1/2, c)3,10 (2H, q, J=7.4 Hz), 3,16-3,20 (4H, m), 4,43 (2H×1/2, c), 4,43 (2H×1/2, c), 7,03 (2H, d, J=9.0 Hz), 7,06 (1H×1/2, c), 7,16 (1H×1/2, c), 7,37-7,40 (1H, m), 7,47 (1H×1/2, c), to 7.61 (1H×1/2, c), 7,80 (2H, d, J=9.0 Hz), 7,84-7,89 (1H, m), of 8.37 (1H×1/2, d, J=7.8 Hz), 8,40 (1H×1/2, d, J=7.8 Hz), to 8.62 (1H×1/2, d, J=4,7 Hz)8,64 (1H×1/2, d, J=4,7 Hz), 10,81 (1H×1/2, USS), 10,84 (1H×1/2, USS).

ESI-MASS (m/e): 492 (M+H).

Example 30

3-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-3-azabicyclo[3.1.0]hexane-2,4-dione

Using 3-azabicyclo[3.1.0]hexane-2,4-dione, the target compound was obtained in the same manner as in example 19 (step 7), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,17 is 1.75 (5H, m), 2.40 a-2,50 (2H, m), 3,05-3,18 (2H, m), br4.61 (1H, c), 4,63 (1H, c), 7,05-7,13 (2H+1/2H, m), 7,39-7,44 (1H, m), 7,44 (1/2N, c), 7,54 (1/2N, c), 7,73 (1/2N, c), 7,82-of 7.90 (3H, m), 8,39 (1H, m), 8,63 (1H, m), 10,8 (1/2H, ush.), 10,9 (1/2H, ush.).

ESI-MASS (m/e): 503 (M+H).

Example 31

N-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}methanesulfonamide

Stage 1. Receive (5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methylamine, or (6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trim ililil)ethoxy]methyl}-1H-benzimidazole-5-yl)methylamine:

While cooling on ice, 74 μl of methanesulfonamide was added to the solution in tetrahydrofuran (2.6 ml) 260 mg of the alcohol compound obtained in example 19 (step 7), and 134 μl of triethylamine and stirred for 30 minutes. Added ice water, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure, obtaining the oil is light yellow in color.

156 mg of sodium azide was added to a solution of the obtained oil in dimethylformamide (3 ml) and stirred at room temperature for 1 hour. Added ice water, extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 3/2)to give 177 mg of yellow oil.

5 mg sulfate pentahydrate copper(II) and 53 mg of sodium borohydride was added to a solution of the resulting oil in methanol (3.2 ml) and stirred at room temperature for 30 minutes. Was added a saturated aqueous solution of ammonium chloride, neutralized with saturated aqueous sodium bicarbonate, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying actuarial evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting the solvent from chloroform to the mixture chloroform/methanol = 20/1), getting 141 mg of the target compound in the form of a yellow oil.

Stage 2. Obtaining N-(5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanesulfonamide or N-(6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanesulfonamide:

While cooling on ice, 25 μl of triethylamine and 11 μl of methanesulfonamide was added to a solution of 63 mg of the obtained amine in chloroform (1 ml). After stirring for 30 minutes was added saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated and the residue was purified by chromatography on a column of silica gel (manifesting the solvent from chloroform to the mixture chloroform/methanol = 20/1)to give 77 mg of the target compound in the form of a yellow oil.

Stage 3. Obtain N-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}methanesulfonamide:

0.5 ml triperoxonane acid was added to 77 mg of the obtained yellow oil was stirred at room temperature for 2 hours. The solvent is evaporated, the residue was neutralized with triethylamine and purified separating thin-layer chromatography (Kieselgel™ 6OF254, Art 5744 (by Merck), chloroform/methanol = 10/1), receive the I and 9.4 mg of target compound in the form of an amorphous substance of white color.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7,3 Hz), 2,84 and 2.86 (total 3H, c), 3,14 (2H, q, J=7,3 Hz)to 4.41 (2H, m), is 4.93 (1H, m), 7,07-7,13 (2H+1/2H, m), 7,41 (1H, m), 7,45 (1/2N, c), to 7.67 (1/2N, c), 7,87 (3H, m), 7,93 (1/2N, c), 8,40 (1H, m), 8,65 (1H, m), is 10.7 and 10.8 (total 1H, ush.).

ESI-MASS (m/e): 487 (M+H).

Example 32

N-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-N-methylmethanesulfonamide

While cooling on ice 14 µl under the conditions and 5.3 mg of sodium hydride (with the addition of 30% liquid paraffin) was added to a solution of 60 mg sulfonamida obtained in example 31 (stage 2), in dimethylformamide (0.6 ml). The mixture was stirred at room temperature for 30 minutes, then was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure, obtaining a butter yellow color.

0.5 ml triperoxonane acid was added to the obtained yellow oil was stirred at room temperature for 2 hours. The solvent is evaporated, the residue was neutralized with triethylamine and purified separating thin-layer chromatography (Kieselgel™ 6OF254, Art 5744 (by Merck), chloroform/methanol = 10/1), receiving of 38.4 mg of target compound in the form of an amorphous substance of white color.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7.4 Hz), and 2.83 (6H, m), of 3.12 (2H, q, J=7.4 Hz), 4,40, and was 4.42 (total is 2H, c)7,00-7,10 (2H, m), 7,14 (1/2N, c), 7,41 (1H, m), of 7.48 (1/2N, c), 7,72 (1/2N, c), 7,83-of 7.95 (3H, m), 7,97 (1/2N, c), to 8.41 (1H, m), 8,65 (1H, m), and 11.0 (1H, ush.).

ESI-MASS (m/e): 501 (M+H).

Example 33

2-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}isothiazolin-1,1-dioxide

Using the alcohol compound obtained in example 19 (step 7), and isothiazoline-1,1-dioxide obtained according to the method described in Organic letters, 2003, Vol.5, No.22, pp.4175-4277, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7.5 Hz), 2,20-of 2.30 (2H, m), 3,05-3,20 (6H, m), 4,28 (2H, OSS), was 7.08 (2H, d, J=8,9 Hz), 7,19 (1/2H, USS), 7,41 (1H, m), 7,50 (1/2H, USS), 7,71 (1/2H, OSS), to 7.84 (2H, d, J=8,9 Hz), 7,89 (1H, m), of 7.96 (1/2H, OSS), to 8.41 (1H, m), 8,65 (1H, m)and 10.7 (1H, ush.).

ESI-MASS (m/e): 513 (M+H).

Example 34

1-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyrazinyl-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione

Stage 1. Obtain methyl 2-fluoro-5-nitro-4-[(2-pyrazinecarboxamide)amino]benzoate:

Using methyl 4-amino-2-perbenzoate obtained in example 19 (stage 2), and pyrazin-2-carboxylic acid, the target compound was obtained in the same manner as in example 19 (stage 3, stage 4), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain methyl 5-[4-(methylsulphonyl)phenoxy]-2-(2-pyrazinyl)-1-{[2-(trimethyl who ilil)ethoxy]methyl}-1H-benzimidazole-6-carboxylate and methyl 6-[4-(methylsulphonyl)phenoxy]-2-(2-pyrazinyl)-1-{[2-(trimethylsilyl) ethoxy]methyl}-1H-benzimidazole-5-carboxylate :

Using methyl 2-fluoro-5-nitro-4-[(2-pyrazinecarboxamide)amino]benzoate, obtained above, and 4-(methylsulphonyl)phenol obtained in reference example 1, a target compound was obtained in the same manner as in example 19 (stage 5, stage 6), or in accordance with this method, or its combination with a customary method.

Stage 3. Receive (5-[4-(methylsulphonyl)phenoxy]-2-(2-pyrazinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol and (6-[4-(methylsulphonyl)phenoxy]-2-(2-pyrazinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanol:

570 mg of the obtained complex methyl ester was dissolved in 4 ml of methanol was added 1 ml of tetrahydrofuran, and then 1 ml of aqueous 5 n sodium hydroxide solution and stirred at room temperature for 2 hours. Controlled pH=3 with aqueous 10% citric acid solution, then extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure, getting 447 mg solid light yellow color.

201 mg of 1,1'-carbodiimide was added to a solution of the obtained solid light yellow in tetrahydrofuran (5 ml) and was stirred for 12 hours.

The reaction liquid was added to a solution of 157 mg of sodium borohydride in water (5 ml) and stirred at the room for the Noah temperature for 30 minutes. Was added aqueous 10% citric acid solution, extracted with ethyl acetate, the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 1/9)to give 234 mg of the target compound in the form of a yellow oil.

Stage 4. Obtain 1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyrazinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione:

Using the obtained alcohol compound, the target compound was obtained in the same manner as in example 19 (step 8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,71 (3H, c), to 2.57 (2H, c), 2,69 (2H, c), 3,06 (3/2N, c)3,07 (3/2H, c), 4,79 (1H, c), 4,80 (1H, c), 7,05-to 7.15 (2H+1/2H, m), 7,47 (1/2N, c), 7,68 (1/2N, c), to 7.77 (1/2N, c), a 7.85-7.95 is (2H, m), at 8.60 (1H, m), 8,68 (1H, m), being 9.61 (1H, DD, J=1,6, 7,0 Hz), 10,59 (1H, ush.).

ESI-MS (m/e): 478 [M+H].

Example 35

1-{[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyrazinyl)-1H-benzimidazole-6-yl]methyl]-2-pyrrolidinone

Using the alcohol compound obtained in example 34 stage (stage 3), the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,90-2,02 (2H, m), 2,30 at 2.45 (2H, m), of 3.07 (3H, c), 3,30 is 3.40 (2H, m), 4,55 (2H, c), 7,00-7,10 (2H, m, 7,18 (3/7H, c), 7,50 (4/7H, c), 7,68 (4/7H, c), 7,78 (3/7H, c), 7,83-a 7.92 (2H, m), 8,55-8,66 (1H, m), 8,67 (1H, m), 9,62 (1H, m), 11,0 (3/7H, ush.), 11,5 (4/7H, ush.).

ESI-MS (m/e): 464 [M+H].

Example 36

1-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyrazinyl]-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione

Stage 1. Receive (5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyrazinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol and (6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyrazinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol:

Using 4-(ethylsulfonyl)phenol obtained in reference example 2, the target compound was obtained in the same manner as in example 34 stage (stage 2, stage 3), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain 1-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyrazinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione:

Using the obtained alcohol, the target compound was obtained in the same manner as in example 19 (step 8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.23 to 1.31 (3H, m), of 2.54 (2H, c)to 2.67 (2H, c), the 3.11 (2H, q, J=14,8 Hz), 4,79 (2H, c), 7,06 (1/2N, c), 7,08-7,11 (2H, m), 7,46 (1/2N, c), to 7.67 (1/2N, c), 7,76 (1/2N, c), 7,81-7,87 (2H, m), to 8.57 at 8.60 (1H, m), 8,66 (1H, m), 9,60 (1H, m), 10,48 (1H, d, J=11.7 Hz).

ESI-MASS (m/e): 492 (M+H).

Example 37

1-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyrazinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

And who uses alcohol compound, obtained in example 36 (stage 1), the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.32 (3H, t, J=7.4 Hz), 1,94 is 2.01 (2H, m), 2,35-to 2.41 (2H, m), 3,14 (2H, q, J=7.4 Hz), 3.33 and-to 3.36 (2H, m), 4,58 (2H, d, J=3.5 Hz), to 7.09 (2H, m), 7,22 (1/2H, m), 7,53 (1/2N, c), 7,66 (1/2N, c), 7,82 (1/2N, c), 7,87 (2H, d, J=8,2 Hz), to 8.62 (1H, m), to 8.70 (1H, d, J=2.3 Hz), 9,63-to 9.66 (1H, m), 10,48 (1/2N, c), of 10.73 (1/2H, s).

ESI-MASS (m/e): 478 (M+H).

Example 38

3-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using the alcohol compound obtained in example 36 (stage 1), and 2-oxazolidone, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, 7.4 Hz), 3,11 (2H, q, J=7.4 Hz), 3,50 (2H, m), 4,25 (2H, m), a 4.53 (2H, c), 7,06-to 7.09 (3H, m), 7,84-7,86 (3H, m), 8,61 (1H, m), 8,68 (1H, d, J=2.3 Hz), 9,62 (1H, d, J=1.6 Hz).

ESI-MASS (m/e): 480 (M+H).

Example 39

1-{[5-[6-(Ethylsulfonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione

Stage 1. Obtain (5-{[6-(ethylsulfonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol and (6-{[6-(ethylsulfonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanol:

Using 6-(ethylal who were radioactive)-3-pyridinol, obtained in reference example 4, the target compound was obtained in the same manner as in example 19 (stages 5-7), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain 1-{[5-[6-(ethylsulfonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione:

Using the obtained alcohol compound, the target compound was obtained in the same manner as in example 19 (step 8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.27 to 1.37 (3H, m), 2.63 in (2H, c), 2,70 (2H, c), 3,30 is-3.45 (2H, m), of 4.77 (1H, 2), 4,79 (1H, c), 7,10 (1/2N, c), 7,35-7,45 (2H, m), 7,45 (1/2H, m), to 7.67 (1/2N, c), 7,80 (1/2N, c), 7,88 (1H, m), 8,03 (1H, m), 8,39 (1H, m), 8,49 (1H, m)8,64 (1H, m), and 10.8 (1H, ush.).

ESI-MS (m/e): 492 [M+H].

Example 40

1-{[5-[6-(Ethylsulfonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using the alcohol compound obtained in example 39 (stage 1), the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: is 1.31 (3H, t, J=7,6 Hz), of 1.95 (2H, m), 2,34 (2H, dt, J=8.0 a, 16 Hz), 3,30 (2H, q, J=7.0 Hz), 3,39 (2H, q, J=7,6 Hz), of 4.54 (1H, c), 4,55 (1H, c), 7,17 (1/2N, c), 7,33 (1H, DD, J=2.7, and an 8.8 Hz), 7,41 (1H, m)of 7.48 (1/2N, c), 7,58 (1/2N, c), 7,79 (1/2N, c), to $ 7.91 (1H, m), 8,01 (1H, m), scored 8.38-to 8.45 (1H+1/2H, m), of 8.47 (1/2H, m), 8,65 (1H, m), 11,0 (1/2H, ush.), 11,1 (1/2H, ush.).

ESI-MS (m/e): 478 [M+H].

<> Example 41

3-{[5-{[6-(Ethylsulfonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using the alcohol compound obtained in example 39 (stage 1), and 2-oxazolidone, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: is 1.31 (3H, t, J=7,6 Hz), 3,34-of 3.42 (2H, q, J=7,6 Hz), 3.43 points-of 3.53 (2H, m), 4,25 (2H, q, J=8.0 Hz), to 4.52 (1H, c), of 4.54 (1H, c), 7,20 (1/2H, m), 7,32-7,37 (1H, m), 7,38 was 7.45 (1H, m), 7,50 (1/2N, c), 7,63 (1/2N, c), a 7.85-a 7.92 (1H+1/2H, m), 8,01 (1H, d, J=8.6 Hz), of 8.37-to 8.45 (1H+1/2H, m), 8,48 (1/2H, m), 8,65 (1H, m), 11,1 (1H, ush.).

ESI-MS (m/e): 480 [M+H].

Example 42

1-{[5-{[6-Methylsulphonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione

Stage 1. Obtain (5-{[6-(methylsulphonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol and (6-{[6-(methylsulphonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanol:

Using 6-(methylsulphonyl)-3-pyridinol obtained in reference example 3, the target compound was obtained in the same manner as in example 19 (stages 5-7), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain 1-{[5-{[6-methylsulphonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-di is :

Using the obtained alcohol compound, the target compound was obtained in the same manner as in example 19 (step 8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,61 (2H, m), 2,69 (2H, m), 3,24 (3H, m), of 4.77 (2H, d, J=9.0 Hz), 7,12 (1/2N, c), 7,35-7,41 (2H, m), 7,44 (1/2N, c), 7,69 (1/2N, c), 7,80 (1/2N, c), 7,87 (1H, m), 8,02 (1H, d, J=13,7, 8.6 Hz), of 8.37 (1H, m), 8,48 (1H, m)8,64 (1H, m), 10,57 (1H, s).

ESI-MASS (m/e): 478 (M+H).

Example 43

1-{[5-{[6-Methylsulphonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using the alcohol compound obtained in example 42 (stage 1), the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,90-to 1.98 (2H, m), is 2.30 to 2.35 (2H, m), 3,21 (3H, c), 3,30 (2H, m), a 4.53 (2H, d, J=3,9 Hz), 7,19 (1/2N, c), 7,33 (1H, c), 7,40 (1H, m), 7,49 (1/2H, m), EUR 7.57 (1/2H, m), 7,78 (1/2H, m), 7,88 (1H c), 8,00 shed 8.01 (1H, m), at 8.36-8,46 (2H, m)8,64 (1H, c), 10,65 (1H, s).

ESI-MASS (m/e): 464 (M+H).

Example 44

1-{[5-{[3-Chloro-4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione

Stage 1. Receive (5-[3-chloro-4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol and (6-[3-chloro-4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanol:

Use the UYa 3-chloro-4-(methylsulphonyl)phenol, obtained in reference example 5, the target compound was obtained in the same manner as in example 19 (stages 5-7), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain 1-{[5-{[3-chloro-4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione:

Using the obtained alcohol compound, the target compound was obtained in the same way as in example 19 (step 8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2.63 in (4H×1/2, c), a 2.71 (4H×1/2, c), or 3.28 (3H×1/2, c), or 3.28 (3H×1/2, c), of 4.77 (2H×1/2, c), 4,78 (2H×1/2, c), 6,99? 7.04 baby mortality (2H×1/2, m), 7,11 (1H×1/2, d, J=2.3 Hz), to 7.15 (1H×1/2, d, J=2.3 Hz), to 7.15 (1H×1/2, c), 7,40-7,44 (1H, m), 7,47 (1H×1/2, c)of 7.69 (1H×1/2, c), 7,81 (1H×1/2, c), 7,86-7,94 (1H, m), 8,08-of 8.15 (1H, m), scored 8.38-to 8.45 (1H, m), 8,64-8,69 (1H, m), to 10.62 (1H×1/2, USS), 10,65 (1H×1/2, USS).

ESI-MASS (m/e): 511 (M+H).

Example 45

1-{[5-{[3-Chloro-4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using the alcohol compound obtained in example 44 (stage 1), the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,93-2,02 (2H, m), 2,33-to 2.41 (2H, m), with 3.27 (3H, c), 3,31-to 3.34 (2H, m), 4,53 (2H×1/2, c), of 4.54 (2H×1/2, c), 6,93-7,03 (1H, m), 7,08-7,10 (1H, m), 7,21 (1H×1/2, c), 7,41-7,44 (1H, m), 7,51 (1H×1/2, c), to 7.59 (1H×1/2, c), 7,80 (1H×1/2, c), 7,88-to 7.93 (1H, m), 8,08 (1H, d, J=9.0 G is), 8,42 (1H, t, J=8,4 Hz), 8,65-8,69 (1H, m), 10,79 (1H×1/2, USS), 10,85 (1H×1/2, USS).

ESI-MASS (m/e): 497 (M+H).

Example 46

3-{[5-{[3-Chloro-4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-oxazolidinone

Using the alcohol compound obtained in example 44 (stage 1), and 2-oxazolidone, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 3,25 (3H, c), 3,42-3,51 (2H, m), 4,22-the 4.29 (2H, m), 4,48 (2H×1/2, c), 4,50 (2H×1/2, c), 6,93-6,99 (1H, m), 7,05-7,10 (1H, m), 7,20 (1H×1/2, c), 7,39-7,44 (1H, m), 7,50 (1H×1/2, c)to 7.64 (1H×1/2, c), the 7.85-of 7.90 (1H, m), of 7.90 (1H×1/2, c), of 8.06 (1H, d, J=8.6 Hz), 8,39 (1H×1/2, d, J=8.6 Hz), to 8.41 (1H×1/2, d, J=8.6 Hz), 8,63-8,68 (1H, m), 10,84 (1H, USS).

ESI-MASS (m/e): 499 (M+H).

Example 47

4-{[6-[(2,5-Dioxo-1-pyrrolidinyl)methyl]-2-(2-pyridinyl)-1H-benzimidazole-5-yl]oxy}benzonitrile

Using 4-cyanoprop, the target compound was obtained in the same manner as in example 19 (stages 5-8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,53 (4H×1/2, c)2,63 (4H×1/2, c), was 4.76 (2H×1/2, c), of 4.77 (2H×1/2, c), of 6.99 (1H, d, J=9.0 Hz), 7,02 (1H, d, J=9.0 Hz), 7,11 (1H×1/2, c), of 7.36-7,40 (1H, m), the 7.43 (1H×1/2, c), 7,58 (1H, d, J=9,0 Hz), to 7.61 (1H, d, J=9.0 Hz), 7,63 (1H×1/2, c), of 7.75 (1H×1/2, c), 7,84-7,89 (1H, m), 8.34 per-8,39 (1H, m), 8,60-8,66 (1H, m), 10,46 (1H×1/2, USS), 10,52 (1H×1/2, USS).

ESI-MASS (m/e): 424 (M+H).

Example 48

1-{[5-[(6-Methyl-3-pyridinyl)oxy]-2-(2-pyridinyl)-1H-shall benzimidazol-6-yl]methyl]pyrrolidin-2,5-dione

Using 4-hydroxy-6-methylpyridin, the target compound was obtained in the same manner as in example 19 (stages 5-8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,53 (3H, d, J=8,2 Hz), 2,60 (2H, c), 2,69 (2H, c), to 4.87 (2H, d, J=9.4 Hz), 7,08-7,13 (1H, m), 7,32 (2H, m), 7,52 (1H, m), 7,65 (1/2H, m), 7,83-a 7.85 (1H, m), compared to 8.26 (1/2N, c), 8,32-to 8.34 (2H, m), at 8.60 (1H, m).

ESI-MASS (m/e): 414 (M+H).

Example 49

1-{[5-[(6-Methyl-3-pyridinyl)sulfonyl]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione

Using 6-methylpyridin-3-thiol obtained according to the method described in WO 2004/081001, the target compound was obtained in the same manner as in example 19 (stages 5-8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 10,59 (USS, 1H), to 8.62 (d, 1H, J=4,7 Hz), 8,40-of 8.37 (m, 2H), a 7.85 (m, 1H), 7,56 (d, 1H, J=15.7 Hz), 7,42-the 7.43 (m, 3H), 7,03 (s, 1H), 4,99 (s, 2H), was 2.76 (s, 2H), 2,68 (s, 2H), 2,47 (s, 3H).

ESI-MASS (m/e): 414 (M+H).

Example 50

1-{[5-[4-(Methoxymethyl]phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione

Stage 1. Obtain methyl 5-(4-formylphenoxy)-2-(2-pyridinyl)-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-carboxylate and methyl 6-(4-formylphenoxy)-2-(2-pyridinyl)-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-carboxylate:

Using 4-hydroxybenzaldehyde, the target compound was obtained in the same way as the example 19 (stages 5-6), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain methyl 5-[4-(hydroxymethyl)phenoxy]-2-(2-pyridinyl)-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-carboxylate and methyl 6-[4-(hydroxymethyl)phenoxy]-2-(2-pyridinyl)-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-carboxylate:

In a bath with ice 54 mg of sodium borohydride was added to a solution of 362 mg of the obtained product in methanol (5 ml) and stirred at room temperature for 20 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction liquid was extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying the solvent was removed, getting 337 mg of the crude product of the target compound in a solid yellow color.

Stage 3. Obtain methyl 5-[4-(methoxymethyl)phenoxy]-2-(2-pyridinyl)-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-carboxylate and methyl 6-[4-(methoxymethyl)phenoxy]-2-(2-pyridinyl)-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-carboxylate:

In a bath with ice 89 μl under the conditions and 57 mg of sodium hydride (with the addition of 30% liquid paraffin) was added to a solution of 337 mg of the obtained product in DMF (5 ml) and stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride we use the and to the reaction liquid, were extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying the solvent was removed, getting 346 mg of the crude product of the target compound in the form of a brown oil.

Stage 4. Obtain 1-{[5-[4-(methoxymethyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione:

Using the resulting product, the target compound was obtained in the same manner as in example 19 (step 7, step 8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2.57 m (4H, d, J=24.3 Hz), 3,37 (3H, c), and 4.40 (2H, c), is 4.85 (2H, c), 6,93 (2H, d, J=8,2 Hz), 7,27 (3H, d, J=8,2 Hz), 7,33-7,37 (1H, m), 7,60 (1H, OSS), to 7.84 (1H, TD, J=7,8 and 8.1 Hz), 8,35 (1H, d, J=7,8 Hz), at 8.60 (1H, d, J=4.3 Hz).

ESI-MASS (m/e): 443 (M+H).

Example 51

1-{5-[4-(2-Oxo-1,3-oxazolin-3-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl}pyrrolidin-2,5-dione

Stage 1. Obtain methyl 5-(4-iodinase)-2-(2-pyridinyl)-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-carboxylate and methyl 6-(4-iodinase)-2-(2-pyridinyl)-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-carboxylate:

Using 4-itfinal, the target compound was obtained in the same manner as in example 19 (stage 5, stage 6), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain methyl 5-[4-(2-oxo-1,3-oxazolin-3-yl)]-2-(2-pyridinyl)-1H-BAA is imidazol-6-carboxylate and methyl 6-[4-(2-oxo-1,3-oxazolin-3-yl)]-2-(2-pyridinyl)-1H-benzimidazole-5-carboxylate :

186 mg of 2-oxazolidone, 20 mg of copper iodide(I) and 148 mg of potassium carbonate were added to a solution of 642 mg of the obtained product in DMF (7 ml) and stirred at 150°C for 28 hours. The reaction liquid was allowed to cool to room temperature, then was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform/methanol = 10/0 to 100/1)to give 427 mg of the target compound in the form of a brown oil.

Stage 3. Obtain 1-{5-[4-(2-oxo-1,3-oxazolin-3-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl}pyrrolidin-2,5-dione:

Using the resulting product, the target compound was obtained in the same manner as in example 34 stage (stage 3, stage 4), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 2.51 of $ 2.53 (2H, m), 2,65-a 2.71 (2H, m), 4,05-4,10 (2H, m), 4,56-of 4.49 (2H, m), a 4.86 (2H, d, Hz, J=12,5 Hz), 6,98 (2H, d, J=12,5 Hz), 7,32 (2H, m), 7,49 (2H, m), 7,63 (1H, d, J=9.8 Hz), to 7.84 (1H, DD, J=7,8, 5,9 Hz), 8.34 per-at 8.36 (1H, m), 8,59-8,61 (1H, m).

ESI-MASS (m/e): 484 (M+H).

Example 52

1-[(5-{[6-(5-Methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl]-1H-benzimidazole-6-yl)methyl]pyrrolidin-2,5-dione

Stage 1. Obtain methyl 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-carboxylate and methyl 6-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-carboxylate :

Using 6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinol obtained in reference example 6, the target compound was obtained in the same manner as in example 19 (stage 5, stage 6), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain (5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1-[{2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol and (6-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1-[{2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanol:

The target compound was obtained in the same manner as in example 34 stage (stage 3), or in accordance with this method, or its combination with a customary method.

Stage 3. Obtaining 1-[(5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl)methyl]pyrrolidin-2,5-dione:

Using the obtained alcohol compound, the target compound was obtained in the same manner as in example 19 (step 8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,58 (2H, c)to 2.67 (2H, c)to 2.67 (3H, c), 4,82 (2H×1/2, c), 4,84 (2H×1/2, c), was 7.08 (1H×1/2, c), 7,30-7,40 (2H, m), 7,44 (1H×1/2, c), to 7.61 (1H×1/2, c), 7,74 (1H×1/2, c), 7,86 (1H×1/2, t, J=8,2 Hz), 7,86 (1H×1/2, t, J=8,2 Hz), 8,02 (1H×1/2, d, J=8.6 Hz), of 8.06 (1H×1/2, d, J=9.4 Hz), 8,35 (1H×1/2, d, J=8,2 Hz), of 8.37 (1H×1/2, d, J=8,2 Hz), 8,53 (1H×1/2, d, J=2.3 Hz), to 8.57 (1H×1/2, d, J=2.3 Hz), 8,61 (1H×1/2, d, J=4.3 Hz), 8,63 (1H, d×1/2, J=4.3 Hz), 1,60 (1H×1/2, OSS), at 10.64 (1H×1/2, USS).

ESI-MASS (m/e): 482 (M+H).

Example 53

1-[(5-{[6-(5-Methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl)methyl]-2-pyrrolidinone

Using the alcohol compound obtained in example 52 (stage 2), the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,90-to 1.98 (2H, m), 2,30-of 2.38 (2H, m)to 2.67 (3H, c), 3,29-to 3.35 (2H, m), of 4.57 (2H×1/2, c), 4,59 (2H×1/2, c), 7,14 (1H×1/2, c), 7,30 (1H×1/2, DD, J=9,0, 2.7 Hz), 7,33 (1H×1/2, DD, J=9,0, 2.3 Hz), 7,38 (1H×1/2, DD, J=8,2, 5,5 Hz), 7,38 (1H×1/2, DD, J=8,2, 5,1 Hz), 7,47 (1H×1/2, c), EUR 7.57 (1H×1/2, c), to 7.77 (1H×1/2, c), 7,86 (1H×1/2, t, J=8,2 Hz), 7,87 (1H×1/2, t, J=8,2 Hz), 8,02 (1H×1/2, d, J=9.0 Hz), of 8.04 (1H×1/2, d, J=9.0 Hz), of 8.37 (1H×1/2, d, J=8,2 Hz), 8,40 (1H×1/2, d, J=8,2 Hz), of 8.47 (1H×1/2, d, J=2.3 Hz), 8,54 (1H×1/2, d, J=2.7 Hz), to 8.62 (1H×1/2, d, J=5.5 Hz), 8,64 (1H×1/2, d, J=5,1 Hz), 10,84 (1H×1/2, USS), 10,94 (1H×1/2, USS).

ESI-MASS (m/e): 468 (M+H).

Example 54

1-[(5-{[6-(5-Methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl)methyl]-2-oxazolidinone

Using the alcohol compound obtained in example 52 (stage 2), and 2-oxazolidone, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: to 2.67 (3H, c), of 3.46-of 3.53 (2H, m), 4,21-4,27 (2H, m), 4,55 (2H×1/2, c), 4,58 (2H×1/2, c), 7,17 (1H×1/2, c), 7,32 (1H×1/2, DD, J=8,6, 2.7 Hz), 7,35 (1H×1/2, DD, J=8,, 2.3 Hz), 7,39 (1H×1/2, DD, J=8,2, 5,5 Hz), 7,39 (1H×1/2, DD, J=8,2, 5.0 Hz), 7,49 (1H×1/2, c)to 7.64 (1H×1/2, c), 7,84-of 7.90 (1H, m), 7,87 (1H×1/2, c), of 8.04 (1H×1/2, d, J=8.6 Hz), of 8.06 (1H×1/2, d, J=8.6 Hz), scored 8.38 (1H×1/2, d, J=8,2 Hz), 8,40 (1H×1/2, d, J=8,2 Hz), of 8.47 (1H×1/2, d, J=2.3 Hz), 8,54 (1H×1/2, d, J=2.7 Hz), to 8.62 (1H×1/2, d, J=5.5 Hz), 8,65 (1H×1/2, d, J=5.0 Hz), 10,79 (1H×1/2, USS), 10,85 (1H×1/2, USS).

ESI-MASS (m/e): 470 (M+H).

Example 55

1-{[5-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione

Stage 1. Receive (5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol and (6-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanol:

Using 4-(5-methyl-1,2,4-oxadiazol-3-yl)phenol obtained in reference example 7, the target compound was obtained in the same manner as in example 52 (stage 1, stage 2), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain 1-{[5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione:

Using the obtained alcohol compound, the target compound was obtained in the same manner as in example 19 (step 8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,44 (4H×1/2, c), to 2.57 (4H×1/2, c)2,63 (3H×1/2, c)of 2.64 (3H×1/2, c)4,82 (2H×1/2, c), 485 (2H×1/2, c)of 6.99 (2H×1/2, d, J=8.6 Hz),? 7.04 baby mortality (2H×1/2, d, J=8.6 Hz), 7,10 (1H×1/2, c), 7,34-7,39 (1H, m), 7,45 (1H×1/2, c), to 7.61 (1H×1/2, c), 7,73 (1H×1/2, c), 7,83-7,87 (1H, m), to 7.99 (2H×1/2, d, J=8.6 Hz), 8,02 (2H×1/2, d, J=8.6 Hz), 8,35 (1H×1/2, d, J=7,0 Hz), of 8.37 (1H×1/2, d, J=6,7 Hz), at 8.60 (1H×1/2, d, J=5.3 Hz), 8,64 (1H×1/2, d, J=5,1 Hz), 10,46 (1H×1/2, c), 10,55 (1H×1/2, s).

ESI-MASS (m/e): 481 (M+H).

Example 56

1-{[5-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using the alcohol compound obtained in example 55 (stage 1), the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,87-of 1.95 (2H, m), 2,30-of 2.36 (2H, m), 3.27 to to 3.33 (2H, m), of 4.57 (2H×1/2, c), 4,59 (2H×1/2, c), 7,01 (2H×1/2, d, J=8.6 Hz), 7,03 (2H×1/2, d, J=8.6 Hz), to 7.15 (1H×1/2, c), 7,35-7,39 (1H, m), 7,49 (1H×1/2, c), 7,56 (1H×1/2, c), of 7.75 (1H×1/2, c), 7,83-7,88 (1H, m), 8,00 (2H×1/2, d, J=8.6 Hz), 8,00 (2H×1/2, d, J=8.6 Hz), of 8.37 (1H×1/2, d, J=8.6 Hz), 8,39 (1H×1/2, d, J=8.6 Hz), 8,61 (1H×1/2, d, J=5.5 Hz), 8,64 (1H×1/2, d, J=5.3 Hz), 10,57 (1H×1/2, USS), 10,66 (1H×1/2, USS).

ESI-MASS (m/e): 467 (M+H).

Example 57

1-[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]-1-ethanol

Stage 1. Obtain methyl 5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-carboxylate and methyl 6-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-carboxylate:

Aldehyde compound, polucen the e in example 1 (stage 8), processed according to the process described in J. Org. Chem. 64(4), 1191 (1999), receiving the target connection. Using 4-(methylsulphonyl)phenol obtained in reference example 1, a target compound can also be obtained in the same way as in example 19 (stage 5, stage 6), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtaining 1-(5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)-1-ethanol or 1-(6-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)-1-ethanol:

400 mg of the obtained complex methyl ester was dissolved in 4 ml of tetrahydrofuran, was added 4 ml of methanol and 1.5 ml of 5 N. aqueous sodium hydroxide solution and stirred at room temperature for 3 hours. The mixture was neutralized aqueous 10% citric acid solution, extracted with ethyl acetate and washed with saturated saline solution. The mixture was dried over anhydrous magnesium sulfate and the solvent evaporated, getting 376 mg solid yellow color.

376 mg of the obtained solid yellow substance was dissolved in 5 ml of dimethylformamide, was added to 0.29 ml of triethylamine, 205 mg of the hydrochloride of N,O-dimethylhydroxylamine, 284 mg of the monohydrate of 1-hydroxybenzotriazole and 205 mg of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and was stirred over night at room temperature. Added water to the reaction liquid was diluted with ethyl acetate and the organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, then the solvent is evaporated and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1-3/1-1/1)to give 347 mg of the amorphous substance of white color.

110 mg of the amorphous substance of white color was dissolved in 2 ml of tetrahydrofuran at -78°C was added 0,76 ml metallyte (1,02M solution in diethyl ether) and stirred at -78°C for 30 minutes. Was added a saturated aqueous ammonium chloride, diluted with ethyl acetate and the organic layer was washed with saturated saline solution. It was dried with anhydrous magnesium sulfate, the solvent evaporated and the residue was purified separating thin-layer chromatography (Kieselgel™ 6OF254, Art 5744 (Merck), hexane/ethyl acetate = 1/2)to give to 66.3 mg of target compound in the form of oil is light yellow in color.

Stage 3. Obtaining 1-(5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)-1-ethanol or 1-(6-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)-1-ethanol:

20 mg obtained acetyl compounds were dissolved in 0.5 ml of methanol was added 20 mg of sodium borohydride and stirred at room themes is the temperature value within 15 minutes. The reaction liquid was diluted with ethyl acetate and washed with saturated saline solution. The mixture was dried with anhydrous magnesium sulfate, the solvent evaporated and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 20/1), getting to 18.3 mg of target compound as a colourless oil.

Stage 4. Obtaining 1-[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]-1-ethanol:

18,3 mg of the obtained product was dissolved in 1 ml triperoxonane acid and stirred at room temperature for 2 hours. The solvent is evaporated, the residue was neutralized with triethylamine and purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 11.2 mg of the target compound in a solid white color.

1H-NMR (CDCl3) δ: 1,53 (3H, m), 3,06 (3H, c), is 5.18 (1H, m), 7,05-7,10 (2H+1/2H, m), 7,40 (1H+1/2H, m), 7,80 (1/2N, c), 7,82-of 7.90 (2H, m), 8,10 (1/2N, c)of 8.37-8,43 (1H, m)8,64 (1H, m), 10,6 (1/2H, ush.), 10,8 (1/2H, ush.).

ESI-MASS (m/e): 410 [M+H].

Example 58

Triptorelin 1-[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]-1,2-ethanediol

Using dialogue compound obtained in example 1 (stage 7), the target compound was obtained in the same manner as in example 57 (stage 4), or in accordance with this method, or its combination with a customary method.

1 H-NMR (CD3OD) δ: 2,69 (1H, USS), 3,17 (3H, c), 3,62-to 3.67 (1H, m), 3,82-a 3.83 (1H, m), 5,12-5,13 (1H, m), 7,27-7,29 (2H, m), 7,42 (1H, c), to 7.67-7,71 (1H, m), 8,00-8,02 (2H, m), 8,14-8,17 (2H, m), 8,32-to 8.34 (1H, m), 8,89 (1H, m).

ESI-MASS (m/e): 410 [M+H].

Example 59

[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methanol

Using dialogue compound obtained in example 1 (stage 7), the target compound was obtained in the same manner as in example 57 (stage 4), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 3,18-3,19 (3H, m), 4,48-4,51 (2H, m), 5,18-5,19 (1/2H, m), to 5.21-5,28 (1/2H, m), 7,05-7,13 (2H, m), 7,40 (1H, c), 7,51-of 7.55 (1H, m), of 7.75 (1H, c), 7,86-of 7.90 (2H, m), 7,98-8,02 (1H, m), 8,29-to 8.34 (1H, m,), 8,72 is 8.75 (1H, m), 13,12 (1/2H, USS), 13,25 (1/2H, USS).

ESI-MASS (m/e): 396 (M+H).

Example 60

N-Methyl-N-{1-[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl]-1H-benzimidazole-6-yl]ethyl}amine

Stage 1. Obtaining N-1-[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl]ethyl-N-methylamine or N-1-[6-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl]ethyl-N-methylamine:

33 mg of acetyl compound obtained in example 57 (step 2), was dissolved in 0.2 ml of methanol was added 0.2 ml of methylamine (40% solution in methanol)was added a solution of 41 mg of zinc chloride in methanol and 38 mg of centripetality sodium and stirred at room te is the temperature for 6 hours. Was added 10% aqueous citric acid solution, neutralized aqueous sodium bicarbonate and was extracted with ethyl acetate. Wednesday was dried with anhydrous magnesium sulfate and the solvent evaporated, receiving 30 mg of target compound in the form of a yellow oil.

Stage 2. Obtaining N-methyl-N-{1-[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]ethyl}amine:

Using the obtained oil, the target compound was obtained in the same manner as in example 57 (stage 4), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,36 (3H, m), is 2.30 (3H, c), of 3.07 (3H, c), 3,98 (1H, m), was 7.08 (2H+2/5H, m), 7,39 (1H, m), 7,45 (3/5H, m), 77,75 (3/5H, m), 7,88 (3H, m), 7,98 (2/5H, m), 8,40 (1H, m), 8,65 (1H, m).

ESI-MASS (m/e): 423 (M+H).

Example 61

N-Methyl-N-{1-[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]ethyl}ndimethylacetamide

Stage 1. Obtaining N-methyl-N-(1-[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl]ethyl)ndimethylacetamide or N-methyl-N-(1-[6-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl]ethyl)ndimethylacetamide:

30 mg of N-methylamine obtained in example 60 (stage 1), was dissolved in 0.3 ml of chloroform, was added 15 μl of triethylamine and 8 ml of acetylchloride and stirred at room temperature for 30 minutes. Added water, diluted what dilatatum and washed with a saturated saline solution. The mixture was dried with anhydrous magnesium sulfate, the solvent evaporated and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 20/1), receiving of 19.1 mg of colorless oil.

Stage 2. Obtaining N-methyl-N-{1-[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]ethyl}ndimethylacetamide:

Using the obtained oil, the target compound was obtained in the same manner as in example 57 (stage 4), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.55 (3H, d, J=7,0 Hz)to 1.86 (3H, c), 2,68 (3H, c), 3,06 (3H, c), 6,03 (1H, m), 6,98 (2H, d, J=8,9 Hz), 7,33 (1H, c), 7,56 (1H, m), a 7.85 (2H, d, J=8,9 Hz), of 7.90-of 8.06 (2H, m), 8,53 (1H, m), 8,71 (1H, m).

ESI-MASS (m/e): 465 [M+H].

Example 62

N,N-Dimethyl-N-{1-[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]ethyl}amine

Using N,N-dimethylamine, the target compound was obtained in the same manner as in example 60 (stage 1), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,33 (3H, m), of 2.20 (6H, m), of 3.07 (3H, c), 3,57 (3/5H, m), 3,71 (2/5H, m), 7,07 (2H, m), 7,14 (2/5H, c), 7,39 (1H, m), 7,45 (3/5H, c)7,75 (3/5H, c), 7,84-of 7.90 (3H, m), 8,02 (2/5H, c), to 8.40 (1H, m), 8,65 (1H, m), and 10.5 (1H, ush.).

ESI-MASS (m/e): 437 [M+H].

Example 63

1-{1-[5-[4-(Methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]ethyl}pyrrolidin-2,5-dione

Using the alcohol compound polucen the e in example 57 (step 3), the target compound was obtained in the same manner as in example 1 (stage 10), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,79 (3H, m), 2,10-of 2.28 (2H, m), 2,28-to 2.40 (2H, m), 3,06 (3H, c)5,69 (1H, m), 7,00 (2H, m), 7,42 (1H+1/2H, m), 7,80-8,00 (3H+1/2H, m), 8,20-of 8.50 (2H, ush.), 8,67 (1H, m), and 10.8 (1H, ush.).

ESI-MASS (m/e): 491 [M+H].

Example 64

{5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}(4-forfinal)methanol

Stage 1. Getting 5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-carbaldehyde and 6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-carbaldehyde:

5 ml of triethylamine and 750 mg of pyridine-sulfur trioxide was added to a solution of 1.0 g of the alcohol compound obtained in example 19 (step 7), in dimethyl sulfoxide (10 ml) and the reaction liquid was stirred at room temperature for 15 minutes. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline solution in this order and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining 1.0 g of target compound in the form of a solid orange color.

Stage 2. Receive {5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl}(4-forfinal)met the Nola or {6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl}(4-forfinal)methanol :

At 0°C, 0.5 ml of 4-performancebased (1M solution in tetrahydrofuran) was added to a solution of 45 mg of the obtained aldehyde in tetrahydrofuran (1 ml) and the reaction liquid was stirred for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and saturated saline solution in this order and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 1/2)to give 35 mg of the target compound as a colorless solid.

Stage 3. Receive {5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}(4-forfinal)methanol:

20 mg of the obtained product was dissolved in 1 ml triperoxonane acid and the reaction liquid was stirred at room temperature for 3 hours. The solvent is evaporated and the residue was purified liquid chromatography medium pressure reverse phase [ODS-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triperoxonane acid]. The solvent of the obtained fractions was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining 5.4 mg of the target joint is in the form of a colorless solid.

1H-NMR (CD3OD) δ: 1,24 (3H, t, J=7.4 Hz), 3,18 (2H, q, J=7.4 Hz), equal to 6.05 (1H, c), 6,88-to 6.95 (4H, m), 7,20-7,42 (1H, m), 7,30 (2H, DD, J=8,2, 5,5 Hz), of 7.48-7,53 (1H, m), 7,76 (2H, d, J=8.6 Hz), to 7.99 (1H, t, J=8.0 Hz), 8,02-to 8.20 (1H, m), 8,28-to 8.34 (1H, m), 8,73-8,78 (1H, m).

ESI-MASS (m/e): 504.

Example 65

5-[4-(Ethylsulfonyl)phenoxy]-6-(4-terbisil)-2-(2-pyridinyl)-1H-benzimidazole

0.5 ml of triethylsilane was added to a solution of 4.9 mg of the alcohol compound obtained in example 64 (stage 2), triperoxonane acid (0.2 ml) and the reaction liquid was stirred overnight at room temperature. The solvent is evaporated under reduced pressure and the residue was purified liquid chromatography medium pressure reverse phase [ODS-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triperoxonane acid]. The solvent of the obtained fractions was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, getting to 5.5 mg of target compound in the form of a solid of light yellow color.

1H-NMR (CD3OD) δ: 1,17 (3H, t, J=7.4 Hz), of 3.12 (2H, q, J=7.4 Hz), of 3.96 (2H, c), 6,83 (2H, t, J=8,8 Hz), 6,92 (2H, d, J=9.0 Hz), to 7.09 (2H, DD, J=8,8, 5.0 Hz), 7,27 (1H, c), the 7.43 (1H, DD, J=7,0, 5.0 Hz), 7,58 (1H, c), 7,72 (2H, d, J=9.0 Hz), 7,92 (1H, t, J=7.4 Hz), by 8.22 (1H, d, J=7,4 Hz), 8,68 (1H, d, J=5.0 Hz).

ESI-MASS (m/e): 488.

Example 66

{5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzoni the azole-6-yl}(4-forfinal)metano

0.1 ml of triethylamine and 15 mg of pyridine-sulfur trioxide was added to a solution of 15 mg of the alcohol compound obtained in example 64 (stage 3), in dimethyl sulfoxide (0.2 ml) and the reaction liquid was stirred at room temperature for 20 minutes. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline solution in this order and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to give crude product. The resulting crude product was dissolved in 1 ml triperoxonane acid and the reaction liquid was stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure and the residue was purified liquid chromatography medium pressure reverse phase [ODS-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triperoxonane acid]. The solvent of the obtained fractions was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining 7.9 mg of the target compound as a colorless solid.

1H-NMR (CD3OD) δ: of 1.18 (3H, t, J=7.4 Hz), and 3.16 (2H, q, J=7.4 Hz), 6,93-6,99 (2H, m), 7,18 (2H, t, J=8.6 Hz), 7,40-of 7.60 (2H, m), to 7.77 (2H, d, J=8.6 Hz), 7,82 (2H, DD, J=8,4, a 5.3 Hz), 7,84-8,00 (1H, m), 8,02 (1H, t, J=7,6 Hz), 8,35 (1H, d, J=7,6 Hz), 8,77-8,80 (1H, m).

ESI-MASS (m/e): 502.

Prima is 67

(2-Forfinal)[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methanol

Stage 1. Receive {5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl}(2-forfinal)methanol or {6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl}(2-forfinal)methanol:

Using aldehyde compound obtained in example 1 (stage 8), and 2-performancebased, the target compound was obtained in the same manner as in example 64 (stage 2), or in accordance with this method, or its combination with a customary method.

Stage 2. Receive (2-forfinal)[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methanol:

Using the resulting product, the target compound was obtained in the same manner as in example 64 (stage 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 3,05 (3H, c), to 6.39 (1H, c), at 6.84 (1H, c), 6,85 (2H, d, J=8.7 Hz), 6,98-7,02 (1H, m), 7,10-to 7.15 (1H, m), 7,25-7,31 (3H, m), 7,49-7,53 (1H, m), of 7.75 (2H, d, J=8.7 Hz), 7,97 shed 8.01 (1H, m), 8,15 (1H, c), and 8.50 (1H, d, J=8.0 Hz), 8,73 (1H, d, J=5,1 Hz).

ESI-MASS (m/e): 490 (M+H).

Example 68

(2-Bromophenyl)[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methanol

Using aldehyde compound obtained in example 1 (stage 8), and 2-bromophenylacetate, target the the group received the same way as in example 64 (stage 2, stage 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 3.15 in (3H, c), of 6.20 (1H, c), 6,95-of 7.60 (2H, m), of 6.96 (2H, d, J=8.5 Hz), 7,08-7,13 (1H, m), 7,29-7,33 (1H, m), a 7.62 (1H, d, J=8,2 Hz), 7,49-7,53 (1H, m), to 7.67 (1H, c), to 7.77 (2H, d, J=8.5 Hz), of 7.96-8,00 (1H, m), 8,27-8,31 (1H, m), 8,70-8,72 (1H, m).

ESI-MASS (m/e): 550, 552 (M+H).

Example 69

6-(2-Terbisil)-5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole

Using aldehyde compound obtained in example 67 (stage 1), the target compound was obtained in the same manner as in example 65, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 3,06 (3H, c), 4,00-of 4.05 (2H, m), of 6.96-7,02 (3H, m), 7,08-7,17 (2H, m), 7,25-7,28 (1H, m), 7,37-the 7.43 (1H, m), 7,53-7,58 (1H, m), 7.68 per-7,80 (1H, m), 7,80-7,94 (3H, m), scored 8.38-8,55 (1H, m), 8,60 is 8.75 (1H, m).

ESI-MASS (m/e): 474 (M+H).

Example 70

1-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1H-benzimidazole-7-yl}methyl)pyrrolidin-2,5-dione

Stage 1. Obtain methyl 5-fluoro-2-nitrobenzoate:

2 ml of concentrated sulfuric acid was added to a solution of 10 g of 5-fluoro-2-nitrobenzoic acid in methanol (200 ml) and was heated under reflux for 22 hours. Was added 200 ml of an aqueous solution of sodium bicarbonate and the resulting solid product was separated by filtration. It was dried under reduced pressure, obtaining 10.7 g of the target joint is in a solid yellow color.

Stage 2. Obtain methyl 5-[4-(ethylsulfonyl)phenoxy]-2-nitrobenzoate:

11 g of potassium carbonate was added to the solution in dimethylformamide (150 ml) 10.7 g of methyl 5-fluoro-2-nitrobenzoate and 11.1 g of 4-(ethylsulfonyl)phenol obtained in reference example 2, and stirred at 80°C for 90 minutes. The reaction liquid was allowed to cool to room temperature, then added 300 ml of water and the resulting solid product was separated by filtration. It was dried under reduced pressure, obtaining of 19.7 g of target compound in the form of a solid creamy white color.

Stage 3. Obtain methyl 2-amino-5-[4-(ethylsulfonyl)phenoxy]benzoate:

0.7 g of Raney Nickel was added to the solution 6,98 g of methyl 5-[4-(ethylsulfonyl)phenoxy]-2-nitrobenzoate in methanol (150 ml) and was stirred overnight in a hydrogen atmosphere. The catalyst was removed by filtration, the solvent evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 2/1 to 1/1)to give 2.65 g of the target compound as a colourless oil.

Stage 4. Obtain methyl 5-[4-(ethylsulfonyl)phenoxy]-2-[(2-pyridylcarbonyl)amino]benzoate:

While cooling on ice and 4.4 ml of triethylamine and 2.8 g of the hydrochloride of the acid chloride pikolinos acid was added to a solution of 2.65 g of methyl 2-amino-5-[4-(ethylsulfonyl)f is noxy]benzoate in chloroform (30 ml) and stirred at room temperature for 90 minutes. Aqueous saturated solution of sodium bicarbonate was added to the reaction liquid was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 2/1 to 1/1)to give 1.9 g of the target compound in the form of a solid creamy white color.

Stage 5. Obtain methyl 5-[4-(ethylsulfonyl)phenoxy]-3-nitro-2-[(2-pyridylcarbonyl)amino]benzoate:

to 1.9 g of methyl 5-[4-(ethylsulfonyl)phenoxy]-2-[(2-pyridylcarbonyl)amino]benzoate was dissolved in 20 ml triperoxonane acid, was added 2.2 g of potassium nitrate and stirred at 80°C for 2 hours. The reaction liquid was allowed to cool to room temperature, triperoxonane acid evaporated under reduced pressure, the residue was dissolved in chloroform and was added saturated aqueous solution of sodium bicarbonate. Was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 2/1 to 1/1)to give 1.86 g of the target compound in a solid yellow color.

:

1.86 g of methyl 5-[4-(ethylsulfonyl)phenoxy]-3-nitro-2-[(2-pyridylcarbonyl)amino]benzoate suspended in 15 ml of dimethylformamide and 15 ml of methanol, was added 4.3 g of dihydrate of tin chloride(II) and 11 ml of concentrated hydrochloric acid and stirred at 80°C for 81 hours. The reaction liquid was allowed to cool to room temperature, then was gradually added an aqueous solution of sodium bicarbonate to neutralize it. Added ethyl acetate and stirred at room temperature for 30 minutes. The obtained salt was removed by filtration, the filtrate was extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated, getting 1.44 g of a crude product of methyl 5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1H-benzimidazole-7-carboxylate in the form of a yellow oil.

While cooling on ice to 0.87 ml of 2-(trimethylsilyl)ethoxymethylene and 197 mg of sodium hydride (with the addition of 30% liquid paraffin) was added to a solution of 1.44 g of methyl 5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1H-benzimidazole-7-carboxylate in dimethylformamide (15 ml) and peremeshivaniya room temperature for 30 minutes. When cooled on ice was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 1/1), receiving of 1.34 g of target compound in the form of a brown oil.

Stage 7. Obtain (6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-yl)methanol and (5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-7-yl)methanol:

While cooling on ice, a solution of 113 mg of lithium aluminum hydride and 681 mg of the above ester compounds in tetrahydrofuran (5 ml) was gradually added to 5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 15 minutes, then was gradually added 10-hydrate of sodium sulfate to stop foaming, was added ethyl acetate and stirred at room temperature for 1 hour. The obtained salt was removed by filtration and the solvent evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform/methanol = 100/0 to 100/5)to give 519 mg of the target compound in the form of a yellow oil is about color.

Stage 8. Obtaining 1-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1H-benzimidazole-7-yl}methyl)pyrrolidin-2,5-dione:

Using the obtained alcohol compound, the target compound was obtained in the same manner as in example 1 (stage 10), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.32 (3H, t, J=7.4 Hz), 2,80 (4H, c), of 3.13 (2H, q, J=7.4 Hz), 4,94 (2H, c), 7,10 (2H, d, J=9.4 Hz), 7.23 percent (1H, d, J=9.4 Hz), 7,40-7,42 (1H, m), 7,53-rate of 7.54 (1H, m), a 7.85-7,88 (3H, m), scored 8.38 (1H, t, J=the 4.5 Hz), 8,80 (1H, DD, J=3,9, 0.8 Hz), for 11.55 (1H, USS).

ESI-MASS (m/e): 491 (M+H).

Example 71

Methyl 5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1H-benzimidazole-7-carboxylate

Using the product obtained in example 70 (stage 6), the target compound was obtained in the same manner as in example 57 (stage 4), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.27 (3H, t, J=7.4 Hz), 3,11 (2H, q, J=7.4 Hz), Android 4.04 (3H, s), to 7.09 (2H, DD, J=7,0, 2.0 Hz), 7,40-the 7.43 (1H, m), 7,71 (1H, d, J=2.3 Hz), 7,76 (1H, d, J=2.3 Hz), 7,82-of 7.90 (3H, m), 8,39 (1H, d, J=7,8 Hz), to 8.70 (1H, d, J=5,1 Hz), 11,36 (1H, USS).

ESI-MASS (m/e): 438 (M+H).

Example 72

[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1H-benzimidazole-7-yl]methanol

Using the product obtained in example 70 (stage 7), the target compound was obtained in the same manner as in example 57 (stage 4), or in accordance with this method, or its combination with conventional the way.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=11,1 Hz), 3,14 (2H, q, J=11,1 Hz), 5,12-5,16 (2H, m)6,94 (1H, d, J=20.7 Hz), 7,07 for 7.12 (2H, m), 7,17 (1/2H, d, J=2.0 Hz), 7,39 (1H, DD, J=18.2, and to 10.7 Hz), of 7.48 (1/2N, c), 7,84-7,89 (3H, m)to 8.41 (1H, d, J=7.8 Hz), 8,66-8,67 (1H, m), to 10.62 (1/2H, USS), 11,02 (1/2H, USS).

ESI-MASS (m/e): 410 (M+H).

Example 73

5-[4-(Ethylsulfonyl)phenoxy]-7-(methoxymethyl)-2-(2-pyridyl)-1H-benzimidazole

In a bath with ice 12 µl under the conditions and 7.8 mg of sodium hydride (with the addition of 30% liquid paraffin) was added to a solution of 53 mg of the product obtained in example 70 (stage 7), in DMF (1 ml) and stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction liquid was extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure to give crude product as brown oil. The obtained product was treated in the same manner as in example 57 (stage 4), or in accordance with this method, or its combination with the conventional method, and thus, the target connection.

1H-NMR (CDCl3) δ: of 1.27 (3H, t, J=7.4 Hz), 3,10 (2H, q, J=7.4 Hz), 3,51 (9/4H, c), 3,53 (3/4H, c), 4,81 (3/2H, c), 5,02 (1/2N, c), of 6.90 (1H, c), 7,09 for 7.12 (2H, m), 7,38-7,39 (1H, m), 7,47 (1H, c), 7,82-7,86 (3H, m), 8,39 (3/4H, d, J=7.8 Hz), 8,43 (1/4H, d, J=7.8 Hz), 8,61 (1/4H, s, J=4,7 Hz), 8,67 (3/4H, d, J=7.8 Hz), 10,67 (1/4H, USS), 10,81 (3/4H, USS).

ESI-MASS (m/e 424 (M+H).

Example 74

5-[4-(Ethylsulfonyl)phenoxy]-7-(2-phenoxymethyl)-2-(2-pyridyl)-1H-benzimidazole

Using the product obtained in example 70 (stage 7), and phenol, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.32 and 1.33 (3H, m), of 3.12 (2H, q, J=7.5 Hz), 5,41 (1H, c), 5,69 (1H, c), 6,82-6,76 (1/2H, m), 7,02-7,06 (5H, m), 7,30-7,42 (4H, m), 7,54-7,56 (1/2H, m), 7,83-7,89 (3H, m), to 8.41-8,44 (1H, m), 8,69-8,72 (1H, m), 10,75 (1/2H, USS), 10,90 (1/2H, USS).

ESI-MASS (m/e): 486 (M+H).

Example 75

N-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridyl]-1H-benzimidazole-7-yl]methyl}-N,N-dimethylamine

Using the product obtained in example 70 (stage 7), and dimethylamine, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 to 1.31 (3H, m), 2,33 (6H, c), of 3.07-3.15 in (2H, m), 3,76 (2H, c), of 6.90 (1H, c), 7,11 (2H, d, J=9.4 Hz), 7,39-7,41 (1H, m), 7,46 (1H, c), 7,82-of 7.90 (3H, m), 8,42 (1H, d, J=8,2 Hz), 8,71 (1H, d, J=4,3 Hz).

ESI-MASS (m/e): 437 (M+H).

Example 76

7-(2,6-Diferensial)-5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl]-1H-benzimidazole

Stage 1. Obtain 6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-carbaldehyde and 5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-7-Carballeda the IDA :

Using the product obtained in example 70 (stage 7), the target compound was obtained in the same manner as in example 64 (stage 1), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain {6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1-{[2-trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-yl}(2,6-differenl)methanol or {5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1-{[2-trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-7-yl}(2,6-differenl)methanol:

Using the obtained aldehyde, 2,6-differenlty obtained according to the method described in Journal of The American Chemical Society, 1966, Vol.31, p.746, the target compound was obtained in the same manner as in example 64 (stage 2), or in accordance with this method, or its combination with a customary method.

Stage 3. Obtain 7-(2,6-diferensial)-5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1H-benzimidazole:

Using the obtained alcohol compound, the target compound was obtained in the same manner as in example 65, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,24-of 1.33 (3H, m), of 3.12 (2H, q, J=25 Hz), 4,17 (1H, c), 4,59 (1H, c), 6,93 (1H, c), 7,03-7,06 (3H, m), 7,19 (1H, m), 7,39-of 7.48 (2H, m), 7,81-to 7.84 (4H, m), 8.34 per-8,44 (1H, m), 8,59-8,67 (1H, m).

ESI-MASS (m/e): 506 (M+H).

Example 77

7-(4-Terbisil)-5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridyl)-1H-benzimidazole

Using legalnoe connection, obtained in example 76 (stage 1), and 4-forperformance, the target compound was obtained in the same manner as in example 76 (stage 2, stage 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.27 (3H, t, J=13,8 Hz), 3,10 (2H, q, J=13,8 Hz)to 4.23 (1H, c), of 4.44 (1H, c), 6,72 (1H, c), 6,85 (1H, c), 6,97-7,01 (4H, m), 7,21 (1/2H, m), 7,34-7,38 (2H, m), 7,43 (1/2H, m), 7,81-a 7.85 (3H, m), 8,39-8,44 (1H, m), 8,61 (1H, c), or 10.60 (1H, USS).

ESI-MASS (m/e): 488 (M+H).

Example 78

1-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridyl]-1H-benzimidazole-7-yl}methyl)-2-pyrrolidinone

Using the product obtained in example 70 (stage 7), the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,27-of 1.42 (3H, m), 2.00 in to 2.13 (2H, m), of 2.51 (2H, m), of 3.13 (2H, q, J=8,3 Hz), 3.43 points-of 3.50 (2H, m), of 4.67 (2H, c), 6,93 (1H, d, J=2.0 Hz), 7,10 (2H, d, J=18,0 Hz), 7,38 (1H, DD, J=7,0, a 4.3 Hz), 7,53 (1H, c), 7,86-7,88 (3H, m), 8,39 (1H, d, J=9,2 Hz), 8,79-8,82 (1H, m), 12,04 (1H, s).

ESI-MASS (m/e): 477 (M+H).

The structure of the compounds of examples 1-78 shown in tables 6-8.

Table 6

Table 7

Table 8

Example 79

6-[(Ethylsulfonyl)methyl]-5-[4-(ethylsulfonyl)phenoxy]-2-pyridinyl)-1H-b is Intimidator

Stage 1. Getting 5-[4-(ethylsulfonyl)phenoxy]-6-[(ethylthio)methyl]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole and 6-[4-(ethylsulfonyl)phenoxy]-5-[(ethylthio)methyl]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole:

While cooling on ice, 15 μl of methanesulfonamide was added to a solution of 50 mg of the alcohol compound obtained in example 19 (step 7), and 26 μl of triethylamine in tetrahydrofuran (0.5 ml) and was stirred for 30 minutes. Added ice water, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure, obtaining the amorphous substance of light-yellow color.

While cooling on ice 11 mg of sodium hydride (with the addition of 30% liquid paraffin) was added to a solution of the obtained amorphous substance and 15 ál ethanthiol in dimethylformamide (0.5 ml) and stirred at room temperature for 1 hour. When cooled on ice was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1), getting to 15.5 mg of the target compound.

<> Stage 2. Obtain 6-[(ethylsulfonyl)methyl]-5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole:

of 0.67 ml 0,4M oxone in methanol was added to a solution of 15.5 mg of the oil obtained in stage 1, in methanol (0.6 ml) and stirred at room temperature for 2 hours. The insoluble substance was removed by filtration, the filtrate was diluted with chloroform and washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure, obtaining an amorphous yellow substance.

The obtained amorphous yellow substance was dissolved in 1 ml triperoxonane acid and stirred at room temperature for 1 hour. The solvent is evaporated, the residue was neutralized with triethylamine and purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 9.8 mg of target compound in the form of a solid of light yellow color.

1H-NMR (CDCl3) δ: is 1.31 (3H, t, J=7.5 Hz), of 1.39 (3H, t, J=7.0 Hz), 2,98 (2H, q, J=7.5 Hz), of 3.13 (2H, q, J=7.0 Hz), 4,39 (2H×1/2, c)to 4.41 (2H×1/2, c), 7,10-7,20 (3H+1/2H, m), 7,42 (1H, m), 7,47 (1/2N, c), 7,81 (1/2N, c), 7,88 (3H, m), 8,02 (1/2N, c), scored 8.38 (1H, m), 8,67 (1H, m), 10,7 (1/2H, ush.), 10,8 (1/2H, ush.).

ESI-MASS (m/e): 486 (M+H).

Example 80

1-{[5-[4-(Isopropylphenyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Stage 1. Getting 6-({[tert-butyl(dimethyl)forces the l]oxy}methyl}-5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole and 5-({[tert-butyl(dimethyl)silyl]oxy}methyl}-6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole :

34 mg of imidazole and 30 mg of tert-butyl(dimethyl)similiarity was added to a solution of 100 mg of the alcohol compound obtained in example 19 (step 7), in N,N-dimethylformamide (2 ml) and was stirred over night at room temperature. When cooled on ice was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate)to give 69 mg of the target compound in the form of a yellow oil.

Stage 2. Getting 6-({[tert-butyl(dimethyl)silyl]oxy}methyl}-5-[4-(isopropylphenyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole and 5-({[tert-butyl(dimethyl)silyl]oxy}methyl}-6-[4-(isopropylphenyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole:

In a nitrogen atmosphere at -78°C, 1 ml 0,126M solution diisopropylamide lithium in tetrahydrofuran, which was previously prepared, was added to a solution of 69 mg simple salelologa ester obtained in stage 1, in tetrahydrofuran (1 ml) and was stirred at this temperature for 30 minutes. At -78°C was added dropwise a solution of 45 mg iodomethane in tetrahydrofuran (1 ml) and dopolnitelnyefunktsii for 1 hour. Then it gradually warmed up to 0°C was added aqueous saturated solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), developing solvent: hexane/ethyl acetate = 1/1)to give 30 mg of the target compound in the form of a yellow oil.

Stage 3. Receive (5-[4-(isopropylphenyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol and (6-[4-(isopropylphenyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanol:

While cooling on ice 49 μl of 1.0m solution of tetrabutylammonium in tetrahydrofuran was added dropwise to a solution of 30 mg simple salelologa ester obtained in stage 2, in tetrahydrofuran (1 ml) and was stirred for 10 minutes. Was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer washed with phosphate buffer (pH 7.0). After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), developing solvent: hexane/ethyl acetate = 1/2)to give 24 mg of the target compound in the form of messagelog color.

Stage 4. Obtain 1-{[5-[4-(isopropylphenyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone:

Using the alcohol product obtained in stage 3, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.30 (6H, d, J=7,0 Hz), 1,88 is 1.96 (2H, m), 2,29-of 2.36 (2H, m), 3,17 (1H, septet, J=7.0 Hz), 3,26-and 3.31 (2H, m), 4,53 (2H×1/2, c), of 4.54 (2H×1/2, c),? 7.04 baby mortality (2H×1/2, d, J=9.0 Hz), 7,06 (2H×1/2, d, J=9.0 Hz), 7,17 (1H×1/2, c), 7,37-7,41 (1H, m), of 7.48 (1H×1/2, c), 7,56 (1H×1/2, c), 7,76 (1H×1/2, c), 7,80 (2H×1/2, d, J=9.0 Hz), 7,80 (2H×1/2, d, J=9.0 Hz), 7,84-of 7.90 (1H, m), at 8.36-to 8.41 (1H, m), 8,62-8,66 (1H, m), 10,66 (1H×1/2, USS), of 10.73 (1H×1/2, USS).

ESI-MASS (m/e): 491 (M+H).

Example 81

4-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)morpholine-3-one

Using the alcohol compound obtained in example 19 (step 7), and morpholine-3-one (obtained according to the method described in US 5349045), the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7.4 Hz), 3,11 (2H, q, J=7,4 Hz)to 3.34 (2H, m), 3,81 (2H, m), is 4.15 (2H, m), 4.72 in (2H, m), 7,07 (2H, m), 7,18 (1/2N, c), 7,40 (1H, m), 7,49 (1/2N, c), 7,68 (1/2N, c), 7,80-of 7.90 (1H+1/2H, m), to 7.84 (2H, d, J=8,8 Hz), 8,39 (1H, m), 8,66 (1H, m), 10,7 (1/2H, ush.), 10,8 (1/2H, ush.).

ESI-MASS (m/e): 493 (M+H).

Example 82

1-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridine) - Rev. l)-1H-benzimidazole-6-yl}methyl)-1H-imidazol-2-carbonitril

Stage 1. Getting 2-renominate:

This compound was obtained according to the method described in WO 2003/011836.

Stage 2. Obtaining 1-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)-1H-imidazol-2-carbonitrile:

Using the alcohol compound obtained in example 19 (step 7), and 2-cyanomelana, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,31 (3H, m), of 3.13 (2H, m), 5,41 (2H, c), 7,00-to 7.15 (4H+1/2H, m), 7,42 (1H, m), 7,47 (1/2H, m), 7,55 (1/2N, c), 7,80-of 7.95 (3H+1/2H, m), 8,39 (1H, m), 8,65 (1H, m), 10,75 (1/2H, ush.), 10,83 (1/2H, ush.).

ESI-MASS (m/e): 485 (M+H).

Example 83

N-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl]ndimethylacetamide

Stage 1. Obtain N-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl}methyl)ndimethylacetamide or N-({6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl}methyl)ndimethylacetamide:

21 ál acetylchloride was added to a solution of 81.5 mg amine, obtained in example 31 (stage 1), and 42 μl of triethylamine in chloroform (0.8 ml). The mixture was stirred for 30 minutes, was added saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate and the organic layer was washed with saturated saline rest the rum. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform-chloroform/methanol = 20/1)to give 82 mg of the target compound as a yellow oil.

Stage 2 Receive N-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)ndimethylacetamide:

12 mg of the obtained yellow oil was dissolved in 0.5 ml triperoxonane acid and stirred at room temperature for 2 hours. The solvent is evaporated, the residue was neutralized with triethylamine and purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 9.8 mg of target compound in the form of a solid of light yellow color.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7.4 Hz), 1,95 (3H, c), the 3.11 (2H, q, J=7.4 Hz), 4,49 (2H, m), of 5.83 (1/2H, ush.), 5,97 (1/2H, ush.), 7.15m (1/2N, c), 7,40 (1H, m), 7,46 (1/2N, c), 7,65 (1/2N, c), a 7.85 (3H+1/2H, m), 8,39 (1H, m), 8,65 (1H, m), 10,7 (1/2H, ush.), 10,8 (1/2H, ush.).

ESI-MASS (m/e): 451 (M+H).

Example 84

N-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)-N-methylacetamide

While cooling on ice 18 µl under the conditions and 5.2 mg of sodium hydride (with the addition of 30% liquid paraffin) was added to a solution of 38 mg of ndimethylacetamide, obtained in example 83 (stage 1), in dimethylformamide (0.3 ml). The mixture was stirred at room temperature for 2 cha is s, then was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure, getting to 18.1 mg of yellow oil.

0.5 ml triperoxonane acid was added to 18,1 mg of the obtained yellow oil was stirred at room temperature for 2 hours. The solvent is evaporated, the residue was neutralized with triethylamine and purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 13.2 mg of target compound in the form of an amorphous substance of white color.

1H-NMR (CDCl3) δ: 1.28 (in 3H, m), 2.05 and 2,08 (total 3H, c), 2,96 and to 2.99 (total 3H, c), of 3.12 (2H, m), 4,58 and 4,66 (total 2H, m), was 7.08 (2H, m), 7,17-7,73 (total 3H, m), 7,82-of 7.90 (3H, m), 8,40 (1H, m), 8,65 (1H, m), and 10.8 (1H, ush.).

ESI-MASS (m/e): 465 (M+H).

Example 85

3-{[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-oxazolidin-2,4-dione

Using 1,3-oxazolidin-2,4-dione obtained according to the method described in JOURNAL OF MEDICINAL CHEMISTRY, 1991, Vol.34, No.5, pp.1538-1544, the target compound was obtained in the same manner as in example 19 (step 8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7.4 Hz), of 3.12 (2H, q, J=7,4 Hz)to 4.52 (2H×1/2, c), 4,59 (2H×1/2, c), to 4.81 (2H×1/2, c), a 4.83 (2H×1/2, c), 7,10 (2H, d, J=8,2 Hz, 7,11 (1H×1/2, c), 7,38-7,44 (1H, m), 7,47 (1H×1/2, c), of 7.70 (1H×1/2, c), 7,83-a 7.92 (3H, m), 7,83-a 7.92 (1H×1/2, m)of 8.37-8,42 (1H, m), 8,62-8,67 (1H, m), 10,85 (1H×1/2, USS), 10,90 (1H×1/2, USS).

ESI-MASS (m/e): 493 (M+H).

Example 86

N-Acetyl-N-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)ndimethylacetamide

Using the alcohol compound obtained in example 19 (step 7), and diacetamide, the target compound was obtained in the same manner as in example 2 or in accordance with this method or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7.4 Hz), 3,11 (2H, q, J=7.4 Hz), 2,42 (6H×1/2, c), 2,43 (6H×1/2, c)to 5.00 (2H, c), 7,11 (2H, d, J=8.6 Hz), 7,15 (1/2N, c), 7,25 (1/2N, c), 7,41 (1H, m), of 7.48 (1/2N, c), EUR 7.57 (1/2N, c), 7,88 (3H, m), scored 8.38 (1H, m)8,64 (1H, m), is 10.75 (1H, ush.).

ESI-MASS (m/e): 493 (M+H).

Example 87

5-[4-(Ethylsulfonyl)phenoxy]-6-(1H-pyrazole-1-ylmethyl)-2-(2-pyridinyl)-1H-benzimidazole

Using the alcohol compound obtained in example 19 (step 7), and pyrazole, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.4 Hz), 3,11 (2H, q, J=7.4 Hz), 5,41 (2H, c), to 6.19 (1H, c), 7,01 (2H, m), 7,11 (1/2N, c), 7,35 is 7.50 (4H, m), 7,65 (1/2N, c), 7,80 (2H, m), 7,86 (1H, m), scored 8.38 (1H, m), to 8.62 (1H, m), 10,8 (1/2H, ush.), 10,9 (1/2H, ush.).

ESI-MASS (m/e): 460 (M+H).

Example 88

5-[4-(Ethylsulfonyl)phenoxy]-6-(1H-imidazol-1-ylmethyl)-2-(2-pyridinyl)-1H-benzimidazole

Use the UYa spirit connection obtained in example 19 (step 7), and imidazole, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.34 (3H, m), of 3.13 (2H, m), 5,20 (2H, c), 6,88-7,20 (4H, m), 7,40 (1H, m), 7,45-of 7.60 (2H, m), 7,70-7,80 (1H, m), 7,80-7,94 (3H, m), 8,39 (1H, m)8,64 (1H, m), 10,7 (1/2H, ush.), 10,8 (1/2H, ush.).

ESI-MASS (m/e): 460 (M+H).

Example 89

4-[({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)amino]-4-oxomalonate acid (triptorelin)

50 mg of the final product obtained in example 19 was dissolved in 1 ml of tetrahydrofuran and 0.2 ml of water was added 60 μl of 5 n sodium hydroxide and stirred at room temperature for 1 hour. The mixture was neutralized with 2 N. hydrochloric acid, diluted with chloroform and dried with anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure and the residue was purified by medium pressure chromatography reverse phase [ODS-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triperoxonane acid]. The solvent of the resulting fraction is evaporated under reduced pressure, getting to 21.1 mg of target compound as a colorless solid.

1H-NMR (DMSO-d6) δ: of 1.12 (3H, t, J=7.5 Hz), 2,34 (2H, m), is 2.41 (2H, m), or 3.28 (2H, q, J=7.5 Hz), the 4.29 (2H, d, J=5.5 Hz), 7,14 (2H, J=8,8 Hz), 7,37 (1H, c), 7,60 (1H, m), 7,69 (1H, c), 7,87 (2H, d, J=8,8 Hz), 8,07 (N, m)to 8.34 (2H, m), 8,79 (1H, d, J=4.5 Hz).

ESI-MASS (m/e): 508 (M+H).

Example 90

N-(Cyanomethyl)-N-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)ndimethylacetamide

Stage 1. Obtain [5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methanol:

Using the alcohol compound obtained in example 19 (step 7), the target compound was obtained in the same manner as in example 57 (stage 4), or in accordance with this method, or its combination with a customary method.

Stage 2. Getting 6-(chloromethyl)-5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole:

11 μl of thionyl chloride was added to a solution of 30 mg of the obtained alcohol compound in chloroform (3 ml) and stirred at room temperature for 1 hour. The mixture was neutralized with saturated aqueous sodium bicarbonate, extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure, receiving 30 mg of target compound in the form of amorphous material, light yellow color.

Stage 3. Obtaining N-(cyanomethyl)-N-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)ndimethylacetamide:

2.1 g of acetonitrile was dissolved in 50 ml of chloroform, cooled on ice was added 5.6 ml of triethylamine and 2 ml of acetylchloride and stirred at the room for the Noah temperature for 3 hours. Was added a saturated aqueous sodium bicarbonate, extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 4/1-1/1-1/9, -chloroform/methanol)to give 0.85 grams of N-(cyanomethyl)ndimethylacetamide in the form of crystal white.

While cooling on ice, 5.2 mg of sodium hydride (with the addition of 30% liquid paraffin) was added to a solution of 21.6 mg of the obtained N-(cyanomethyl)ndimethylacetamide in dimethylformamide (0.25 ml). The mixture was stirred at room temperature for 30 minutes, the solution was added 30 mg of chloride, obtained in stage 2, in dimethylformamide (0.75 ml) and was stirred for 1 hour. Was added a saturated aqueous solution of ammonium chloride, was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 3,3 mg of target compound in the form of an amorphous substance of white color.

1H-NMR (CDCl3) δ: 1,31 (3H, m), 2,22 (3H, m)and 3.15 (2H, m), 4,10-4,30 (2H, m), and 4.75 (2H, m), 7,12-7,20 (2H+1/2H, m), 7,42 (1H, m)to 7.50 (1H, c), to 7.77 (1/2N, c), of 7.90 (3H, m), 8,39 (1H, m), 8,65 (1H, m), 10,6 (1/2N, ush.), 10,7 (1/2H, ush.)./p>

ESI-MASS (m/e): 490 (M+H).

Example 91

1-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl)-1H-pyrrole-2,5-dione

At -78°C of 0.21 ml of diethylazodicarboxylate (40% solution in toluene) was added to a solution of 50 mg of triphenylphosphine in tetrahydrofuran (0.5 ml) and was stirred for 5 minutes. At -78°C to the reaction liquid was gradually added a solution of 100 mg of the alcohol compound obtained in example 19 (step 7), in tetrahydrofuran (0.5 ml) was added 18 mg of maleimide. After dissolution of maleimido the reaction liquid was allowed to cool to room temperature and was stirred for 2 hours. The solvent is evaporated under reduced pressure and the residue was purified liquid chromatography medium pressure reverse phase [ODS-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triperoxonane acid]. The solvent of the resulting fraction is evaporated under reduced pressure, getting 11 mg of yellow oil.

11 mg of the obtained yellow oil was dissolved in 0.3 ml triperoxonane acid and stirred at room temperature for 2 hours. The solvent is evaporated and the residue was neutralized with triethylamine and purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1), getting to 4.1 mg of target compound in the form of amorphous material, light yellow color.

1H-NMR (CDCl3) δ:of 1.30 (3H, m)of 3.12 (2H, m), 4,80 (2H, c), 6,62 (2H×1/2, c), to 6.67 (2H×1/2, c), was 7.08 (2H, m), 7,13 (1/2N, c), 7,40 (1H, m), 7,46 (1/2N, c), to 7.59 (1/2N, c), 7,78 (1/2N, c), 7,80 (3H, m), of 8.37 (1H, m), 8,67 (1H, m), or 10.6 (1H, m).

ESI-MASS (m/e): 489 (M+H).

Example 92

1-[1-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl}-1H-imidazol-2-yl]alanon

Stage 1. Getting 2-acetylimidazole:

At -78°C 1.6 ml of methylacrylamide (3M solution in diethyl ether) was added to a solution of 151 mg 1H-imidazol-2-carbonitrile obtained in example 82 (stage 1), in tetrahydrofuran (3 ml) and was stirred at this temperature for 1 hour. Was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and chloroform, the organic layer was dried and the solvent evaporated under reduced pressure, getting 187 mg of the target compound in a solid yellow color.

Stage 2. Obtaining 1-[1-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl)-1H-imidazol-2-yl]ethanone:

Using the obtained 2-acetylimidazole and the alcohol compound obtained in example 19 (step 7), the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: is 1.31 (3H, t, J=7.2 Hz), 2,61 (3H×1/2, c)of 2.64 (3H×1/2, c), of 3.13 (2H, d, J=7,2 Hz), 5,71 (2H×1/2, c), 5,74 (2H×1/2, c), 7,05-to 7.15 (4H+1/2H, m), 7,32 (1/2N, c), 7,38 (1H, m), 7,41 (1/2N, c), 7,53 (1/2H, ), the 7.85 (3H, m), of 8.37 (1H, m), 8,67 (1H, m), 10,80 (1/2H, ush.), 10,82 (1/2H, ush.).

ESI-MASS (m/e): 502 (M+H).

Example 93

N-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl]-2,2,2-Cryptor-N-methylacetamide

While cooling on ice, 40 ál anhydride triperoxonane acid was added to a solution of 50 mg of the amine obtained in example 31 (stage 1), in pyridine (0.5 ml) and was stirred for 30 minutes. Added ice water, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform-chloroform/methanol = 20/1), receiving of 37.8 mg of target compound in a solid white color.

Using 25 mg of the obtained solid white color, the target compound was obtained by the same method as in example 84, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.28 (in 3H, m)3,00-3,20 (5H, m), to 4.73 (2H×1/2, c), was 4.76 (2H×1/2, c), 7,00-7,10 (2H, m), 7,19 (1/2N, c), 7,41 (1H, m), 7,50 (1/2N, c), 7,55 (1/2N, c), 7,70-of 7.90 (3H+1/2H, m), to 8.41 (1H, m), 8,64 (1H, m), and 10.8 (1H, ush.).

ESI-MASS (m/e): 519 (M+H).

Example 94

N-Ethyl-N-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl)ndimethylacetamide

Using ethyliodide, the target compound was obtained in the same way, CA is in example 84, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,13 (3H, m)of 1.29 (3H, m)2,07 (3H×1/2, c), 2,11 (3H×1/2, c), 3,11 (2H, m), 3,29 (2H×2, m)to 3.45 (2H×1/2, m), 4,56 (2H×1/2, c), of 4.66 (2H×1/2, m), 7,00-7,11 (2H+1/2H, m), 7,41 (1H+1/2H, m,), to 7.64 (1/2H, m), 7,86 (3H+1/2H, m), 8,39 (1H, m)8,64 (1H, m), and 10.8 (1H, ush.).

ESI-MASS (m/e): 479 (M+H).

Example 95

1-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl)-3-hydroxypyrrolidine-2,5-dione

Stage 1. Obtaining 1-[(5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methyl]-3-hydroxypyrrolidine-2,5-dione or 1-[(6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methyl]-3-hydroxypyrrolidine-2,5-dione:

31 mg of [5-oxo-2-(trichloromethyl)-1,3-dioxolane-4-yl]acetylchloride obtained according to the method described in Synthesis, 2002, Vol.15, pp.2165-2166, and 40 μl of pyridine was added to a solution of 54 mg of the amine obtained in example 31 (stage 1), in chloroform (0.5 ml) and stirred at 80°C for 3 hours. The reaction liquid was allowed to cool to room temperature, diluted with ethyl acetate and washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified liquid chromatography medium pressure reverse phase [ODS-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triflorum what usnei acid]. The solvent of the resulting fraction is evaporated under reduced pressure, the residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, getting to 20.8 mg of target compound in the form of colorless crystal.

Stage 2. Obtaining 1-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl)-3-hydroxypyrrolidine-2,5-dione:

20,8 mg of the obtained crystal was dissolved in 0.5 ml triperoxonane acid and stirred at room temperature for 2 hours. The solvent is evaporated, was added saturated aqueous sodium bicarbonate, extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 9.1 mg of the target compound as a colorless crystal.

1H-NMR (CDCl3) δ: of 1.27 (3H, t, J=7.2 Hz), 2,47 (1H, m), of 2.97 (1H, m), 3,23 (2H, q, J=7.2 Hz), 4,79 (1H, m), 4,88 (2H, m), 7,16 (2H, d, J=8,8 Hz), 7,35 (1H, m), 7,52 (1H, m), 7,78 (1H, m), to $ 7.91 (2H, d, J=8,8 Hz), of 8.00 (1H, t, J=8,2 Hz), 8,30 (1H, d, J=8,2 Hz), 8,76 (1H, m).

ESI-MASS (m/e): 507 (M+H).

Example 96

4-[({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)amino]-2-hydroxy-4-oxomalonate to the slot (triptorelin)

Aqueous 1 n sodium hydroxide solution was added to a solution of 50 mg of the compound obtained in example 95 (stage 1), in tetrahydrofuran (0.5 ml) and stirred at room temperature for 15 minutes. The mixture was neutralized 2 N. hydrochloric acid, then was diluted with chloroform and dried with anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure and the residue was purified by medium pressure chromatography reverse phase [OD-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triperoxonane acid]. The solvent of the resulting fraction is evaporated under reduced pressure, getting to 43.5 mg of an amorphous yellow substance.

The obtained crystal was dissolved in 1 ml triperoxonane acid and stirred at room temperature for 2 hours. The solvent is evaporated and the residue was purified by medium pressure chromatography reverse phase [ODS-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triperoxonane acid]. The solvent of the resulting fraction is evaporated under reduced pressure, getting to 19.9 mg of target compound in the form of amorphous material, light yellow color.

1H-NMR (CD3OD) δ: of 1.27 (3H, t, J=7.4 Hz), 2,59 (1H, DD, J=8,2 Hz, 14,5 Hz), 2,71 (1H, d, J=4,1, 14,5 Hz)at 3.25 (2H, q, J=7.4 Hz), 4,55 (1H, m), 4,56 (2H, m), 7,27 (2H, d, J=8,8 Hz), 7,45 (1H, c), of 7.70 (1H, m), 7,94 (1H c), of 7.97 (2H, d, J=8,8 Hz), 8,15 (1H, t, J=7,6 Hz), 8,32 (1H, d, J=7,6 Hz), of 8.90 (1H, d, J=4,7 Hz.

ESI-MASS (m/e): 507 (M+H).

Example 97

(2Z)-4-[({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)amino]-4-oxo-2-butenova acid (triptorelin)

27 mg of maleic anhydride was added to a solution of 100 mg of the amine obtained in example 31 (stage 1), in chloroform (1 ml) and stirred at room temperature for 1 hour. The solvent is evaporated and the residue was purified by medium pressure chromatography reverse phase [ODS-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triperoxonane acid]. The solvent of the resulting fraction is evaporated under reduced pressure, obtaining the level of 121.8 g of yellow oil.

40 mg of the obtained yellow oil was dissolved in 0.5 ml triperoxonane acid and stirred at room temperature for 2 hours. The solvent is evaporated and the residue was purified by medium pressure chromatography reverse phase [ODS-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triperoxonane acid]. The solvent of the resulting fraction is evaporated under reduced pressure, getting to 19.3 mg of target compound in the form of colorless crystal.

1H-NMR (DMSO-d6) δ: of 1.12 (3H, t, J=7.2 Hz), with 3.27 (2H, q, J=7.2 Hz), of 4.45 (2H, d, J=5.3 Hz), 6,23 (1H, d, J=12.3 Hz), 6.35mm (1H, d, J=12.3 Hz), to 7.15 (2H, d, J=8,8 Hz), 7,39 (1H, c), 7,60 (1H, m), 7,79 (1H, c), 7,86 (2H, d, J=8,8 Hz), of 8.06 (1H, t, J=7,6 Hz), 8,35 (1H, d, J=7,6 Hz), 8,79 (1H, d, J=7,6 Hz), 9,39 (1H, m).

ESI-MASS (m/e): 507 (M+H).

Example 98

(4S)-1-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl)-4-hydroxypyrrolidine-2-he

Stage 1. Obtain (S)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-2-it:

1,02 g of imidazole and 1.58 g of tert-butyldimethylchlorosilane was added to a solution of 1.01 g (S)-4-hydroxy-2-pyrrolidone in dimethylformamide (5 ml) and was stirred over night at room temperature. Added water to the reaction liquid, and stirred under cooling on ice.

The precipitated crystal was collected by filtration and dried, obtaining 2,07 g of target compound in the form of colorless crystal.

Stage 2. Receipt of (4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-({5-[4-ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl]}methyl)pyrrolidin-2-or (4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-({6-[4-ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl]}methyl)pyrrolidin-2-it:

While cooling on ice, 15 μl of methanesulfonamide was added to a solution of 50 mg of the alcohol compound obtained in example 19 (step 7), and 26 μl of triethylamine in tetrahydrofuran (0.5 ml) and was stirred for 30 minutes. Added ice water, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure, obtaining the amorphous substance of light-yellow color.

While cooling on ice, 22 mg of sodium hydride (added the eat 30% liquid paraffin) was added to a solution of 120 mg of colorless crystal, obtained in stage 1, in dimethylformamide (1 ml) and stirred at room temperature for 1 hour. The solution is light yellow amorphous substance obtained in the specified operation, in tetrahydrofuran (1.5 ml) was added to the reaction liquid, and additionally stirred at room temperature for 1 hour. When cooled on ice was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified liquid chromatography medium pressure reverse phase [ODS-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triperoxonane acid]. The solvent of the resulting fraction is evaporated under reduced pressure, the residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining of 55.5 mg of target compound as a yellow oil.

Stage 3. Receipt of (4S)-1-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl)-4-hydroxypyrrolidine-2-it:

of 55.5 mg of the obtained yellow oil was dissolved in 1 ml triperoxonane acid and 0.2 ml of water and stirred at room temperature for 2 hours. The solvent you Arevalo, to the residue was added saturated aqueous sodium bicarbonate, extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1), receiving and 24.2 mg of the target compound in the form of an amorphous substance of white color.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=7.4 Hz), 2,43 (1H, m), 2,65 (1H, m), 3,10 (2H, q, J=7.4 Hz), 3,30 (1H, m), 3,55 (1H, m), 4,30-4,70 (3H, m), 7,00 (2H, d, J=8,4 Hz), 7,09 (1/3H, c), 7,30 was 7.45 (1H+2/3H), 5,51 (2/3H, m), 7,62-of 7.90 (3H+1/3H, m), at 8.36 (1H, d, J=7,6 Hz), to 8.62 (1H, d, J=4.5 Hz), 11,0 (1/3H, ush.), 11,4 (2/3H, ush.).

ESI-MASS (m/e): 493 (M+H).

Example 99

(4R)-1-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl)-4-hydroxypyrrolidine-2-he

Using (R)-4-hydroxy-2-pyrrolidone, the target compound was obtained in the same manner as in example 98, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=7.4 Hz), 2,43 (1H, m), 2,65 (1H, m), 3,10 (2H, q, J=7.4 Hz), 3,30 (1H, m), 3,55 (1H, m), 4,30-4,70 (3H, m), 7,00 (2H, d, J=8,4 Hz), 7,09 (1/3H, c), 7,30 was 7.45 (1H+2/3H), 5,51 (2/3H, m), 7,62-of 7.90 (3H+1/3H, m), at 8.36 (1H, d, J=7,6 Hz), to 8.62 (1H, d, J=4.5 Hz), 11,0 (1/3H, ush.), 11,4 (2/3H, ush.).

ESI-MASS (m/e): 493 (M+H).

Example 100

(4R)-1-({5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl)-4-herperidin-2-he

Stage 1. According to the teaching of (4S)-1-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl]}methyl)-4-hydroxypyridine-2-or (4S)-1-({6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl]}methyl)-4-hydroxypyridine-2-it :

to 0.72 ml of a 1M solution of tetrabutylammonium in tetrahydrofuran was added to a solution of 267 mg of the compound obtained in example 98 (step 2), in tetrahydrofuran (2.5 ml) and stirred at room temperature for 30 minutes. Phosphate buffer (0.1 m, pH 6) was added to the reaction liquid was extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform-chloroform/methanol = 20/1), getting to 77.5 mg of target compound as a colourless oil.

Stage 2. Obtain (4R)-1-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]}methyl)-4-herperidin-2-it:

46 μl of bis(2-methoxymethyl)aminoterephthalic sulfur was added to a solution of 77.5 mg of the obtained oil in chloroform (0.8 ml) and stirred at room temperature for 15 minutes. The mixture was purified by chromatography on a column of silica gel (manifesting solvent: chloroform-chloroform/methanol = 20/1), getting to 42.1 mg of target compound as a colourless oil.

to 42.1 mg of the obtained yellow oil was dissolved in 1 ml triperoxonane acid and stirred at room temperature for 2 hours. The solvent is evaporated, to the residue was added saturated aqueous bicarbona the sodium, was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1), getting to 11.1 mg of target compound in the form of an amorphous substance of white color.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7.4 Hz), 2,55 is 2.75 (2H, m), 3,11 (2H, q, J=7.4 Hz), 3,45-3,70 (2H, m), 4,47-of 4.75 (2H, m), 5,10-and 5.30 (1H, m), 7.03 is-7,10 (2H, m), 7,16 (1/2N, c), 7,40 (1H, m), 7,49 (1/2N, c), 7,56 (1/2N, c), of 7.75-a 7.92 (3H+1/2H, m), 8,40 (1H, m)8,64 (1H, m), 10,9 (1/2H, ush.), 11,0 (1/2H, ush.).

ESI-MASS (m/e): 495 (M+H).

Example 101

6-[(1,1-Dioxothiazolidine-2-ylmethyl]-5-[(6-methylpyridin-3-yl)oxy]-2-(2-pyridinyl)-1H-benzimidazole

Stage 1. Receive (5-[(6-methylpyridin-3-yl)oxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol and (6-[(6-methylpyridin-3-yl)oxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanol:

Using 4-hydroxy-6-methylpyridin, the target compound was obtained in the same manner as in example 19 (stages 5-7), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain 6-[(1,1-dioxothiazolidine-2-yl)methyl]-5-[(6-methylpyridin-3-yl)oxy]-2-(2-pyridinyl)-1H-benzimidazole:

Using the obtained alcohol compound, the target compound was obtained those the same way as in example 33, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: to 2.29 (2H, m), of 2.54 (3H, c), 3,14 (2H, m), 3,24 (2H, m), 4,37 (2H×1/2, c), to 4.38 (2H×1/2, c)7,00 (1/2N, c), 7,05-7,24 (2H, m), 7,35 (1/2N, c), 7,38 (1H, m), to 7.67 (1/2N, c), 7,86 (1H, m), 7,92 (1/2N, c), of 8.27 (1H, m), scored 8.38 (1H, m)8,64 (1H, m), 10,6 (1/2H, ush.), 10,7 (1/2H, ush.).

ESI-MASS (m/e): 495 (M+H).

Example 102

1-[4-[(6-((2-Oxopyrrolidin-1-yl)methyl]-2-(2-pyridinyl)-1H-benzimidazole-5-yl)oxy]phenyl]-2-pyrrolidinone

Stage 1. Getting 2-fluoro-4-nitrobenzaldehyde:

43,3 g of 2-fluoro-4-nitrobenzoic acid was dissolved in 600 ml of dimethylformamide, was added 1,1'-carbodiimide and stirred at room temperature for 2 hours. Added 11.1 g of sodium borohydride and was additionally stirred for 30 minutes. Was added a saturated aqueous solution of ammonium chloride was added 800 ml of water, was extracted with 1.2 liters of ethyl acetate and the organic layer was washed with saturated saline solution. The solvent is evaporated under reduced pressure, the residue was again diluted with ethyl acetate and the organic layer was washed with water and saturated salt solution. It was dried with anhydrous sodium sulfate and the solvent evaporated, getting to 32.7 g of brown oil.

The oil obtained was dissolved in 200 ml of dimethylsulfoxide, was gradually added 60 ml of triethylamine 88.7 g of a complex of sulfur trioxide/pyridine and paramesh the Wali at room temperature for 2 hours. The mixture was diluted with ethyl acetate and the organic layer was washed with water, aqueous 0.1 N. hydrochloric acid and saturated saline. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate) and crystallization (methanol/diethyl ether)to give 14.0 g of target compound in the form of a solid orange color.

Stage 2. Obtain 1-(2-fluoro-4-nitrobenzyl)pyrrolidin-2-it:

100 ml of methanol was added to 1 g of the obtained 2-fluoro-4-nitrobenzaldehyde and 3.0 g of the hydrochloride of methyl-4-aminobutyric acid, was then added 87 ml of a 0.3 m solution of centripetality zinc/methanol (1/2 solution of zinc chloride and centripetality sodium in methanol) and stirred for 1 hour. Was added a saturated aqueous sodium bicarbonate, diluted with ethyl acetate and washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure, obtaining of 5.2 g of amorphous material, red color.

The obtained amorphous substance was dissolved in methanol, was added 1.5 ml 4,7M solution of sodium methoxide/methanol and stirred at room temperature for 1.5 hours, and then at 45°C for 30 minutes. The solvent is evaporated and the residue was purified by chromatography on a column of silica gel (quite widespread is the overall solvent: hexane/ethyl acetate = 5/1-1/1-0/1), getting to 1.9 g of the target compound as an orange oil.

Stage 3. Obtaining 1-(4-amino-2-terbisil)pyrrolidin-2-it:

To a solution of 1.5 g of the compound obtained in stage 2, in methanol (20 ml) was added Raney Nickel and was stirred over night at room temperature. After filtration the filtrate was evaporated under reduced pressure, gaining 1.4 g of the target compound as an orange oil.

Stage 4. Obtain N-{5-fluoro-2-nitro-4-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyridine-2-carboxamide:

Hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added to a solution of 1.13 g of compound obtained in stage 3, and 801 mg of 2-pikolinos acid in pyridine (25 ml) and was stirred over night at room temperature. The solvent is evaporated under reduced pressure, the residue was dissolved in 200 ml of chloroform and washed with 80 ml of 0.2 N. hydrochloric acid (×4), 50 ml of 0.5 n sodium hydroxide solution (×3) and saturated salt solution. After drying, the solvent is evaporated under reduced pressure, getting 1.51 g solid of light yellow color.

A solution of 1.51 g solid light yellow fuming nitric acid (7 ml) was stirred at room temperature for 1 hour, then poured into saturated aqueous sodium hydrogen carbonate solution under ice cooling and stirred at room Tempe is the atur for 1 hour. The insoluble substance was separated by filtration, washed with water, then dried overnight under reduced pressure, getting 1.56 g of target compound in the form of a solid of light yellow color.

Stage 5. Obtaining 1-[4-[(6-((2-oxopyrrolidin-1-yl)methyl)-2-(2-pyridinyl)-1H-benzimidazole-5-yl)oxy]phenyl]-2-pyrrolidinone:

20 mg of calcium carbonate was added to a solution of 20 mg of the compound obtained in stage 4, and 12 mg of 1-(4-hydroxyphenyl)pyrrolidin-2-it is in dimethylformamide (0.5 ml) and stirred at 80°C for 30 minutes. Then was added 126 mg of the dihydrate of tin chloride and stirred at 80°C for 30 minutes. Water and chloroform were added to the reaction liquid and the insoluble substance was separated by filtration. The filtrate was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified liquid chromatography medium pressure reverse phase [ODS-AS-360-CC (YMC), mobile phase: water/acetonitrile/0.1% of triperoxonane acid]. The solvent of the resulting fraction is evaporated under reduced pressure, the residue was diluted with chloroform, washed with saturated aqueous sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure.

Next, the residue was purified share what her thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1), getting to 13.7 mg of target compound in the form of an amorphous substance of white color.

1H-NMR (CDCl3) δ: 1,91-2,02 (2H, m), 2,14-2,22 (2H, m), a 2.36-to 2.41 (2H, m), 2,60-to 2.65 (2H, m), 3.33 and-3,39 (2H, m), 3,84-3,88 (2H, m), 4,60 (2H×1/2, c), 4,63 (2H×1/2, c)of 6.96 (1H×1/2, c), 6,98 (2H×/2, d, J=9.0 Hz), 6,99 (2H×1/2, d, J=9.0 Hz), 7,34-7,39 (1H, m), 7,38 (1H×1/2, c), 7,53 (1H×1/2, c), 7,54 (2H×1/2, d, J=9.0 Hz), 7,55 (2H×1/2D, J=9.0 Hz), 7,71 (1H×1/2, c), 7,82-7,88 (1H, m), 8.34 per-of 8.40 (1H, m), 8,60-8,65 (1H, m), 10,55 (1H×1/2, USS), as 10.63 (1H×1/2, USS).

ESI-MASS (m/e): 468 (M+H).

Example 103

1-[4-[(6-((2-Oxopyrrolidin-1-yl]methyl)-2-(2-pyridinyl)-1H-benzimidazole-5-yl)oxy]phenyl]pyridine-2(1H)he

Using 1-(4-hydroxyphenyl)pyridine-2(1H)-he obtained in reference example 12, the target compound was obtained in the same manner as in example 102 (stage 5), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.93 and is 2.00 (2H, m), 2,35-to 2.41 (2H, m), 3,31-to 3.38 (2H, m), 4,60 (2H×1/2, c), br4.61 (2H×1/2, c), 6,22-6,28 (1H, m), 6,64-6,69 (1H, m), 7,01 (2H×1/2, d, J=8.6 Hz), 7,05 (2H×1/2, d, J=8.6 Hz), 7,10 (1H×1/2, c), 7,31-the 7.43 (3H, m), 7,32 (2H, d, J=8.6 Hz), of 7.48 (1H×1/2, c), 7,56 (1H×1/2, c), 7,74 (1H×1/2, c), 7,84-7,89 (1H, m), at 8.36-to 8.40 (1H, m), 8,63-8,66 (1H, m), of 10.73 (1H×1/2, OSS), was 10.82 (1H×1/2, USS).

ESI-MASS (m/e): 478 (M+H).

Example 104

5-((6-((2-Oxopyrrolidin-1-yl)methyl)-2-(2-pyridinyl)-1H-benzimidazole-5-yl)oxy)pyridine-2-carbonitrile

Using 5-hydroxypyridine-2-carbonitrile obtained in reference example 10, the target compound was obtained in the same with the special as in example 102 (stage 5), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,91 of 1.99 (2H, m), 2,27-is 2.37 (2H, m), 3.27 to to 3.33 (2H, m), a 4.53 (2H, c), 7,20 (1H×1/2, c), 7.23 percent-7,28 (1H, m), 7,40-the 7.43 (1H, m), 7,49 (1H×1/2, c), EUR 7.57 (1H×1/2, c), a 7.62 (1H×1/2, d, J=8.6 Hz), to 7.64 (1H×1/2, d, J=8,2 Hz), 7,79 (1H×1/2, c), 7,87-a 7.92 (1H, m), of 8.37-to 8.45 (2H, m), 8,64-8,67 (1H, m), is 10.75 (1H×1/2, USS), 10,84 (1H×1/2, USS).

ESI-MASS (m/e): 411 (M+H).

Example 105

1-{[5-[(6-(Methoxymethyl)pyridine-3-yl)oxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using 6-(methoxymethyl)pyridine-3-ol obtained in reference example 11, the target compound was obtained in the same manner as in example 102 (stage 5), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.93 and is 2.00 (2H, m), 2,35-to 2.41 (2H, m), 3,32-3,39 (2H, m), 3,48 (3H×1/2, c), of 3.48 (3H×1/2, c), of 4.57 (2H, c), br4.61 (2H×1/2, c), 4,63 (2H×1/2, c), 7,03 (1H×1/2, c), 7,25-7,29 (1H, m), 7,35 (1H×1/2, c), of 7.36-7,40 (2H, m), 7,55 (1H×1/2, c), 7,74 (1H×1/2, c), 7,84-of 7.90 (1H, m), 8,30-to 8.41 (2H, m), 8,61-8,65 (1H, m), of 10.73 (1H×1/2, USS), 10,84 (1H×1/2, USS).

ESI-MASS (m/e): 430 (M+H).

Example 106

1-({5-[4-(5-Methyl-1,3,4-oxadiazol-2-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)pyrrolidin-2-he

Using 6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-ol obtained in reference example 12, the target compound was obtained in the same manner as in example 102 (stage 5), or in accordance with this method, or its combination with the normal with the particular.

1H-NMR (CDCl3) δ: 1,95 (2H, m), 2,33 (2H, m), 2,61 (3H, c), and 3.31 (2H, m), 4,58 (2H, c),? 7.04 baby mortality (2H, d, J=8,8 Hz), 7,10-7,80 (2H, ush.), 7,39 (1H, m), 7,88 (1H, dt, J=1,7, 8.0 Hz), of 7.97 (2H, d, J=8,8 Hz), 8,39 (1H, d, J=8.0 Hz), 8,65 (1H, d, J=5.0 Hz), 10,0-11,0 (1H, ush.).

ESI-MASS (m/e): 467 (M+H).

Example 107

1-({5-[4-(3-Methyl-1,2,4-oxadiazol-5-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)pyrrolidin-2-he

Using 6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine-3-ol obtained in reference example 13, the target compound was obtained in the same manner as in example 102 (stage 5), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,93 (2H, m), 2,33 (2H, m), 2,46 (3H, m), 3,30 (2H, m), of 4.57 (2H, m), 7,05 (2H, m), 7,19 (1/2N, c), 7,40 (1H, m), 7,52 (1/2N, c), EUR 7.57 (1/2N, c), 7,78 (1/2N, c), 7,86 (1H, m), of 8.06 (2H, d, J=8,8 Hz), 8,40 (1H, m), 8,66 (1H, m)and 10.7 (1H, ush.), 10,8 (1/2H, ush.).

ESI-MASS (m/e): 467 (M+H).

Example 108

1-({5-[4-(1-Methyl-1H-tetrazol-5-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)pyrrolidin-2-he

Using 6-(1-methyl-1H-tetrazol-5-yl)pyridine-3-ol obtained in reference example 14, the target compound was obtained in the same manner as in example 102 (stage 5), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,94 (2H, m), 2,35 (2H, m)to 3.33 (2H, m), 4,18 (3H, c), 4,59 (2H, c), 7,13 (2H, c), 7,20 (1/2N, c), 7,40 (1H, m), 7,51 (1/2N, c), 7,56 (1/2N, c), of 7.70 (2H, d, J=8,8 Hz), to 7.77 (1/2N, c), 7,88 (1H, m), 8,39 (1H, m)8,64 (1H, m), 10,9 (1/2H, ush.), 11,0 (1/2H, ush.).

ES-MASS (m/e): 467 (M+H).

Example 109

1-({5-[4-(1,3-Oxazol-4-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)pyrrolidin-2-he

Using 6-(1,3-oxazol-4-yl)pyridine-3-ol obtained in reference example 15, the target compound was obtained in the same manner as in example 102 (stage 5), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,94 (2H, m), a 2.36 (2H, m)to 3.34 (2H, m), to 4.62 (2H, m), 7,00 (2H, m), 7,07 (1/2H, m), 7,37 (1H, m), 7,46 (1/2N, c), 7,54 (1/2N, c)of 7.69 (2H, d, J=8,8 Hz), 7,74 (1/2N, c), 7,86 (1H, m), of 7.90 (1H, c), 7,94 (1H, c), 8,39 (1H, m), 8,63 (1H, m), 10,8 (1/2H, ush.), 10,9 (1/2H, ush.).

ESI-MASS (m/e): 452 (M+H).

Example 110

1-[(5-((2'-Forbiden-4-yl)oxy)-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)-2-pyrrolidinone

Stage 1. Obtain N-{5-fluoro-2-nitro-4-{[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyrazin-2-carboxamide:

Using pyrazin-2-carboxylic acid, the target compound was obtained in the same manner as in example 102 (stage 4), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtaining 1-[(5-((2'-forbiden-4-yl)oxy)-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methyl)-2-pyrrolidinone:

Using the compound obtained in stage 1, and 6-(2-forfinal)pyridine-3-ol obtained in reference example 16, the target compound was obtained in the same manner as in example 102 (stage 5), or in accordance with this method, or its combination with ordinary the m method.

1H-NMR (CDCl3) δ: 1,94-2,02 (2H, m), 2,37 is 2.44 (2H, m), 3,36-of 3.46 (2H, m), of 4.67 (2H, c), 7,05 (2H, d, J=8.6 Hz), 7,13-7,34 (3H, 1H×1/2, m), 7,40 was 7.45 (1H, m), of 7.48 (1H×1/2, c), 7,51 (2H, d, J=8.6 Hz), 7,66 (1H×1/2, c), to 7.77 (1H×1/2, c), 8,59 (1H, c)8,64 (2H, d, J=2.7 Hz), 9,62 (1H, c), of 10.47 (1H×1/2, USS), 10,95 (1H×1/2, USS).

ESI-MASS (m/e): 480 (M+H).

Example 111

1-{[2-(5-Bromo-2-pyridinyl)-5-[(6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl)oxy]-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Stage 1. Obtain methyl 4-{[(5-bromopyrazine-2-yl)carbylamine]-2-perbenzoate:

Using methyl 4-amino-2-perbenzoate obtained in example 19 (stage 2), and 5-bromopyrazine-2-carboxylic acid, the target compound was obtained in the same manner as in example 19 (step 3), or in accordance with this method, or its combination with a customary method.

Stage 2. Receive (2-(5-bromopyrazine-2-yl)-5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)methanol and (2-(5-bromopyrazine-2-yl)-6-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)methanol:

Using the compound obtained in stage 1, the target compound was obtained in the same manner as in example 52 (stage 1, 2), or in accordance with this method, or its combination with a customary method.

Stage 3. Obtain 1-{[2-(5-bromo-2-pyridinyl)-5-[(6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl)oxy]-1H-benzimida the ol-6-yl]methyl}-2-pyrrolidinone :

Using the alcohol obtained in stage 2, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,92 of 1.99 (2H, m), 2,31-2,39 (2H, m), 3,30-to 3.36 (2H, m), 4,59 (2H×1/2, c), br4.61 (2H×1/2, c), 7,17 (1H×1/2, c), 7,30-7,37 (1H, m), 7,47 (1H×1/2, c), 7,60 (1H×1/2, c), 7,78 (1H×1/2, c), 7,98-8,02 (1H, m,), of 8.04 (1H×1/2, d, J=8.6 Hz), 8,07 (1H×1/2, d, J=9.0 Hz), compared to 8.26 (1H×1/2, d, J=8.6 Hz), 8,29 (1H×1/2, d, J=8.6 Hz), 8,49 (1H×1/2, d, J=2.3 Hz), 8,55 (1H×1/2, d, J=2.3 Hz), 8,69 (1H×1/2, d, J=1.6 Hz), 8,71 (1H×1/2, d, J=2.0 Hz), the 10.40 (1H×1/2, USS), 10,52 (1H×1/2, USS).

ESI-MASS (m/e): 546, 548 (M+H).

Example 112

1-Methyl-3-{[5-[(6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl)oxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}imidazolidine-2,4-dione

Using the alcohol compound obtained in example 52 (stage 2), and 1-methylhydantoin, the target compound was obtained in the same manner as in example 19 (step 8), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,68 (3H, c), 2,89 (3H×1/2, c), 2,95 (3H×1/2, c), 3,70 (2H×1/2, c), 3,82 (2H×1/2, c), a 4.83 (2H×1/2, c), is 4.85 (2H×1/2, c), 7,07 (1H×1/2, c), 7,30-7,41 (2H, m), 7,45 (1H×1/2, c), 7,66 (1H×1/2, c), 7,81 (1H×1/2, c), 7,84-7,89 (1H, m), 8,02 (1H×1/2, d, J=8.6 Hz), with 8.05 (1H×1/2, d, J=9.0 Hz), at 8.36 (1H×1/2, d, J=7.8 Hz), scored 8.38 (1H×1/2, d, J=7.8 Hz), 8,55-8,59 (1H, m), 8,61-8,65 (1H, m), as 10.63 (1H, USS).

ESI-MASS (m/e): 497 (M+H).

Example 113

6-((1,1-Deoxidization-2-yl]methyl)-5-((6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl)oxy)-2-(pyridinyl)-1H-benzimidazole

Using the alcohol compound obtained in example 52 (stage 2), the target compound was obtained in the same manner as in example 33, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,19-of 2.27 (2H, m), 2,69 (3H, c), 3.04 from-of 3.12 (2H, m), 3,16 is 3.23 (2H, m)to 4.33 (2H×1/2, c), 4,35 (2H×1/2, c), 7,18 (1H×1/2, c), 7,31-the 7.43 (2H, m), 7,50 (1H×1/2, c), 7,72 (1H×1/2, c), a 7.85-a 7.92 (1H, m), of 7.96 (1H×1/2, c), of 8.04 (1H×1/2, d, J=8.6 Hz), 8,07 (1H×1/2, d, J=8.6 Hz), scored 8.38 (1H×1/2, d, J=7.8 Hz), to 8.41 (1H×1/2, d, J=8,2 Hz), 8,48 (1H×1/2, d, J=2.7 Hz), 8,55 (1H×1/2, d, J=2.3 Hz), 8,64 (1H×1/2, d, J=4.3 Hz), 8,66 (1H×1/2, d, J=4,7 Hz), 10,57 (1H×1/2, USS), or 10.60 (1H×1/2, USS).

ESI-MASS (m/e): 504 (M+H).

Example 114

4-{[5-[(6-(5-Methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl)oxy]-2-(2-pyridinyl]-1H-benzimidazole-6-yl]methyl}morpholine-3-one

Using the alcohol compound obtained in example 52 (stage 2), the target compound was obtained in the same manner as in example 81, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,69 (3H, c), the 3.35 (2H×1/2, t, J=5,1 Hz), 3,39 (2H×1/2, t, J=5,1 Hz), 3,83 (2H×1/2, t, J=5,1 Hz), of 3.84 (2H×1/2, t, J=5,1 Hz)to 4.15 (2H×1/2, c), 4,19 (2H×1/2, c), was 4.76 (2H×1/2, c), 4,78 (2H×1/2, c), 7,17 (1H×1/2, c), 7,29-to 7.35 (1H, m), 7,38-7,42 (1H, m), 7,49 (1H×1/2, c), the 7.65 (1H×1/2, c), 7,83 (1H×1/2, c), a 7.85 to $ 7.91 (1H, m), of 8.04 (1H×1/2, d, J=8.6 Hz), 8,07 (1H×1/2, d, J=8.6 Hz), of 8.37 (1H×1/2, d, J=7.8 Hz), 8,40 (1H×1/2, d, J=8,2 Hz), charged 8.52 (1H×1/2, d, J=2.7 Hz), to 8.57 (1H×1/2, d, J=2.7 Hz), 8,64 (1H×1/2, d, J=5,1 Hz), 8,66 (1H×1/2, d, J=5.5 Hz), 10,59 (1H×1/2, USS), is 10.68 (1H×1/2, USS).

ESI-MASS (m/e): 48 (M+H).

Example 115

3-{[5-[(6-(5-Methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl)oxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-oxazolidin-2,4-dione

Using the alcohol compound obtained in example 52 (stage 2), the target compound was obtained in the same manner as in example 85, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,68 (3H, c), 4,58 (2H×1/2, c), with 4.64 (2H×1/2, c), a 4.86 (2H×1/2, c), 4,89 (2H×1/2, c), 7,06 (1H×1/2, c), 7,32-7,42 (2H, m), 7,46 (1H×1/2, c), to 7.68 (1H×1/2, c), 7,86 (1H×1/2, c), 7,89 (1H, d, J=6,3 Hz), 8,02-8,08 (1H, m), of 8.37-8,42 (1H, m), 8,53-8,58 (1H, m), 8,61-8,66 (1H, m), 10,97 (1H, USS).

ESI-MASS (m/e): 484 (M+H).

Example 116

1-{[5-[(6-(5-Methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl)oxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1H-imidazol-2-carbonitril

Using the alcohol compound obtained in example 52 (stage 2), the target compound was obtained in the same manner as in example 82, or in accordance with this method, or its combination with a customary method.

1H-NMR (DMSO-d6) δ: 2,66 (3H, c), 5,52 (2H, c), to 7.09 (1H, d, J=6,7 Hz), to 7.15 (1H×1/2, c), 7,26-to 7.35 (1H, m), 7,50 to 7.62 (2H, m), 7,50 to 7.62 (1H×1/2, s, overlap), 7,71 (1H×1/2, c), 7,93-of 8.04 (2H, m), 7,93-of 8.04 (1H×1/2, s, invisible), 8,29-to 8.34 (1H, m), 8,42-to 8.45 (1H, m), 8,72-8,77 (1H, m), 13,26 (1H×1/2, USS), 13,45 (1H×1/2, USS).

ESI-MASS (m/e): 476 (M+H).

Example 117

4-{[5-[(6-(5-Methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl)oxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}morpholine-3,5-dione

And who uses alcohol compound, obtained in example 52 (stage 2), the target compound was obtained in the same manner as in example 16, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,69 (3H, c), the 4.29 (4H×1/2, c)4,36 (4H×1/2, c)to 5.13 (2H×1/2, c)to 5.13 (2H×1/2, c), was 7.08 (1H×1/2, c), 7,30-7,39 (2H, m), 7,45 (1H×1/2, c), 7,53 (1H×1/2, c), 7,73 (1H×1/2, c), a 7.85-7,89 (1H, m), 8,03 (1H×1/2, d, J=9.0 Hz), 8,07 (1H×1/2, d, J=9.4 Hz), of 8.37 (1H×1/2, d, J=7,0 Hz), 8,39 (1H×1/2, d, J=7,0 Hz), 8,58-8,65 (2H, m), a 10.74 (1H, USS).

ESI-MASS (m/e): 498 (M+H).

Example 118

3-{[5-[(6-(5-Methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl)oxy]-2-(2-pyridinyl]-1H-benzimidazole-6-yl]methyl}-1,3-thiazolidin-2,4-dione

Using the alcohol compound obtained in example 52 (stage 2), the target compound was obtained in the same manner as in example 17, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,69 (3H, c), 3,82 (2H×1/2, c), 3,90 (2H×1/2, c), 4,94 (2H×1/2, c), equal to 4.97 (2H×1/2, c), was 7.08 (1H×1/2, c), 7,30-7,41 (2H, m), 7,45 (1H×1/2, c), 7,60 (1H×1/2, c), 7,80 (1H×1/2, c), 7,86-of 7.90 (1H, m), 8,03-8,08 (1H, m), at 8.36-to 8.40 (1H, m), 8,55-8,65 (2H, m), a 10.74 (1H×1/2, USS), 10,79 (1H×1/2, USS).

ESI-MASS (m/e): 500 (M+H).

Example 119

1-{[5-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-(2-pyrazinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using N-{5-fluoro-2-nitro-4-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyrazin-2-carboxamide obtained in example 110 (stage 1), and 4-(5-methyl-1,2,4-oxadiazol-3-yl)phenol obtained in reference is the example 7, the target compound was obtained in the same manner as in example 102 (stage 5), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,92 is 2.00 (2H, m), 2,34-to 2.41 (2H, m), 3,32-3,39 (2H, m), br4.61 (2H×1/2, c)to 4.62 (2H×1/2, c),? 7.04 baby mortality (2H×1/2, d, J=8.6 Hz), 7,05 (2H×1/2, d, J=8.6 Hz), 7,17 (1H×1/2, c), 7,51 (1H×1/2, c), the 7.65 (1H×1/2, c)7,79 (1H×1/2, c), 8,02 (2H, d, J=8.6 Hz), 8,57-8,61 (1H, m), 8,66 (1H, d, J=2.0 Hz), being 9.61-for 9.64 (1H, m), 10,45 (1H×1/2, USS), 10,83 (1H×1/2, USS).

ESI-MASS (m/e): 468 (M+H).

Example 120

3-{[5-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-oxazolidin-2,4-dione

Using the alcohol compound obtained in example 55 (stage 1), the target compound was obtained in the same manner as in example 85, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl32 drops CD3OD) δ: 2,66 (3H, c), of 4.44 (2H×1/2, c)to 4.52 (2H×1/2, c), to 4.87 (2H×1/2, c), the 4.90 (2H×1/2, c), 7,03 (2H×1/2, d, J=8.6 Hz), 7,06 (2H×1/2, d, J=8.6 Hz), 7,17 (1H×1/2, c), 7,38-the 7.43 (1H, m), 7,47 (1H×1/2, c), 7,71 (1H×1/2, c), 7,88-to $ 7.91 (1H, m), 7,92 (1H×1/2, c), 8,01 (2H×1/2, d, J=8.6 Hz), 8,03 (2H×1/2, d, J=8.6 Hz), scored 8.38-8,42 (1H, m), 8,61-8,67 (1H, m), peak NH invisible.

ESI-MASS (m/e): 483 (M+H).

Example 121

3-{[5-[(6-(5-Methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl)oxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

Using N-{5-fluoro-2-nitro-4-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyrazin-2-carboxamide obtained in example 110 (stage 1), and 6-(5-methyl-1,2,4-oxadi the evil-3-yl)-3-pyridinol, obtained in reference example 6, the target compound was obtained in the same manner as in example 102 (stage 5), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,95-2,02 (2H, m), a 2.36-to 2.42 (2H, m), 2,69 (3H, c), 3,34-to 3.41 (2H, m), to 4.62 (2H, c), 7,18 (1H×1/2, c), 7,34 (1H, d, J=7.8 Hz), 7,50 (1H×1/2, c)of 7.69 (1H×1/2, c), 7,79 (1H×1/2, c), of 8.06 (1H, d, J=8.6 Hz), 8,49-to 8.57 (1H, m), at 8.60 (1H, c), 8,67 (1H, d, J=2.7 Hz), 9,63 (1H, c), of 10.58 (1H×1/2, USS), 10,98 (1H×1/2, USS).

ESI-MASS (m/e): 469 (M+H).

Example 122

5-Hydroxy-1-[(6-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-5-yl)methyl]pyrrolidin-2-he

7 mg of sodium borohydride and 8 mg of lithium chloride was added to a solution of 30 mg of the compound obtained in example 51, 2 ml of tetrahydrofuran and 0.2 ml of methanol and stirred at room temperature for 1 hour. Was added aqueous 10% solution of citric acid, was extracted with chloroform, the organic layer was dried and the solvent evaporated under reduced pressure. The residue was purified by thin-layer chromatography (manifesting solvent: chloroform/methanol = 9/2)to give 7 mg of the target compound in a solid white color.

1H-NMR (CDCl3) δ: 1,91-of 1.88 (1H, m), 2,22-of 2.20 (2H, m), 2.57 m) is 2.55 (1H, m)of 2.64 (3H, c), 4,37 (2H, d, J=15,5 Hz), 5,24 (1H, m), of 7.36-to 7.35 (2H, m), 7,83 (2H, d, J=7.8 Hz), of 7.96 (1H, d, J=8,8 Hz), 8.34 per-8,33 (3H, m), 8,63-at 8.60 (1H, m).

ESI-MASS (m/e): 484 (M+H).

Example 123

1-{[5-[(6-(5-IU the Il-1,2,4-oxadiazol-3-yl)pyridine-3-yl)oxy]-2-(1-oxidability-2-yl)-1H-benzimidazole-6-yl]methyl}-2-pyrrolidinone

2 mg methyltrioxorhenium(VII) was added to a solution of 20 mg of the compound obtained in example 53, in chloroform (2 ml), was added 100 μl of aqueous 30% hydrogen peroxide and stirred at room temperature for 4 hours. Was added an aqueous sodium thiosulfate solution and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 5/1)to give 1.0 mg of the target compound as a white crystal.

1H-NMR (CDCl3) δ: 1,99 (2H, m), 2.40 a (2H, m), 2,71 (3H, c)to 3.36 (2H, m), 4,46 (2H×1/2, m)and 4.65 (2H×1/2, c), 7,27 (1/2N, c), 7,40 (2H, m), 7,45-of 7.60 (1H+1/2H, m), 7,66 (1/2H, m), 7,82 (1/2N, c), of 8.09 (1H, m)to 8.41 (1H, m), to 8.57 (1H, m), 8,72 (1H, m), 13,2 (1/2N, c)and 13.3 (1/2H, s).

ESI-MASS (m/e): 484 (M+H).

Example 124

4-Hydroxy-1-{[5-[(6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl)oxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2-he

Using the alcohol compound obtained in example 52 (stage 2), the target compound was obtained in the same manner as in example L-001471821, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 2,30-of 2.50 (1H, m), 2,60-of 2.75 (1H, m), 2,68 (3H, c), 3,30-3,55 (1H, m), 3,55-3,70 (1H, m), 4,40-4,80 (3H, m), 7,10-7,80 (4H, m), 7,86 (1H, m), 8,02 (1H, d, J=8,8 Hz), scored 8.38 (1H, d, J=7.8 Hz), 8,46 (1H, d, J=2.7 Hz), 8,65 (1H, d, J=4,9 Hz).

ESI-MASS (m/e): 484 (M+H).

Example 125

1-[Hydroxy-(5-{[6-[5-methyl-1,2,4-oxadiazol-3-yl]-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl)methyl]-2-pyrrolidinone

Stage 1. Receive (5-[{6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}methanol:

Using the alcohol compound obtained in example 52 (stage 2), the target compound was obtained in the same manner as in example 59, or in accordance with this method, or its combination with a customary method.

Stage 2. Getting 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-carbaldehyde:

1.5 ml of triethylamine and 796 mg of a complex of sulfur trioxide/pyridine was added to a solution of 400 mg of the obtained alcohol compound in dimethyl sulfoxide (5 ml) and stirred at room temperature for 30 minutes. Added ice water, extracted with chloroform, and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was led in a mixture of diethyl ether/methanol, getting 183 mg of target compound in the form of amorphous material, light yellow color.

Stage 3. Obtaining 1-[hydroxy-(5-{[6-[5-methyl-1,2,4-oxadiazol-3-yl]-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl)methyl]-2-pyrrolidinone:

7 mg of sodium carbonate were added to a solution of 8.7 ál 1-PI is rolidone in N,N-dimethylformamide (500 μl). Under stirring at 80°C was added 10 mg of the aldehyde obtained in advance, and was stirred over night at 80°C. the Solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 5/1)to give 1.0 mg of target compound in the form of amorphous material, light yellow color.

1H-NMR (CDCl3) δ: 0,79-0,94 (1H, m), 1.77 in is 1.91 (1H, m), 1,97-of 2.09 (1H, m), 2,14-of 2.34 (1H, m), 2,68 (3H, c), and 2.83 vs. 2.94 (1H, m), 3,37-to 3.52 (1H, m), 6.87 in-6,95 (1H, m), 7,18 (1H×1/2, c), 7,33-7,46 (2H, m), 7,50 (1H×1/2, c), 7,86-7,94 (1H, m), 7,99-8,08 (1H, m, 1H×1/2, c), 8,31 (1H×1/2, c)at 8.36-8,46 (2H, m), 8,60-8,72 (1H, m), of 10.58 (1H×1/2, USS), 10,86 (1H×1/2, USS).

ESI-MASS (m/e): 484 (M+H).

Example 126

5-[4-(Ethylsulfonyl)phenoxy]-6-[(2-herperidin-3-yl)methyl]-2-(2-pyridinyl)-1H-benzimidazole

Stage 1. Receive (5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)(2-forfinal)methanol or (6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)(2-forfinal)methanol:

At -78°C and 6.2 ml of a 1.5m solution of utility/hexane was added to a solution of 1.31 ml diisopropylethylamine in tetrahydrofuran (10 ml) and stirred at 0°C for 30 minutes. At -78°C 0.8 ml of 2-herperidin was added to the reaction liquid, and stirred at -78°C for 2 hours. Then the solution was added 1 g of the aldehyde obtained when the ore 64 (stage 1), in tetrahydrofuran (5 ml) and stirred at -78°C for 1 hour. Was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying it was purified by chromatography on a column of silica gel (manifesting solvent: chloroform-chloroform/methanol = 50/1), getting to 0.72 g of the target compound as a brown oil.

Stage 2. Getting 5-[4-(ethylsulfonyl)phenoxy]-6-[(2-herperidin-3-yl)methyl]-2-(2-pyridinyl)-1H-benzimidazole:

26 μl of thionyl chloride was added to a solution of 75 mg of the obtained oil in chloroform (0.75 ml) and stirred at room temperature for 20 minutes. The solvent is evaporated under reduced pressure, was added 0.7 ml triperoxonane acid and 39 mg of zinc and heated under reflux for 30 minutes. The solvent is evaporated under reduced pressure, the residue was diluted with chloroform, was added saturated aqueous sodium bicarbonate and aqueous ammonia, and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 15.2 mg of the target compound as a colorless crystal.

1H-NMR (CDCl3) δ: of 1.30 (3H, m), 3,11 (2H,m), a 4.03 (2H, c)to 7.00 (3H, m), 7,15 (1/2N, c), 7,37-EUR 7.57 (3H, m), 7,75 (1/2N, c), 7,79 (2H, m), 7,87 (1H, m), 8,02 (1H, m), 8,39 (1H, m)8,64 (1H, m), 10,6 (1/2H, ush.), 10,7 (1/2H, ush.).

ESI-MASS (m/e): 489 (M+H).

Example 127

(5-(4-Ethylsulfonyl)phenoxy)-2-(2-pyridinyl)-1H-benzimidazole-6-yl)acetonitrile

Stage 1. Receive (5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-[{2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)acetonitrile or (6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-[{2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)acetonitrile:

While cooling on ice 268 μl of methanesulfonamide was added to a solution of 930 mg of the alcohol compound obtained in example 19 (step 7), and 494 μl of triethylamine in tetrahydrofuran (20 ml) and was stirred for 20 minutes. The mixture was diluted with 60 ml of ethyl acetate and added water. The organic layer was separated and washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure, obtaining a colorless amorphous substance.

While cooling on ice 269 mg of sodium cyanide was added to a solution of the obtained amorphous substance in N,N-dimethylformamide (20 ml) and stirred at room temperature for 3 hours. When cooled on ice was added saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying races is varicel evaporated under reduced pressure, the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate), obtaining 623 mg of yellow oil.

Stage 2. Receive (5-(4-ethylsulfonyl)phenoxy)-2-(2-pyridinyl)-1H-benzimidazole-6-yl)acetonitrile:

28 mg of the obtained oil was dissolved in 1 ml triperoxonane acid and stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, the residue was diluted with chloroform and then neutralized with a saturated aqueous solution of sodium bicarbonate. Was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 14 mg of the target compound as a colorless amorphous substance.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7.4 Hz), of 3.13 (2H, q, J=7.4 Hz), 3,82 (2H, c), 7,10-7,16 (1H×1/2, s, overlap), 7,13 (2H, d, J=8,2 Hz), 7,39-7,44 (1H, m), of 7.48 (1H×1/2, c), 7,71 (1H×1/2, c), a 7.85 to $ 7.91 (1H, m), 7,88 (2H, d, J=8,2 Hz), to $ 7.91 (1H×1/2, c)of 8.37-8,42 (1H, m), 8,63-8,69 (1H, m), of 10.72 (1H×1/2, USS), 10,79 (1H×1/2, USS).

ESI-MASS (m/e): 419 (M+H).

Example 128

2-(5-(4-(Ethylsulfonyl)phenoxy)-2-(2-pyridinyl)-1H-benzimidazole-6-yl)ndimethylacetamide

A solution of 30 mg of cyanocobalamine obtained in example 127, 80% sulfuric acid (1 ml) was stirred for whom the night at 70°C. While cooling on ice, the reaction solution was added dropwise to saturated aqueous sodium hydrogen carbonate solution, which is neutralized them, and then was extracted with chloroform. The organic layer was dried, the solvent evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 5.7 mg of the target compound as a colorless amorphous substance.

1H-NMR (CDCl32 drops CD3OD) δ: of 1.30 (3H, t, J=7.4 Hz), of 3.13 (2H, q, J=7.4 Hz), 3,61 (2H×1/2, c), 3,63 (2H×1/2, c), 7,10 (2H, d, J=9.0 Hz), 7,18 (1H×1/2, c), 7,40-the 7.43 (1H, m), 7,47 (1H×1/2, c), a 7.62 (1H×1/2, c), 7,83 (1H×1/2, c)to 7.84 (2H, d, J=9.0 Hz), 7,88-to 7.93 (1H, m), of 8.37-8,42 (1H, m), 8,62-8,66 (1H, m), peaks of NH and NH2the invisible.

ESI-MASS (m/e): 437 (M+H).

Example 129

2-[5-(4-(Ethylsulfonyl)phenoxy)-2-(2-pyridinyl)-1H-benzimidazole-6-yl]-N,N-dimethylacetamide

Stage 1. Receive (5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)acetic acid or (6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)acetic acid:

10 ml of 5 N. aqueous sodium hydroxide solution was added to a solution of 1.04 g of cyanocobalamine obtained in example 127 (stage 1), in ethanol (15 ml) and stirred overnight at 70°C. the Ethanol is evaporated under reduced pressure, the residue was diluted holdem is Reforma and cooled on ice to the reaction solution was added aqueous 10% solution of citric acid, thus, making it slightly acidic. Was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate)to give 631 mg of an amorphous yellow substance.

Stage 2. Receiving target connections:

8,7 mg of 1-hydroxybenzotriazole and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added to a solution of 17.7 mg of the obtained carboxylic acid in chloroform (1 ml)and then was added to 48 μl of a solution of 2.0m dimethylamine in tetrahydrofuran and stirred at room temperature for 1.5 hours. When cooled on ice was added water and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 20/1)to give 10.8 g of an amorphous yellow substance.

Using the 10.8 mg of the obtained amorphous substance, 8.6 mg of target compound was obtained as a colorless amorphous substance in the same way as in example 127 (stage 2), or in accordance with this method, or its combination with conventional methods for the om.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.4 Hz), 2,90 (3H×1/2, c), only 2.91 (3H×1/2, c), 2,98 (3H, c), the 3.11 (2H, q, J=7.4 Hz), to 3.73 (2H×1/2, c), 3,74 (2H×1/2, c), was 7.08 (2H, d, J=9.0 Hz), 7,12 (1H×1/2, c), 7,37-7,40 (1H, m), 7,44 (1H×1/2, c), 7,55 (1H×1/2, c), to 7.77 (1H×1/2, c), 7,80-7,89 (1H, m), 7,82 (2H, d, J=9.0 Hz), at 8.36-8,42 (1H, m), 8,61-8,65 (1H, m), 10,88 (1H×1/2, USS), 10,94 (1H×1/2, USS).

ESI-MASS (m/e): 465 (M+H).

Example 130

Methyl [5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]acetate

80 ál (trimethylsilyl)diazomethane was added to a solution of 27.8 mg of carboxylic acid, obtained in example 129 (stage 1), in a mixture of 500 μl of tetrahydrofuran and 500 μl of methanol and was stirred for 1 hour. Then add 80 ál (trimethylsilyl)diazomethane and was stirred for 30 minutes. The solvent is evaporated under reduced pressure, the residue was diluted with ethyl acetate and was added saturated aqueous solution of sodium bicarbonate. Were extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 20/1), getting to 11.9 mg compounds SEM.

Using the 10.8 mg of the obtained compound SEM, 7.4 mg of target compound was obtained in the same manner as in example 127 (stage 2), or in accordance with this method, or its combination with a customary method.

1N the Mrs (CDCl 3) δ: of 1.29 (3H, t, J=7.4 Hz), of 3.12 (2H, q, J=7.4 Hz), 3,57 (3H×1/2, c)to 3.58 (3H×1/2, c), and 3.72 (2H, c), to 7.09 (2H, d, J=9.0 Hz), 7,10 (1H×1/2, c), 7,38-7,42 (1H, m), 7,47 (1H×1/2, c)to 7.50 (1H×1/2, c), 7,83 (1H×1/2, c), 7,83 (2H, d, J=9.0 Hz), 7,86-to $ 7.91 (1H, m), scored 8.38-8,43 (1H, m), 8,62-8,67 (1H, m), was 10.82 (1H, USS).

ESI-MASS (m/e): 452 (M+H).

Example 131

5-[4-(Ethylsulfonyl)phenoxy]-6-(2-oxo-2-(1-pyrrolidinyl)ethyl)-2-(2-pyridinyl]-1H-benzimidazole

Using pyrrolidin, the target compound was obtained in the same manner as in example 129 (step 2), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.4 Hz), 1,72-1,89 (4H, m), 3,11 (2H, q, J=7.4 Hz), to 3.38 (4H, t, J=6,7 Hz), 3,68 (2H×1/2, c), of 3.69 (2H×1/2, c), 7,06 (2H×1/2, d, J=9.0 Hz), 7,06 (2H×1/2, d, J=9.0 Hz), to 7.09 (1H×1/2, c)of 7.36-7,40 (1H, m), the 7.43 (1H×1/2, c), 7,60 (1H×1/2, c), 7,79-7,89 (3H, m), 7,81 (1H×1/2, c)at 8.36 (1H×1/2, d, J=8,2 Hz), 8,40 (1H×1/2, d, J=8,2 Hz), 8,61-8,65 (1H, m), 10,78 (1H×1/2, USS), 10,90 (1H×1/2, OSS).

ESI-MASS (m/e): 491 (M+H).

Example 132

N,N-Diethyl-2-[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]ndimethylacetamide

Using N,N-diethylamine, the target compound was obtained in the same manner as in example 129 (step 2), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 0,98 (3H×1/2, t, J=5,9 Hz), and 1.00 (3H×1/2, t, J=5,9 Hz), of 1.05 (3H, t, J=7.0 Hz), 1,24 (3H, t, J=7.4 Hz), of 3.07 (2H, q, J=7.4 Hz), 3,22-of 3.32 (4H, m)to 3.67 (2H×1/2, c), of 3.69 (2H×1/2, c),? 7.04 baby mortality (2H, d, J=9.0 Hz), 7,05 (1H×1/2, c), 7,32-7,37 (1H, m), 7,40 (1H×1/2, c), 7,51 (1H×1/2, c), to 7.77 (2H, d, J=9.0 Hz), 779 (1H×1/2, c), 7,83 (1H, t, J=8.0 Hz), with 8.33 (1H×1/2, d, J=8.0 Hz), at 8.36 (1H×1/2, d, J=8.0 Hz), 8,57-8,61 (1H, m), of 10.76 (1H×1/2, USS), 10,86 (1H×1/2, USS).

ESI-MASS (m/e): 493 (M+H).

Example 133

6-(2-(1-Azetidine)-2-oxoethyl)-5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole

Using the hydrochloride of azetidine and diisopropylethylamine, the target compound was obtained in the same manner as in example 129 (step 2), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.4 Hz), 2,11-of 2.21 (2H, m), of 3.12 (2H, q, J=7.4 Hz), 3,47 (2H×1/2, c)to 3.49 (2H×1/2, c), 3,88-of 3.94 (2H, m), a 4.03-4,08 (2H, m), 7,07-7,11 (2H, 1H×1/2, m), 7,37-7,41 (1H, m), the 7.43 (1H×1/2, c), 7,63 (1H×1/2, c), 7,82-of 7.90 (2H, 1H, 1H×1/2, m), at 8.36 (1H×1/2, d, J=7.8 Hz), 8,40 (1H×1/2, d, J=7.8 Hz), 8,62-8,66 (1H, m), 10,78 (1H, USS), 10,90 (1H, USS).

ESI-MASS (m/e): 477 (M+H).

Example 134

2-[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]-N-methylacetamide

Using methylamine hydrochloride and diisopropylethylamine, the target compound was obtained in the same manner as in example 129 (step 2), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.4 Hz), 2,70 (3H×1/2, c)of 2.72 (3H×1/2, c), the 3.11 (2H, q, J=7,4 Hz)and 3.59 (2H×1/2, c), 3,62 (2H×1/2, c)5,52 (1H×1/2, USS), 5,59 (1H×1/2, USS), 7,05 (2H×1/2, d, J=8.6 Hz), 7,07 (2H×1/2, d, J=8.6 Hz), to 7.15 (1H×1/2, c), 7,39-the 7.43 (1H, m), of 7.48 (1H×1/2, c), 7,56 (1H×1/2, c), 7,83 (2H, d, J=8.6 Hz), 7,87-to $ 7.91 (1H, m), 7,88 (1H×1/2, c)of 8.37-8,42 (1H, m), 8,63-8,67 (1H, m), 10,81 (1H×1/2, USS), 10,85 1H×1/2, OSS).

ESI-MASS (m/e): 451 (M+H).

Example 135

2-[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]ethanol

Stage 1. Getting 2-(5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)ethanol or 2-(6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)ethanol:

While cooling on ice, 43 mg of 1,1'-bicarbonic-1H-imidazole was added to a solution of 100 mg of carboxylic acid, obtained in example 129 (step 1)in tetrahydrofuran (2 ml) and stirred at room temperature for 2.5 hours. While cooling on ice, the reaction mixture was added dropwise to 1.5 ml of an aqueous solution of 34 mg of sodium borohydride and stirred for 5 minutes. The mixture was neutralized with 10% citric acid, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform/methanol), getting to 95.3 mg alcohol connection.

Stage 2. Obtain 2-[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]ethanol:

9.0 mg of the obtained alcohol compound was dissolved in 1 ml triperoxonane acid and stirred at room temperature in ECENA 1.5 hours. The solvent is evaporated and the residue was diluted with chloroform and neutralized with a saturated aqueous solution of sodium bicarbonate. Was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure, obtaining 9.0 mg of triptoreline. Potassium carbonate was added to a solution of 9.0 mg of triptoreline in methanol (1 ml) and stirred at room temperature for 30 minutes. The mixture was diluted with chloroform and was added saturated aqueous solution of ammonium chloride, was extracted with chloroform and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 6.6 mg of the target compound as a colorless amorphous substance.

1H-NMR (CDCl32 drops CD3OD) δ: of 1.30 (3H, t, J=7.4 Hz), 2,89-of 2.93 (2H, m), of 3.12 (2H, q, J=7.4 Hz), 3,85-to 3.89 (2H, m), 7,05 (2H, d, J=8.6 Hz), 7,16 (1H×1/2, c), 7,39-7,44 (1H, m), 7,41 (1H×1/2, c), 7,53 (1H×1/2, c), 7,79 (1H×1/2, c)of 7.82 (2H, d, J=8.6 Hz), 7,88-to 7.93 (1H, m), of 8.37-to 8.41 (1H, m), 8,62-8,67 (1H, m), NH peaks and invisible.

ESI-MASS (m/e): 424 (M+H).

Example 136

1-(2-[5-[4-(Ethylsulfonyl)phenoxy]-2-pyridinyl)-1H-benzimidazole-6-yl]ethyl)pyrrolidin-2,5-dione

10,7 mg su is Zinaida and 28.3 mg of triphenylphosphine were added to a solution of 20 mg of the alcohol compound, obtained in example 135 (stage 1), in tetrahydrofuran (1 ml) and cooled on ice was added 42 μl of diethylazodicarboxylate (40% solution in toluene) and stirred at room temperature for 30 minutes. Added ice water, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform/methanol) and dividing LC reverse phase, receiving 14,8 mg yellow oil.

14,8 mg of the obtained oil was dissolved in 1 ml triperoxonane acid and stirred at room temperature for 1 hour. The solvent is evaporated, the residue was diluted with chloroform and neutralized with a saturated aqueous solution of sodium bicarbonate. Was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 11 mg of the target compound as a colorless amorphous substance.

1H-NMR (CDCl3) δ: 1,29 (3H×1/2, t, J=7.2 Hz), of 1.30 (3H×1/2, t, J=7.2 Hz), 2.63 in (4H×1/2, c)to 2.65 (4H×1/2, c), 2,90-2,96 (2H, m), 3,11 (2H×1/2, kV, J=7,2 Hz), 3,12 (2H×1/2, kV, J=7,2 Hz), 3,79-a 3.83 (2H, m), 7,12 (2H×1/2, d, J=8.6 Hz), 7,17 (2×1/2, d, J=9.0 Hz), 7,37-7,42 (1H, m), 7,46 (1H×1/2, c)of 7.48 (1H×1/2, c), the 7.65 (1H×1/2, c), 7,82-7,89 (1H, m), 7,83 (2H×1/2, d, J=8.6 Hz), 7,86 (2H×1/2, d, J=9.0 Hz), 7,89 (1H×1/2, c)at 8.36-to 8.40 (1H, m), 8,62-8,67 (1H, m), 10,54 (1H, USS).

ESI-MASS (m/e): 505 (M+H).

Example 137

1-(2-[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]ethyl)-2-pyrrolidinone

Stage 1. Receive (5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-6-yl)acetaldehyde or (6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-yl)acetaldehyde:

300 μl of triethylamine and 120 mg of a complex of sulfur trioxide/pyridine was added to a solution of 28.9 mg of the alcohol compound obtained previously in example 135 (stage 1), in dimethyl sulfoxide (1 ml) and stirred at room temperature for 5 minutes. Added ice water, extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating liquid chromatography reverse phase, getting to 11.7 mg of the target compound as a colorless amorphous substance.

Stage 2. Obtain 1-(2-[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]ethyl)-2-pyrrolidinone:

6.6 mg of the hydrochloride of methyl 4-aminobutanoic was added to a solution of 11.7 mg obtained alder is Yes in tetrahydrofuran (1 ml) and stirred at room temperature for 10 minutes. Then added 106 μl of a solution of 0,25M complex cyanobac sodium-1/2-zinc chloride and stirred at room temperature for 1 hour. When cooled on ice was added saturated aqueous sodium hydrogen carbonate solution, was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 4.4 mg of colorless amorphous substance.

100 μl of 5 N. aqueous sodium hydroxide solution was added to a solution of 4.4 mg of amorphous material in a mixture of 250 μl of tetrahydrofuran and 250 μl of methanol and stirred at room temperature for 45 minutes. While cooling on ice, the mixture was neutralized with 10% citric acid, extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was dissolved in 500 μl triperoxonane acid and stirred at room temperature for 2.5 hours. The solvent is evaporated and the residue was diluted with chloroform and neutralized with a saturated aqueous solution of sodium bicarbonate. Was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying the solvent Vapaavuori reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1)to give 3,3 mg of target compound as a colorless amorphous substance.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7,6 Hz), 1,90-to 1.98 (2H, m), 2,30-of 2.38 (2H, m), 2,87 (2H, t, J=7.0 Hz), of 3.12 (2H, q, J=7,6 Hz), 3,20 to be 3.29 (2H, m), of 3.57 (2H, t, J=7.0 Hz), to 7.09 (2H, d, J=8.6 Hz), 7,11 (1H×1/2, c), 7,12 (2H, d, J=8.6 Hz), 7,37-7,42 (1H, m), of 7.48 (1H×1/2, c), 7,52 (1H×1/2, c), 7,73 (1H×1/2, c), 7,82-of 7.90 (3H, m), of 8.37-to 8.41 (1H, m), 8,62-8,68 (1H, m), at 10.64 (1H×1/2, USS), 10,71 (1H×1/2, USS).

ESI-MASS (m/e): 491 (M+H).

Example 138

2-[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]-N-methoxy-N-methylacetamide

Using the hydrochloride of N,O-dimethylhydroxylamine and diisopropylethylamine, the target compound was obtained in the same manner as in example 129 (step 2), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.4 Hz), 3,11 (2H, q, J=7,6 Hz), 3,12 (3H×1/2, c), of 3.13 (3H×1/2, c)to 3.58 (3H×1/2, c), of 3.60 (3H×1/2, c), a-3.84 (2H, c), to 7.09 (1H×1/2, c), 7,10 (2H, d, J=8.6 Hz), of 7.36-7,40 (1H, m), was 7.45 (1H×1/2, c), 7,53 (1H×1/2, c), 7,80-a 7.85 (1H×1/2, m(C)), 7,82 (2H×1/2, d, J=8.6 Hz), 7,83 (2H×1/2, d, J=8.6 Hz), the 7.85-of 7.90 (1H, m), at 8.36-8,42 (1H, m), 8,62-8,66 (1H, m), of 10.76 (1H, USS).

ESI-MASS (m/e): 481 (M+H).

Example 139

1-[5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]acetone

While cooling on ice 14 μl of a solution of 3.0m of methylacrylamide in tetrahydrofuran was added to a solution of 8.7 mg of the compound obtained in example 138, in tetrahydrofuran (500 μl) and stirred is at room temperature for 30 minutes, then was added 14 μl of a solution of 3.0m of methylacrylamide in tetrahydrofuran and stirred at room temperature for 5 minutes. When cooled on ice was added a saturated aqueous solution of ammonium chloride, was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by separation using thin layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 20/1)to give 4.0 mg of the target compound.

1H-NMR (CDCl3) δ: of 1.30 (3H, t, J=7,4 Hz)of 2.16 (3H, c), of 3.12 (2H, q, J=7.4 Hz), of 3.78 (2H, c), to 7.09 (2H, d, J=8.6 Hz), 7,12 (1H×1/2, c), 7,37-7,44 (1H, m), the 7.43 (1H×1/2, c), 7,47 (1H×1/2, c), 7,74 (1H×1/2, c), 7,84 (2H×1/2, d, J=8.6 Hz), the 7.85 (2H×1/2, d, J=8.6 Hz), a 7.85 to $ 7.91 (1H, m), at 8.36-8,42 (1H, m), 8,63-8,67 (1H, m), is 10.68 (1H, USS).

ESI-MASS (m/e): 436 (M+H).

Example 140

5-[4-(Ethylsulfonyl)phenoxy]-6-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2-(2-pyridinyl)-1H-benzimidazole

8 μl of aqueous 50% solution of hydroxylamine was added to a solution of 33 mg of cyanocobalamine obtained in example 127 (stage 1), in ethanol (1 ml) and stirred over night. After concentration of 6 μl of acetanhydride was added to a solution of the obtained residue in acetic acid (500 μl) and stirred at room temperature for 1 hour and then at 70°C for 5 hours. After concentration the residue was dissolved in 1 ml triperoxonane is islote and stirred at room temperature for 1 hour. The solvent is evaporated, the residue was diluted with chloroform and neutralized with a saturated aqueous solution of sodium bicarbonate. Was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by separation using liquid chromatography reverse phase and separating the thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 15/1)to give 9.1 mg of the target compound as a colorless amorphous substance.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.2 Hz), 2,48 (3H×1/2, c), 2,49 (3H×1/2, c), the 3.11 (2H, q, J=7.2 Hz), of 4.12 (2H, c), 7,06 (2H, d, J=8,2 Hz), 7,14 (1H×1/2, c), 7,37-the 7.43 (1H, m), 7,49 (1H×1/2, c), 7,55 (1H×1/2, c), for 7.78 (1H×1/2, c)of 7.82 (2H, d, J=8,2 Hz), 7,86-of 7.90 (1H, m), of 8.37-to 8.41 (1H, m), 8,62-8,66 (1H, m), 10,70 (1H, USS).

ESI-MASS (m/e): 476 (M+H).

Example 141

5-[4-(Ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-6-(2H-tetrazol-5-ylmethyl)-1H-benzimidazole (triptorelin)

Stage 1. Getting 5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-6-(2H-tetrazol-5-ylmethyl)-1-[{2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole or 6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-6-(2H-tetrazol-5-ylmethyl)-1-[{2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole:

162 μl trimethylsilane and 30.4 mg oxide dibutylamine was added to a solution of 35 mg of cyanocobalamine obtained in example 127 (stage 1), in toluene (3 ml) and during the night was heated under reflux. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform/methanol)to give 160 mg of the amorphous substance K yellow color.

Stage 2. Getting 5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-6-(2H-tetrazol-5-ylmethyl)-1H-benzimidazole (triptoreline):

13.3 g of the obtained amorphous yellow substance was dissolved in 1 ml triperoxonane acid and stirred at room temperature for 1.5 hours. The solvent is evaporated under reduced pressure and the residue was purified separating liquid chromatography reverse phase, getting to 11.1 mg of the target compound as a colorless amorphous substance.

1H-NMR (CD3OD) δ: of 1.23 (3H, t, J=7.4 Hz), 3,19 (2H, q, J=7.4 Hz), 4,48 (2H, c), 7,07 (2H, d, J=9.0 Hz), 7,41 (1H, c), 7,63 (1H, DD, J=8,2, a 4.7 Hz), to 7.84 (2H, d, J=9.0 Hz), 7,95 (1H, c), of 8.09 (1H, TD, J=8,2, 1,6 Hz), 8,30 (1H, d, J=8,2 Hz), 8,84 (1H, d, J=4,7 Hz).

ESI-MASS (m/e): 462 (M+H).

Example 142

5-[4-(Ethylsulfonyl)phenoxy]-6-((2-methyl-2H-tetrazol-5-yl)methyl)-2-(2-pyridinyl)-1H-benzimidazole

Stage 1. Getting 5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-6-(2-methyl-2H-tetrazol-5-ylmethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole or (6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-6-(2-methyl-2H-tetrazol-5-ylmethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole:

12.5 mg of tert-butoxide and potassium 133 mg iodomethane was added to a solution of 50 mg of tetrazole, obtained in example 141 (stage 1), N,N-dimethylformamide (1 ml) and stirred at room temperature for 1 hour. Added 12.5 mg of tert-butoxide potassium and stirred at room temperature for 30 minutes. When cooled on ice was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 15/1)to give 15,0 mg compounds of low polarity (target compound) and 17.5 mg of compounds of high polarity in the form of a colorless amorphous substance.

Stage 2. Getting 5-[4-(ethylsulfonyl)phenoxy]-6-((2-methyl-2H-tetrazol-5-yl)methyl)-2-(2-pyridinyl)-1H-benzimidazole:

Using 15 mg of the obtained compound of low polarity, the target compound was obtained in the same manner as in example 127 (stage 2), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,29 (3H×1/2, t, J=7.4 Hz), of 1.30 (3H×1/2, t, J=7.4 Hz), 3,11 (2H×1/2, kV, J=7,4 Hz), 3,11 (2H×1/2, kV, J=7,4 Hz), 4,18 (3H×1/2, c), is 4.21 (3H×1/2, c), or 4.31 (2H, c), 7,00 (2H×1/2, d, J=8.6 Hz), 7,02 (2H×1/2, d, J=8.6 Hz), 7,17 (1H×1/2, c), 7,37-7,42 (1H, m), 7,49 (1H×1/2, c), to 7.59 (1H×1/2, c), to 7.77 (2H×1/2, d, J=8.6 Hz), 7,80 (2H×1/2, d, J=8.6 Hz), 7,81 (1H×1/2, c), a 7.85 to $ 7.91 (1H, m), at 8.36-to 8.41 (1H, is), 8,62-8,67 (1H, m), of 10.58 (1H, USS).

ESI-MASS (m/e): 476 (M+H).

Example 143

5-[4-(Ethylsulfonyl)phenoxy]-6-((1-methyl-1H-tetrazol-5-yl)methyl)-2-(2-pyridinyl)-1H-benzimidazole

Using 17,5 mg compounds of high polarity, obtained in example 142 (stage 1), the target compound was obtained in the same manner as in example 127 (stage 2), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: is 1.31 (3H, t, J=7.4 Hz), of 3.13 (2H, q, J=7.4 Hz), 3,90 (3H×1/2, c), 3,91 (3H×1/2, c), 4,34 (2H, c), 7,02 (2H×1/2, d, J=8.6 Hz), 7,05 (2H×1/2, d, J=8.6 Hz), 7,17 (1H×1/2, c), 7,39-the 7.43 (1H, m), 7,46 (1H×1/2, c)of 7.48 (1H×1/2, c), of 7.70 (1H×1/2, c), to 7.84 (2H, d, J=8.6 Hz), a 7.85 to $ 7.91 (1H, m), 8,35-to 8.40 (1H, m), 8,63-8,67 (1H, m), 10,65 (1H, USS).

ESI-MASS (m/e): 476 (M+H).

Example 144

5-[4-(Ethylsulfonyl)phenoxy]-6-(1-(1-methyl-1H-tetrazol-5-yl]methyl)-2-(2-pyridinyl)-1H-benzimidazole

While cooling on ice and 7.1 mg of sodium hydride and 20 mg iodomethane was added to a solution of 64 mg of tetrazole obtained in example 141 (stage 1), N,N-dimethylformamide (2 ml) and stirred at room temperature for 2 hours. When cooled on ice was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (erck), chloroform/methanol = 15/1)to give 10.0 mg of amorphous material, light yellow color. 10.0 mg of amorphous material, light yellow color was dissolved in 1 ml triperoxonane acid and stirred at room temperature for 1 hour. The solvent is evaporated, the residue was diluted with chloroform and neutralized with a saturated aqueous solution of sodium bicarbonate. Was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 10/1), receiving of 7.1 mg of the target compound as a colorless amorphous substance.

1H-NMR (CDCl3) δ: is 1.31 (3H, t, J=7.4 Hz), is 1.81 (3H×1/2, d, J=7,2 Hz), of 1.84 (3H×1/2, d, J=6.8 Hz), 3,14 (2H, q, J=7.4 Hz), 3,74 (3H×1/2, c), with 3.79 (3H×1/2, c), 4,60-of 4.75 (1H, m), 7.03 is-7,13 (2H, m), 7,16 (1H×1/2, c), 7,37-7,44 (1H, m), 7,39 (1H×1/2, c)of 7.48 (1H×1/2, c), 7,71 (1H×1/2, c), of 7.75-to $ 7.91 (3H, m), 8,32-8,42 (1H, m), 8,58-to 8.70 (1H, m), 10,63 (1H×1/2, USS), 10,66 (1H×1/2, USS).

ESI-MASS (m/e): 490 (M+H).

Example 145

N-[{6-[(4-Ethylsulfonyl)phenoxy]-2-pyridin-2-yl-1H-benzimidazole-4-yl}methyl]methanesulfonamide

Using the product obtained in example 70 (stage 7), the target compound was obtained in the same manner as in example 31, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.28 (in 3H, the, J=a 10.6 Hz), and 2.83 (3H, c), 3,10 (2H, t, J=10,6 Hz), 4,74 (2H, d, J=6.3 Hz), 6,34 (1H, c), 6,98 (1H, c), was 7.08 (2H, d, J=6.3 Hz), 7,18 (1H, c), of 7.48-7,42 (1H, m), of 7.90-a 7.85 (3H, m), of 8.37 (1H, d, J=7.4 Hz), 8,64 (1H, d, J=5,1 Hz), at 10.64 (1H, USS).

ESI-MASS (m/e): 487 (M+H).

Example 146

3-[{6-[4-Ethylsulfonyl)phenoxy]-2-pyridin-2-yl-1H-benzimidazole-4-yl}methyl]-1,3-oxazolidin-2-he

Using the product obtained in example 70 (stage 7), the target compound was obtained in the same manner as in example 3, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.4 Hz), 3,11 (2H, q, J=7.4 Hz), 3,62 is 3.57 (2H, m), 4,35-to 4.33 (2H, m), of 4.67 (2H, c)6,91 (1H, c), to 7.09 (2H, d, J=8.6 Hz), 7,37-to 7.35 (1H, m), 7,52 (1H, c), 7,84-of 7.82 (3H, m), a 8.34 (1H, d, J=8,2 Hz), a total of 8.74 (1H, d, J=3,9 Hz), 11,72 (1H, USS).

ESI-MASS (m/e): 479 (M+H).

Example 147

1-[{6-[4-Ethylsulfonyl)phenoxy]-2-pyridin-2-yl-1H-benzimidazole-4-yl}methyl]piperidine-2-he

Using the product obtained in example 70 (stage 7), the target compound was obtained in the same manner as in example 6, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.4 Hz), 1,77 is 1.70 (4H, m), of 2.51 (2H, m), 3,11 (2H, q, J=7.4 Hz), 3,34-of 3.32 (2H, m), was 4.76 (2H, c), 6,90-6,98 (1H, m), was 7.08 (2H, d, J=8,8 Hz), of 7.36-7,34 (1H, m), 7,51 is 7.50 (1H, m), 7,83-of 7.82 (3H, m), a 8.34 (1H, d, J=7.8 Hz), 8,78 (1H, d, J=5,1 Hz), 12,13 (1H, USS).

ESI-MASS (m/e): 491(M+H).

Example 148

6-[4-(Ethylsulfonyl)phenoxy]-4-(3-terbisil)-2-pyridin-2-yl-1H-benzimidazole

COI is lsua aldehyde compound, obtained in example 76 (stage 1), and 3-performancebased, the target compound was obtained in the same manner as in example 76 (stages 2, 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,26-of 1.23 (3H, m), 3,11 of 2.92 (2H, m)to 4.23 (1H, c), of 4.44 (1H, c), 6,72 (1/2N, c), 6,89-6,86 (2H, m), 7,12-7,02 (5H, m), 7,35-7,33 (1H, m), 7,84 to 7.75 (4H, m), 8,43 (1/2H, d, J=8.6 Hz), 8,58-8,54 (1H, m), 10,66 (1H, USS).

ESI-MASS (m/e): 488 (M+H).

Example 149

4-(3,4-Diferensial)-6-[4-(ethylsulfonyl)phenoxy]-2-pyridin-2-yl-1H-benzimidazole

Using aldehyde compound obtained in example 76 (stage 1), and 3,4-differentialalgebraic, the target compound was obtained in the same manner as in example 76 (stages 2, 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,28-1,22 (3H, m), 3,11 was 3.05 (2H, m), 4,11 (1H, c), 4,39 (1H, c), 6,72 (1H, c), 7,06-7,03 (5H, m), 7,40-to 7.35 (2H, m), 7,85 for 7.78 (3H, m), to 8.41 (1H, c), at 8.60-8,54 (1H, m), 10,59 (1H, USS).

ESI-MASS (m/e): 506 (M+H).

Example 150

1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]pyrrolidin-2-he

Stage 1. Obtain (6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-(2-pyridyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-yl)methanol and (5-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-(2-pyridyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-7-yl)methanol:

Using 6-(ethylsulfonyl)-3-pyridine is l, obtained in reference example 4, the target compound was obtained in the same manner as in example 70 (stage 2-7), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtaining 1-[(6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]pyrrolidin-2-it:

Using the obtained alcohol compound, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=7,6 Hz), 2,05-of 1.97 (2H, m), 2,48 is 2.46 (2H, m), 3,39-to 3.36 (4H, m), with 4.64 (2H, c), 6,89 (1H, d, J=1.6 Hz), of 7.36-7,34 (2H, m), 7,49 (1H, c), of 7.82 (1H, t, J=7.0 Hz), 7,98 (1H, d, J=8.6 Hz), with 8.33 (1H, d, J=7.8 Hz), 8,46 (1H, d, J=2.7 Hz), 8,75-8,73 (1H, m).

ESI-MASS (m/e): 478 (M+H).

Example 151

4-({6-[4-(Ethylsulfonyl)phenoxy]-2-pyridin-2-yl-1H-benzimidazole-4-yl}methyl)morpholine-3-one

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 81, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.26 in (3H, t, J=7.4 Hz), is 3.08 (2H, q, J=7.4 Hz), 3,40 (2H, c), 3,82-of 3.80 (2H, m), 4.26 deaths (2H, c), of 4.77 (2H, c), 6,89 (1H, c), 7,07-7,05 (2H, m), 7,35-7,33 (1H, m), 7,51 (1H, c), 7,81 (3H, d, J=9.0 Hz), with 8.33 (1H, d, J=7,4 Hz), 8,76-8,73 (1H, m), 11,93 (1H, USS).

ESI-MASS (m/e): 493 (M+H).

Example 152

1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimida the ol-4-yl)methyl]pyridine-2(1H)-he

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 5, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.26 in (3H, t, J=8.6 Hz), 3,39-of 3.32 (2H, m), are 5.36 (2H, c), of 6.26 (1H, t, J=6.8 Hz), to 6.75 (1H, d, J=9.0 Hz), 7,03 (1H, d, J=2.0 Hz), of 7.36-7,34 (3H, m), the 7.43 (1H, d, J=6,7 Hz), 7,51 (1H, d, J=2.0 Hz), 7,86 for 7.78 (1H, m), 7,99-of 7.95 (1H, m), 8,31 (1H, d, J=7.8 Hz), of 8.47 (1H, d, J=2.7 Hz), 8,77 (1H, d, J=4,7 Hz), 12,49 (1H, c).

ESI-MASS (m/e): 488 (M+H).

Example 153

6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-4-[(pyridine-2-yloxy)methyl]-1H-benzimidazole

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 5, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,30-1,22 (3H, m)to 3.36 (2H, q, J=7,6 Hz), of 5.68 (2H, c), PC 6.82 (1H, d, J=8,2 Hz), 6,97-to 6.95 (1H, m), 7,12 (1H, c), 7,37-7,34 (2H, m), 7,51 (1H, c), a 7.62-of 7.60 (1H, m), a 7.85-7,83 (1H, m), of 7.97 (1H, d, J=8.6 Hz), 8,35 (1H, d, J=7.8 Hz), 8,43-8,42 (1H, m), 8,49-8,48 (1H, m), to 8.70 (1H, d, J=5,1 Hz), 12,27 (1H, s).

ESI-MASS (m/e): 488 (M+H).

Example 154

1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]-3-methylpyrrolidine-2-he

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 10, or in accordance with this method is m, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,28-of 1.23 (6H, m), 1,64-of 1.55 (1H, m), 2,18 with 2.14 (1H, m), 2,43-of 2.34 (1H, m), 2,58-of 2.50 (1H, m)to 3.36 (2H, q, J=7.4 Hz), 3,61 (1H, m), and 4.40 (1H, d, J=14,9 Hz), 4,89 (1H, d, J=14,9 Hz), to 6.88 (1H, c), 7,34-to 7.32 (2H, m), of 7.48 (1H, c), 7,82-7,80 (1H, m), 7,98 (1H, d, J=8.6 Hz), a 8.34 (1H, d, J=10.4 Hz), 8,45-8,44 (1H, m), 8,77-a total of 8.74 (1H, m), 12,12 (1H, USS).

ESI-MASS (m/e): 492 (M+H).

Example 155

1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]-1H-imidazole-4,5-dicarbonitrile

Using the alcohol compound obtained in example 150 (stage 1), and 4,5-dicyanoimidazole, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.4 Hz), 3,37 (2H, q, J=7.4 Hz), to 5.66 (2H, c), 7,12 (1H, d, J=2.0 Hz), 7,32 (1H, d, J=2.0 Hz), 7,40 (1H, DD, J=8,6, 2.7 Hz), 7,49-7,47 (1H, m), 7,99-of 7.97 (1H, m), 8,03 (1H, d, J=8.6 Hz), by 8.22 (1H, c), 8,42 (1H, s, J=8,2 Hz), of 8.47 (1H, m), 8,64-8,63 (1H, m).

ESI-MASS (m/e): 511 (M+H).

Example 156

1-{1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]-1H-pyrrol-3-yl}alanon

Using the alcohol compound obtained in example 150 (stage 1), and 3-acetylpyrrole, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.27 (3H, t, J=7.4 Hz), a 2.36 (3H, c), the 3.35 (2H, q, J=7,4 Hz), and 5.5 (2H, c)to 6.57 (1H, c), to 6.67 (1H, c), to 6.80 (1H, c), 7,12 (1H, c), of 7.36-to 7.32 (2H, m), of 7.48 (1H, c), 7,88-7,86 (1H, m), of 7.97 (1H, d, J=8.6 Hz), 8,42-8,39 (2H, m), at 8.60 (1H, c), 10,95 (1H, s).

ESI-MASS (m/e): 502 (M+H).

Example 157

1-{1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]-1H-pyrrol-2-yl}alanon

Using the alcohol compound obtained in example 150 (stage 1), and 2-acetylpyrrole, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,30-1,22 (3H, m), 2,39 (1H, c), of 2.54 (2H, c), 3,39-of 3.32 (2H, m), of 5.81 (1H, c), between 6.08 (1H, c), 6,15-6,14 (1/2N, c), 6,21-6,20 (1/2N, c), 6,61 (1/2N, c), 6,97-to 6.95 (1H, m), 7,07-7,02 (2H, m), 7,38-7,30 (2H, m), 7,47 (1/2N, c), 7,88-7,80 (1H, m), of 7.96-7,94 (1H, m), 8,31 (1H, d, J=7,4 Hz), scored 8.38-of 8.37 (1/2N, c), 8,46-8,43 (1H, m), 8,60-8,59 (1/2H, m), 8,70-8,69 (1/2N, c), to 10.62 (1/2H, OSS), to 11.61 (1/2N, USS).

ESI-MASS (m/e): 502 (M+H).

Example 158

1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]-5-methylpyrrolidine-2-he

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 9, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,21-of 1.20 (3H, m)of 1.28 (3H, t, J=7.4 Hz), 1,63-of 1.56 (1H, m), 2,24-of 2.23 (1H, m), 2,56-of 2.54 (1H, m), 3,36-of 3.31 (4H, m), 4,36 (2H, c), 6,89 (1H, m), of 7.36-7,34 (2H, m), 7,49 (1H, c), 7,83-7,80 (1H, m), 7,99 (1H, d, J=8.6 Hz), with 8.33 (1H, d, J=7.8 Hz), 8,46-to 8.45 (1H, m), 8,84 is 8.75 (1H, m).

<> ESI-MASS (m/e): 492 (M+H).

Example 159

1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]-1H-imidazol-2-carbonitril

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 82, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=7.4 Hz), to 3.36 (2H, q, J=7.4 Hz), 5,72 (2H, c), to 6.95 (1H, c), 7,14 (1H, c), 7,18 (1H, c), 7,34 (1H, DD, J=8,6, 2.7 Hz), 7,40-7,38 (1H, m), 7,46 (1H, c), 7,89 (1H, t, J=7.8 Hz), 8,00 (1H, d, J=8.6 Hz), 8,44-8,43 (2H, m), 8,61 at 8.60 (1H, m), 11,09 (1H, USS).

ESI-MASS (m/e): 486 (M+H).

Example 160

6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-4-[(2-herperidin-3-yl)methyl]-2-pyridin-2-yl-1H-benzimidazole

Stage 1. Obtain 6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-carbaldehyde and 5-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-(2-pyridyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-7-carbaldehyde:

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 64 (stage 1), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain (6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-yl)(2-herperidin-3-yl)methane is a or (5-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-7-yl)(2-herperidin-3-yl)methanol :

At -78°C to 0.80 ml normal utility (1.5m solution in hexane) was added to a solution of 169 μl of Diisopropylamine in tetrahydrofuran (1 ml) and, while cooling on ice, stirred for 30 minutes, getting liedeseplein. At -78°C was added 103 ál 2-herperidin and was stirred for 3 hours at this temperature. At -78°C a solution of 130 mg of the aldehyde obtained in stage 1, in tetrahydrofuran (2 ml) was added to this reaction liquid, and stirred for about 1 hour, while maintaining the same temperature. A saturated aqueous solution of ammonium chloride was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was dried, the solvent evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 2/1)to give 106 mg (6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-yl)(2-herperidin-3-yl)methanol as an orange oil.

Stage 3. Obtain 6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-4-[(2-herperidin-3-yl)methyl]-2-pyridin-2-yl-1H-benzimidazole:

At room temperature of 8.2 μl of thionyl chloride was added to a solution of 24 mg of the alcohol compound obtained in stage 2, in chloroform (0.5 ml) and was stirred for 30 minutes. The solvent is evaporated p. and reduced pressure, give crude product. 12 mg of zinc was added to a solution of this crude product in triperoxonane acid (0.7 ml) and stirred at 100°C for 30 minutes. After returning to room temperature the mixture was filtered through Celite (solvent for elution: chloroform, methanol), the solvent evaporated under reduced pressure, the residue was washed with a saturated aqueous solution of sodium bicarbonate, dried, the solvent evaporated under reduced pressure and the residue was purified by thin-layer chromatography on columns (showing solvent: chloroform/methanol = 9/1)to give 3.5 g of the target compound in a solid white color.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=7,6 Hz), the 3.35 (2H, q, J=7,6 Hz), 4,25 (1H, c), to 4.46 (1H, c), 6,86-PC 6.82 (1H, m), 7,10-was 7.08 (2H, m), 7,35-to 7.32 (2H, m), 7,87-a 7.85 (2H, m), 7,98 (1H, d, J=8.6 Hz), 8,10-of 8.04 (1H, m), 8,43-to 8.40 (2H, m), 8,62 at 8.60 (1H, m), 10,53 (1H, USS).

ESI-MASS (m/e): 490 (M+H).

Example 161

1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1H-benzimidazole-4-yl)methyl]pyrrolidin-2-he

Stage 1. Obtain methyl 2-amino-5-[{[6-(ethylsulfonyl)pyridine-2-yl]oxy}benzoate:

Using 6-(ethylsulfonyl)-3-pyridinol obtained in reference example 4, the target compound was obtained in the same manner as in example 70 (stages 2, 3), or in accordance with this method, or its combination with a customary method.

Stage 2. Obtain methyl 5-{[6-(this is sulfonyl)pyridine-3-yl]oxy}-3-nitro-2-[(pyrazin-2-ylcarbonyl)amino]benzoate :

4.7 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added to a solution of 5.5 g of methyl 2-amino-5-[{[6-(ethylsulfonyl)pyridine-3-yl]oxy}benzoate and 2.4 g pyrazin-2-carboxylic acid in pyridine (150 ml) and stirred at room temperature for 6 hours. The solvent is evaporated under reduced pressure, was added to the residue chloroform and the organic layer was washed water of 0.25 N. hydrochloric acid, water of 0.25 N. the sodium hydroxide solution and saturated saline solution. After drying was concentrated under reduced pressure, recrystallized from toluene, and the obtained crystal was separated by filtration. It was dried under reduced pressure, obtaining 5.6 g of target compound in the form of a crystal brown.

Using 5.6 g of the obtained solid substance, 5,44 g of target compound was obtained as an amorphous substance brown in the same way as in example 70 (stage 5), or in accordance with this method, or its combination with a customary method.

Stage 3. Obtain methyl 6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-carboxylate and methyl 5-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-7-carboxylate:

3.1 g of iron was added to the solution 5,44 g obtained avrprog the substances in acetic acid (60 ml) and stirred at 80°C for 40 minutes. After filtration the solvent is evaporated under reduced pressure, to the residue was added ice water, extracted with chloroform, and the organic layer was washed with saturated saline solution. After drying it was evaporated under reduced pressure, recrystallized from toluene, and the obtained crystal was separated by filtration. It was dried under reduced pressure, obtaining 4.0 g of target compound in the form of the crystal grey color.

80 ml of dimethylformamide and 80 ml of tetrahydrofuran was added to 4.0 g of the obtained crystal was heated and dissolved. Upon cooling, water was added to 2.4 ml of 2-(trimethylsilyl)ethoxymethylene and 476 mg of sodium hydride (with the addition of 30% liquid paraffin) and stirred at room temperature for 1 hour. When cooled on ice was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 1/9)to give 5,22 g of target compound in the form of an amorphous yellow substance.

Stage 4. Obtain (6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-yl)methanol and (5-{[6-(ethylal is of IMT)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-7-yl)methanol :

Using with 5.22 g of the obtained complex methyl ester, of 1.57 g of target compound was obtained as an amorphous yellow substance in the same manner as in example 34 stage (stage 3), or in accordance with this method, or its combination with a customary method.

Stage 5. Obtaining 1-[(6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1H-benzimidazole-4-yl)methyl]pyrrolidin-2-it:

Using the obtained alcohol compound, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.29 (3H, t, J=7.4 Hz), 2,07 of 1.99 (2H, m), 2,48 (2H, t, J=8,2 Hz), 3,44-to 3.34 (4H, m), to 4.62 (2H, c), 6,92 (1H, m), at 8.36 (1H, m), 7,53 (1H, m), of 8.00 (1H, d, J=8.6 Hz), of 8.47-8,46 (1H, m), 8,63-to 8.62 (1H, m), 8,72-to 8.70 (1H, m), to 9.57 (1H, d, J=1.2 Hz), 12,18 (1H, s).

ESI-MASS (m/e): 479 (M+H).

Example 162

4-[(2-Chloropyridin-3-yl)methyl]-6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole

Using 2-chloropyridin, the target compound was obtained in the same manner as in example 160 (stages 2, 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.30 and to 1.21 (3H, m)to 3.35 (2H, q, J=7.4 Hz), 4,34 (1H, c), of 4.57 (1H, c), 6,80-of 6.78 (1H, m), 7,15-7,13 (1H, m), 7,46-7,31 (3H, m), of 7.75 (1H, d, J=7.8 Hz), 7,86-a 7.85 (1H, m), of 7.97 (1H, d, J=8.6 Hz), 8,40-8,29 (3H, m), 8,61 (1H, c), as 10.63 (1H, s).

ESI-MASS (m/e): 506 (M+H).

Example 163

6-{[6-(Ethylsulfonyl)Piri is INF-3-yl]oxy}-4-[(3-herperidin-4-yl)methyl]-2-pyridin-2-yl-1H-benzimidazole

Stage 1. Obtain (6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1-[{2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-yl)(3-herperidin-4-yl)methanol or (5-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1-[{2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-7-yl)(3-herperidin-4-yl)methanol:

At -20°C 0,92 ml normal utility (1.5m solution in hexane) was added to a solution of 154 mg of 4-diazabicyclo[2,2,2]octane in diethyl ether (1.5 ml) and was stirred at this temperature for 1 hour. Then added 119 μl of 3-herperidin at -78°C and stirred at this temperature for 2 hours. At -60°C was added a solution of 149 mg of 6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1-[{2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-carbaldehyde in tetrahydrofuran (2 ml) and was stirred at this temperature for 1 hour. Then was added a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic layer was dried, the solvent evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 2/1 to 0/1)to give 32 mg of the target compound as a yellow oil.

Stage 2. Obtain 6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-4-[(3-herperidin-4-yl)methyl]-2-pyridin-2-yl-1H-benzimidazole:

The target compound was obtained in the same is the procedure, as in example 160 (stage 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.30 and to 1.21 (3H, m)to 3.35 (2H, q, J=7.4 Hz), 4,49 (2H, c), to 6.80 (1H, c), 7,10 (1H, c), 7,38-to 7.32 (3H, m), 7,86 (1H, t, J=7.2 Hz), 7,98 (1H, t, J=8.6 Hz), 8,28 compared to 8.26 (1H, m), 8,45-to 8.41 (3H, m), 8,61 at 8.60 (1H, m), 10,56 (1H, s).

ESI-MASS (m/e): 490 (M+H).

Example 164

1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]-1H-pyrrol-2-carbonitril

Using 2-cyanoprop, the target compound was obtained in the same manner as in example 150, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=7.4 Hz), to 3.36 (2H, q, J=7.4 Hz), of 5.68 (2H, c), 6,16 (1H, c), 6,79 to 6.75 (2H, m), 7,17 for 7.12 (2H, m), 7,32 (1H, DD, J=8,8, 2,5 Hz), 7,39-7,37 (1H, m), 7,89-7,87 (1H, m), of 7.97 (1H, d, J=8,6 Hz), 8,44-to 8.41 (2H, m), 8,61 at 8.60 (1H, m), 10,92 (1H, USS).

ESI-MASS (m/e): 485 (M+H).

Example 165

(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)(3-herperidin-2-yl)methanol

Using 3-herperidin, the target compound was obtained in the same manner as in example 160 (stages 2, 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.28 (3H, t, J=7,6 Hz)to 3.36 (2H, q, J=7,6 Hz), to 6.67 (1H, c), to 6.80 (1H, c), 7,33-7,29 (3H, m), 7,53-7,51 (1H, m), to 7.77-7,74 (1H, m), to 7.99 (2H, d, J=9.0 Hz), to 8.41-8,39 (2H, m), 8,48-to 8.45 (1H, m), 8,68-8,66 (1H, m).

ESI-MASS (m/e): 506 (M+H).

Example 166

1-{1-[(6-{[6-(Atila hanil)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]-1H-imidazol-2-yl}alanon

Using 2-acetylimidazole obtained in example 92 (stage 1), the target compound was obtained in the same manner as in example 150, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.42 (3H, t, J=7.4 Hz), 2,78 (2H, c), only 2.91 (1H, c), a 3.50 (2H, q, J=7.4 Hz), 5,99 (2/3H, c), 6,24 (4/3H, c), 7,03 (2/3H, c), 7,12 (1/3H, c), 7,25 (1H, d, J=7.8 Hz), 7,53-7,40 (3H, m), of 7.64 (2/3H, c), 7,70 (1/3H, c), 8,03-8,01 (1H, m), 8,12-8,10 (1H, m), 8,57-8,48 (2H, m), 8,75-a total of 8.74 (2/3H, m), cent to 8.85-8,82 (1/3H, m), 11,08 (2/3H, c), 11,70 (1/3H, s).

ESI-MASS (m/e): 503 (M+H).

Example 167

4-[(3,5-Differencein-4-yl)methyl]-6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole

Using 3,5-giftability, the target compound was obtained in the same manner as in example 160 (stages 2, 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.26 in (3H, t, J=7,6 Hz)to 3.36 (2H, q, J=7,6 Hz), 4,46 (2H, c), for 6.81 (1H, c), 7,30 (2H, m), 7,40-7,39 (1H, m), 7,88 (1H, t, J=7.0 Hz), of 7.97 (1H, d, J=8.6 Hz), with 8.33 (2H, c), 8,42-8,39 (2H, m), 8,64-8,63 (1H, m).

ESI-MASS (m/e): 508 (M+H).

Example 168

1-{1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]-1H-pyrrol-2-yl}-2,2,2-triptoreline

Using 2,2,2-Cryptor-1-(1H-pyrrol-2-yl)-1-Etalon, the target compound was obtained in the same manner as in example 150, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.27 (3H, t, J=7,4 Hz), 35 (2H, kV, J=7,4 Hz), equal to 6.05 (2H, c), of 6.29 (1H, c), of 6.73 (1H, c), to 7.09 (1H, c), 7,39-7,37 (1H, m), 7,58 (1H, c), 7,89-7,86 (1H, m), 7,94 (1H, d, J=8,2 Hz), to 8.41 is 8.38 (3H, m), 8,62 at 8.60 (2H, m), 10,90 (1H, s).

ESI-MASS (m/e): 556 (M+H).

Example 169

4-(2,6-Diferensial)-6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-yl-1H-benzimidazole

Using 1,3-differental, the target compound was obtained in the same manner as in example 160 (stages 2, 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.27 (3H, t, J=7.4 Hz), the 3.35 (2H, q, J=7.4 Hz), 4,24 (1H, c), of 4.57 (1H, c), 6,89-6,91 (3H, m), 7,19-7,17 (1H, m), 7,29-7,27 (1H, m), 7,39-7,37 (2H, m), a 7.85-to 7.84 (1H, m), 7,95 (1H, d, J=8.6 Hz), 8,45-8,35 (2H, m), 8,69-8,66 (1H, m), a 10.74 (1H, s).

ESI-MASS (m/e): 507 (M+H).

Example 170

1-{1-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]-1H-pyrazole-3-yl}alanon

Using hydrochloride 5-acetylthiazole, the target compound was obtained in the same manner as in example 150, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.30 and 1,24 (3H, m), of 2.54 (1H, c), is 2.88 (2H, c), 3,39-to 3.33 (2H, m), 5,59 (1H, c), to 5.85 (1H, c), 6,84 to 6.75 (1H, m), 7,02 (1H, c), 7,38-7,33 (2H, m), 7,51 is 7.50 (1H, m), of 7.90-of 7.82 (1H, m), 7,99-of 7.97 (1H, m), with 8.33 (1H, d, J=7.8 Hz), 8,43-to 8.41 (1H, m), of 8.47-8,46 (1H, m), 8,62-8,61 (1H, m), 10,81 (1/3H, c), to 11.79 (2/3H, s).

ESI-MASS (m/e): 503 (M+H).

Example 171

1-[(6-{[6-(5-Methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-pyridine-2-yl-1H-benzimidazole-4-yl)methyl]pyrrolidin-2-he/p>

1.54 g of 6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-ol and 1.86 g of potassium carbonate were added to a solution of 955 mg of methyl 5-fluoro-2-nitrobenzoate in dimethylformamide (10 ml) and stirred at 80°C for 1 hour. The mixture was cooled to room temperature, then was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, the organic layer was dried and the solvent evaporated under reduced pressure, getting to 1.38 g of methyl 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-nitrobenzoate in a solid yellow color.

a 1.96 ml of aqueous 5 n sodium hydroxide solution was added to a solution of 700 mg of methyl 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-nitrobenzoate in 5 ml methanol and 5 ml of tetrahydrofuran and stirred at room temperature for 2.5 hours. Aqueous 10% solution of citric acid was added for neutralization, and then was extracted with ethyl acetate, the organic layer was dried and the solvent evaporated under reduced pressure, getting 399 mg of 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-nitrobenzoic acid in the form of a solid of light yellow color.

282 mg of N,N'-carboxydismutase was added to a solution of 399 mg of the specified carboxylic acid in tetrahydrofuran (5 ml) and stirred at room temperature for 30 minutes. While cooling on ice indicated the reaction liquid is obavljale to aqueous solution of 219 mg sodium borohydride (5 ml) and was stirred for 20 minutes. The neutralized aqueous 10% citric acid solution, extracted with ethyl acetate, the organic layer was dried and the solvent evaporated under reduced pressure, getting 367 mg (5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-nitrophenyl)methanol in the form of a solid of light yellow color.

to 0.92 ml of triethylamine and 530 mg of a complex of sulfur trioxide/pyridine was added to a solution of 367 mg (5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-nitrophenyl)methanol in dimethyl sulfoxide (5 ml) and stirred at room temperature for 30 minutes. Was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, the organic layer was dried, the solvent evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 3/7)to give 174 mg of 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-nitrobenzaldehyde in a solid yellow color.

123 mg of the hydrochloride of 4-aminobutanoic acid and 0.11 ml of triethylamine was added to a solution of 174 mg of the above compound in chloroform (4 ml) and stirred at room temperature for 30 minutes. Then added 339 mg triacetoxyborohydride sodium and stirred over night. Was added a saturated salt solution was extracted with chloroform, the organic is Loy was dried and the solvent evaporated under reduced pressure, getting 210 mg of 1-(5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-nitrobenzyl)pyrrolidin-2-it is in the form of a solid of light yellow color.

599 mg of the dihydrate of tin chloride was added to a solution of 210 mg of the above compound in 2 ml of dimethylformamide and 2 ml of methanol and stirred at 80°C for 90 minutes. The mixture was cooled to room temperature, then neutralized with a saturated aqueous solution of sodium bicarbonate and the resulting salt was removed by filtration. The organic layer of the filtrate was washed with water and saturated salt solution. After drying, the solvent is evaporated, getting 144 mg of a crude product of 1-(2-amino-5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}benzyl)pyrrolidin-2-it is in the form of a yellow oil.

While cooling on ice 0.33 ml of triethylamine and 210 mg of the acid chloride pikolinos acid was added to a solution of 144 mg of 1-(2-amino-5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}benzyl)pyrrolidin-2-it in chloroform (2 ml) and stirred at room temperature for 1 hour. Added ice water, extracted with chloroform, the organic layer was dried, the solvent was removed and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 2/8)to give 117 mg of N-{4-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyridine-2-to rockslide in the form of a solid of light yellow color.

126 mg of potassium nitrate was added to a solution of 117 mg of N-{4-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyridine-2-carboxamide in triperoxonane acid (3 ml) and stirred at 80°C for 7 hours. Triperoxonane acid evaporated under reduced pressure, then was added to the residue chloroform and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried and the solvent evaporated under reduced pressure, getting 122 mg of N-{4-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-nitro-6-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyridine-2-carboxamide as a brown oil.

266 mg of the dihydrate of tin chloride was added to a solution of 122 mg of the above compound in 1 ml of dimethylformamide and 1 ml of methanol and was stirred over night at 80°C. the Mixture was cooled to room temperature, then was added a saturated aqueous solution of sodium bicarbonate and the resulting salt was removed by filtration. The organic layer of the filtrate was washed with water and saturated salt solution. After drying, the solvent is evaporated and the residue was purified by thin-layer chromatography on columns (showing solvent: chloroform/methanol = 9/1)to give 20 mg of 1-[(6-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]pyrrolidin-2-it is in the form of solid matter what color it.

1H-NMR (CDCl3) δ: 2,03-to 1.98 (2H, m), 2,48 is 2.46 (2H, m)to 2.66 (3H, c), 3,39 (2H, t, J=7.2 Hz), to 4.62 (2H, c), of 6.90 (1H, d, J=2.3 Hz), 7,34-7,31 (2H, m)to 7.50 (1H, c), 7,82-7,80 (1H, m), 8,01-to 7.99 (1H, m), with 8.33 (1H, d, J=7,4 Hz), 8,53 (1H, d, J=2.7 Hz), 8,76 is 8.75 (1H, m), 11,99 (1H, s).

ESI-MASS (m/e): 468 (M+H).

Example 172

4-[(2,4-Dichloropyridine-3-yl)methyl]-6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole

Using 3,5-dichloropyridine, the target compound was obtained in the same manner as in example 160 (stages 2, 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,28-of 1.20 (3H, m)to 3.34 (2H, q, J=7.4 Hz), of 4.54 (1H, c), 4,84 (1H, c), 6,37 (1H, c), 7,03 (1H, d, J=2.0 Hz), 7,27-of 7.23 (1H, m), 7,41-7,31 (2H, m), 7,87-a 7.85 (1H, m), 7,94 (1H, q, J=9.0 Hz), 8,23 is 8.22 (1H, m), 8,44-at 8.36 (2H, m), 8,65 at 8.60 (1H, m), 11,00 (1H, s).

ESI-MASS (m/e): 540 (M+H).

Example 173

4-(2,6-Diferensial)-6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1H-benzimidazole

While cooling on ice, 44 μl of triethylamine and 16 μl of methanesulfonamide was added to a solution of 57 mg of the alcohol compound obtained in example 161 (stage 4), in tetrahydrofuran (1.0 ml) and was stirred at this temperature for 30 minutes. Was added to the reaction liquid saturated salt solution was extracted with ethyl acetate, the organic layer was dried and the solvent evaporated under reduced pressure, receiving 67 mg of crude product as a yellow oil.

27 mg brough the IDA lithium was added to a solution of 67 mg of the above crude product in dimethylformamide (1 ml) and stirred at room temperature for 40 minutes. Added water to the reaction liquid was extracted with ethyl acetate, the organic layer was dried, the solvent evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 2/8)to give 32 mg of 4-(methyl bromide)-6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole in the form of a yellow oil.

5.9 g of tetranitroaniline/palladium were added to a solution of 31 mg of the obtained bromide in dimethoxyethane (1.0 ml) and stirred at 50°C for 10 minutes. Added 12 mg (2,6-differenl)Bronevoy acid, 0.5 ml of ethanol and 0.1 ml of water (2M) solution of sodium carbonate and heated under reflux for 1.5 hours. The mixture was cooled to room temperature, was extracted with chloroform, the organic layer was dried and the solvent evaporated under reduced pressure, receiving 39 mg of crude product as a yellow oil.

0.7 ml triperoxonane acid was added to 39 mg of the above crude product and stirred for 1 hour. Excess triperoxonane acid evaporated under reduced pressure, the residue was dissolved in chloroform and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried, the solvent was removed and the residue was purified thin-layer column items is matography (manifesting solvent: chloroform/methanol = 9/1), getting 13 mg of the target compound in a solid yellow color.

1H-NMR (CDCl3) δ: 1.26 in (3H, t, J=7.4 Hz), to 3.36 (2H, q, J=7.4 Hz), 4,25 (4/3H, c), 4,56 (2/3H, c), 6,93-6,91 (2H, m), 7,06? 7.04 baby mortality (1H, m), 7,20-to 7.18 (1H, m), 7,32-7,30 (1H, m), the 7.43 (1H, c), of 7.97 (1H, d, J=9.0 Hz), 8,44 (1H, d, J=16.0 Hz), 8,66-8,64 (2H, m), 9,66-9,58 (1H, m), accounted for 10.39 (1/3H, c), 10,61 (2/3H, s).

ESI-MASS (m/e): 508 (M+H).

Example 174

Methyl 6-(4-(ethylsulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylate

Methyl 6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-carboxylate was subjected to interaction with triperoxonane acid to obtain the target compounds.

Example 175

6-(4-(Ethylsulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylic acid

10 ml of aqueous 1 n sodium hydroxide solution was added to 2.3 g of complex methyl ester obtained in example 174, and the reaction liquid was stirred overnight at 50°C. To the reaction liquid was added 4 ml of 3 N. hydrochloric acid and the precipitated precipitate was separated by filtration, obtaining the target compound.

Example 176

(6-(4-Ethylsulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazole-5-yl)methanol

700 mg of 1,1'-carbonyldiimidazole was added to a solution of 1.5 g of carboxylic acid, obtained in example 175, in dimethylformamide (5 ml) and the reaction liquid was stirred at room temperature during the 15 minutes. The reaction liquid was added to 5 ml of an aqueous solution of 1.5 g of sodium borohydride and the reaction liquid was stirred at room temperature for 5 minutes, then was diluted with ethyl acetate, washed with water and saturated saline solution in this order and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining the target compound in the form of a solid orange color.

Example 177

6-(4-(Ethylsulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazole-5-carbaldehyde

5 ml of triethylamine and 750 mg of pyridine-sulfur trioxide was added to a solution of 1.0 g of the alcohol compound obtained in example 176, in dimethyl sulfoxide (10 ml) and the reaction liquid was stirred at room temperature for 15 minutes. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline solution in this order and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, obtaining the target compound in the form of a solid orange color.

On the basis of the phenol obtained in reference examples, the following compounds of example 178 to example 209 was obtained in the same manner as in examples 174-177, or its combination with a customary method.

Example 178

Methyl 6-(4-(methylsulphonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxyla the

Example 179

6-(4-(Methylsulphonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylic acid

Example 180

(6-(4-Methylsulphonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazole-5-yl)methanol

Example 181

6-(4-(Methylsulphonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazole-5-carbaldehyde

Example 182

Methyl 6-((6-(ethylsulfonyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylate

Example 183

6-((6-(Ethylsulfonyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylic acid

Example 184

(6-((6-(Ethylsulfonyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-yl)methanol

Example 185

6-((6-(Ethylsulfonyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-carbaldehyde

Example 186

Methyl 6-((6-(methylsulphonyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylate

Example 187

6-((6-(Methylsulphonyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylic acid

Example 188

(6-((6-Methylsulphonyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-yl)methanol

Example 189

6-((6-Methylsulphonyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-carbaldehyde

Example 190

Methyl 6-(6-(5-methyl-(1,2,4)oxadiazol-3-yl)pyridine-3-yloxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylate

u> Example 191

6-(6-(5-Methyl-(1,2,4)oxadiazol-3-yl)pyridine-3-yloxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylic acid

Example 192

(6-(6-(5-Methyl-(1,2,4)oxadiazol-3-yl)pyridine-3-yloxy)-2-pyridin-2-yl-1H-benzimidazole-5-yl)methanol

Example 193

6-(6-(5-Methyl-(1,2,4)oxadiazol-3-yl)pyridine-3-yloxy)-2-pyridin-2-yl-1H-benzimidazole-5-carbaldehyde

Example 194

Methyl 6-((6-(methoxymethyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylate

Example 195

6-((6-(Methoxymethyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylic acid

Example 196

(6-((6-(Methoxymethyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-yl)methanol

Example 197

6-((6-(Methoxymethyl)pyridine-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-carbaldehyde

Example 198

Methyl 6-(4-ethylsulfonyl)phenoxy)-2-pyrazin-2-yl-1H-benzimidazole-5-carboxylate

Example 199

6-(4-Ethylsulfonyl)phenoxy)-2-pyrazin-2-yl-1H-benzimidazole-5-carboxylic acid

Example 200

(6-(4-Ethylsulfonyl)phenoxy)-2-pyrazin-2-yl-1H-benzimidazole-5-yl)methanol

Example 201

6-(4-Ethylsulfonyl)phenoxy)-2-pyrazin-2-yl-1H-benzimidazole-5-carbaldehyde

Example 202

Methyl 6-((6-ethylsulfonyl)pyridine-3-yl)oxy)-2-pyrazin-2-yl-1H-benzimidazole-5-carboxylate

Primer

6-((6-Ethylsulfonyl)pyridine-3-yl)oxy)-2-pyrazin-2-yl-1H-benzimidazole-5-carboxylic acid

Example 204

(6-((6-Ethylsulfonyl)pyridine-3-yl)oxy)-2-pyrazin-2-yl-1H-benzimidazole-5-yl)methanol

Example 205

6-((6-Ethylsulfonyl)pyridine-3-yl)oxy)-2-pyrazin-2-yl-1H-benzimidazole-5-carbaldehyde

Example 206

Methyl 6-((6-cyano-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazole-5-carboxylate

Example 207

6-((6-Cyano-3-yl)oxy)-2-pyrazin-2-yl-1H-benzimidazole-5-carboxylic acid

Example 208

(6-((6-Cyano-3-yl)oxy)-2-pyrazin-2-yl-1H-benzimidazole-5-yl)methanol

Example 209

6-((6-Cyano-3-yl)oxy)-2-pyrazin-2-yl-1H-benzimidazole-5-carbaldehyde

Example 210

1-({5-[4-(2-Methyl-2H-tetrazol-5-yl)phenoxy]-2-pyridin-2-yl-1H-benzimidazole-6-yl}methyl)pyrrolidin-2-he

Using 4-(2-methyl-2H-tetrazol-5-yl)phenol obtained in reference example 17, the target compound was obtained in the same manner as in example 102 (stage 5), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,95 (2H, m), is 2.37 (2H, m)to 3.33 (2H, m), 4,39 (3H, c), br4.61 (2H, c), 7,05 (2H, d, J=8,8 Hz), 7,20-of 7.60 (1H, ush.), 7,38 (1H, m), the 7.65 (1H, ush.), 7,87 (1H, m), 8,08 (2H, d, J=8,8 Hz), 8,39 (1H, d, J=8.0 Hz), 8,64 (1H, d, J=4.5 Hz).

ESI-MASS (m/e): 467 (M+H).

Example 211

1-[(2-(5-Herperidin-2-yl)-5-{[6-(5-methyl-1,2,4-oxadi the ol-3-yl)pyridine-3-yl]oxy}-1H-benzimidazole-6-yl)methyl]pyrrolidin-2-he

Using a 5-herperidin-2-carboxylic acid obtained in reference example 18, the target compound was obtained in the same manner as in example 53, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.97 (2H, m), 2,35 (2H, m), 2,69 (3H, c)to 3.33 (2H, m), 4,60 (2H, c), 7,17 (1/2N, c), 7,33 (1H, m), 7,46 (1/2N, c), 7,58 (2H+1/2H, m), 7,76 (1/2N, c), 8,03 (1H, m), 8,40 at 8.60 (3H, m), 10,5 (1/2H, ush.), 10,8 (1/2H, ush.).

ESI-MASS (m/e): 486 (M+H).

Example 212

(3S)-1-({6-[4-(Ethylsulfonyl)phenoxy]-2-pyridin-2-yl-1H-benzimidazole-5-yl}methyl)-3-hydroxypyrrolidine-2-he

Stage 1. Obtain (3S)-3-{[tert-butyldimethylsilyl]oxy}pyrrolidin-2-it:

In a bath with ice 3,1 ml trimethylsilyldiazomethane (2.0m solution in hexane) was added to a solution of 500 mg of (2S)-4-amino-2-hydroxybutiric acid in 5 ml of methanol and 4 ml of chloroform and stirred over night. The solvent is evaporated under reduced pressure, getting 503 mg (3S)-3-hydroxypyrrolidine-2-it is in the form of a solid white color.

In a bath with ice 570 mg of imidazole and 947 mg of tert-butyldimethylsilyloxy was added to a solution of 503 mg (3S)-3-hydroxypyrrolidine-2-it is in dimethylformamide (5 ml) and stirred at room temperature for 1 hour. Added water to the reaction liquid was extracted with ethyl acetate, the organic layer was washed with water and saturated saline, and dried. The solvent is perivale under reduced pressure, getting 452 mg of the target compound as a pale yellow oil.

Stage 2. Obtain (3S)-1-({6-[4-(ethylsulfonyl)phenoxy]-2-pyridin-2-yl-1H-benzimidazole-5-yl}methyl)-3-hydroxypyrrolidine-3-it:

Using the alcohol compound obtained in example 19 (step 7), and (3S)-3-{[tert-butyldimethylsilyl]oxy}pyrrolidin-2-he obtained in stage 1, the target compound was obtained in the same manner as in example 2 or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.25 (3H, t, J=7.4 Hz), 1,95 (1H, c), 2,43 (1H, c)to 3.09 (2H, q, J=7.4 Hz), 3,37-3,47 (2H, m), 4,45-of 4.49 (2H, m), and 4.68 (1H, m), 7,07 (2H, d, J=8.0 Hz), 7,37-7,39 (1H, m), the 7.43 (1H, c), 7,81-7,89 (3H, m), to 7.99 (1H, c), 8,44 (1H, d, J=8.0 Hz), at 8.60 (1H, d, Hz, J=4,1).

ESI-MASS (m/e): 493 (M+H).

Example 213

1-[(2-(5-Methoxypyridine-2-yl)-5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-1H-benzimidazole-6-yl)methyl]pyrrolidin-2-he

Using a 5-methoxypyridine-2-carboxylic acid obtained in reference example 19, the target compound was obtained in the same manner as in example 53, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,94 (2H, m), 2,35 (2H, m), 2,68 (3H, c), 3,30 (2H, m), of 3.94 (3H, c), 4,58 (2H, m), 7,14 (1/2N, c), 7,25-7,38 (2H, m), 7,45 (1/2N, c), 7,55 (1/2N, c), 7,74 (1/2N, c), 8,03 (1H, m), 8,28 is 8.38 (2H, m), of 8.47 (1/2H, m), 8,54 (1/2H, m), 10,7 (1/2H, m), 10,8 (1/2H, ush.).

ESI-MASS (m/e): 498 (M+H).

Example 214

(6-{[6-(Ethylsulfonyl)pyridine-3-yl]ox is}-2-pyridin-2-yl-1H-benzimidazole-4-yl)acetonitrile

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 127, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,29 (3H, m), 3,37 (2H, q, J=7.4 Hz), 4,27 (2H, c), 7,16 (2H, d, J=13.3 Hz), 7,35-7,39 (2H, m), 7,87 (1H, t, J=7.8 Hz), 8,01 (1H, c), 8,39 (1H, d, J=7.8 Hz), 8,46 (1H, d, J=2.7 Hz), to 8.62 (1H, c), 10,83 (1H, USS).

ESI-MASS (m/e): 420 (M+H).

Example 215

6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2-pyridin-2-yl-1H-benzimidazole

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 140, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.26 in (3H, m), of 2.56 (3H, c), 3,33-to 3.38 (2H, m), 4,28 (1H, c), 4,59 (1H, c), 6,91-7,00 (1H, m), 7,31-7,37 (2H, m), 7,45 (1H, c), a 7.85 (1H, t, J=8.6 Hz), 7,97 shed 8.01 (1H, m), of 8.37-8,44 (2H, m), 8,59-8,61 (1/2H, m), 8,68 (1/2H, d, J=4,7 Hz).

ESI-MASS (m/e): 477 (M+H).

Example 216

1-{2-[(6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]phenyl}alanon

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 173, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1.28 (in 3H, q, J=7.4 Hz), 2,53 (1H, c), a 2.71 (2H, c)to 3.36 (2H, the, J=7.4 Hz), 4,36 (4/3H, c), 4,76 (2/3H, c), of 6.96 (1H, d, J=2.2 Hz), 7,51 (2H, DD, J=10,3, 4.6 Hz), to 7.61-to 7.68 (5H, m), 7,79 (1H, t, J=8.6 Hz), 7,98 (1H, d, J=8.6 Hz), 8,30 (1H, d, J=8.6 Hz), 8,48 (1H, d, J=2,9 Hz), 8,66 (1H, d, J=4.9 Hz), 12,11 (1H, USS).

ESI-MASS (m/e): 513 (M+H).

Example 217

2-[(6-{6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]benzonitrile

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 173, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,22-of 1.29 (3H, m), 3,30-3,37 (2H, m), 4,45 (2/3H, c), 4,68 (4/3H, c), 6,79-for 6.81 (1H, m), 7,03 (1H, d, J=2.0 Hz), 7,28-7,34 (2H, m), EUR 7.57 (1H, d, J=7.8 Hz), to 7.61-7,66 (3H, m), a 7.85 (1H, t, J=7,6 Hz), to 7.95 (1H, d, J=8.6 Hz), of 8.37-8,44 (2H, m), 8,56 (1H, d, J=4,7 Hz), 11,08 (1/3H, USS), of 11.26 (2/3H, USS).

ESI-MASS (m/e): 496 (M+H).

Example 218

6-{[6-(Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-4-(2H-tetrazol-5-ylmethyl)-1H-benzimidazole

41 mg of sodium azide and 87 mg of the hydrochloride of triethylamine was added to a solution of 116 mg (6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-4-yl)acetonitrile in toluene (2 ml) and stirred overnight at 100°C. the Reaction liquid was allowed to cool to room temperature, then added hydrochloric acid (1 BC), were extracted with ethyl acetate and the organic layer was washed with saturated saline solution. The solvent in perivale under reduced pressure, getting 121 mg of crude product as a yellow oil.

0.7 ml triperoxonane acid was added 121 mg of the above crude oil and stirred at room temperature for 1 hour. Excess triperoxonane acid evaporated under reduced pressure and the residue was purified by high-performance liquid chromatography on a column of reverse phase (water/acetonitrile = 90/10 to 10/90)to give 14 mg of the target compound in a solid white color.

1H-NMR (CDCl3) δ: 1,29 (3H, m), 3,37 (2H, q, J=7,4 Hz), and 4.68 (2H, c), 7,07 (1H, c), 7,33 and 7.36 (2H, m), of 7.48-7,50 (1H, m), 7,98-of 8.00 (2H, m), 8,44 (2H, m), 8,69 (1H, m).

ESI-MASS (m/e): 463 (M+H).

Example 219

2-[(6-{6-Ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]benzamide

Using the alcohol compound obtained in example 150 (stage 1), the target compound was obtained in the same manner as in example 173, or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,32-of 1.56 (3H, m), 3.33 and is 3.40 (2H, m), and 4.40 (2H, c), 7,06 (1H, d, J=8.6 Hz), 7,27-7,42 (5H, m), of 7.48-to 7.50 (2H, m), 7,76-7,80 (2H, m), 7,97 shed 8.01 (1H, m), of 8.47-8,48 (1H, m), 8,63 (1H, m).

ESI-MASS (m/e): 514 (M+H).

Example 220

1-[Hydroxy(5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-6-yl)methyl]pyrrolidin-2-he

Stage 1. Obtain (5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-gasoline idazole-6-yl)methanol :

Using 6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinol obtained in reference example 6, the target compound was obtained in the same manner as in example 19 (stage 5) and example 34 (stage 3), or in accordance with this method, or its combination with a customary method.

Stage 2. Getting 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-6-carbaldehyde:

1.5 ml of triethylamine and 796 mg of a complex of sulfur trioxide/pyridine was added to a solution of 400 mg of the alcohol compound obtained in stage 1, in dimethyl sulfoxide (5 ml) and stirred at room temperature for 30 minutes. Added ice water, extracted with chloroform, and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure, the residue was recrystallized from a mixture of diethyl ether/methanol, getting 183 mg of target compound in the form of amorphous material, light yellow color.

Stage 3. Obtaining 1-[hydroxy(5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-6-yl)methyl]pyrrolidin-2-it:

7 mg of sodium carbonate were added to a solution of 8.7 μl of 2-pyrrolidone in N,N-dimethylformamide (500 μl). Under stirring at 80°C was added 10 mg of the aldehyde obtained in stage 2, and was stirred over night at 80°C. the Solvent is evaporated under decreased the pressure and the residue was purified separating thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol = 5/1)to give 1.0 mg of target compound in the form of amorphous material, light yellow color.

1H-NMR (CDCl3) δ: 0,79-0,94 (1H, m), 1.77 in is 1.91 (1H, m), 1,97-of 2.09 (1H, m), 2,14-of 2.34 (1H, m), 2,68 (3H, c), and 2.83 vs. 2.94 (1H, m), 3,37-to 3.52 (1H, m), 6.87 in-6,95 (1H, m), 7,18 (1H×1/2, c), 7,33-7,46 (2H, m), 7,50 (1H×1/2, c), 7,86-7,94 (1H, m), 7,99-8,08 (1H, m, 1H×1/2, c), 8,31 (1H×1/2, c)at 8.36-8,46 (2H, m), 8,60-8,72 (1H, m), of 10.58 (1H×1/2, USS), 10,86 (1H×1/2, USS).

ESI-MASS (m/e): 484 (M+H).

Example 221

1-[(2-(5-Herperidin-2-yl)-5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-1H-benzimidazole-6-yl)methyl]pyrrolidin-2-he

Using a 5-herperidin-2-carboxylic acid obtained in reference example 18, the target compound was obtained in the same manner as in example 53 (stage 2, stage 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: of 1.97 (2H, m), 2,35 (2H, m), 2,69 (3H, c)to 3.33 (2H, m), 4,60 (2H, c), 7,17 (1/2N, c), 7,33 (1H, m), 7,46 (1/2N, c), 7,58 (2H+1/2H, m), 7,76 (1/2N, c), 8,03 (1H, m), 8,40 at 8.60 (3H, m), 10,5 (1/2H, ush.), 10,8 (1/2H, ush.).

ESI-MASS (m/e): 486 (M+H).

Example 222

1-[(2-(5-Methoxypyridine-2-yl)-5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-1H-benzimidazole-6-yl)methyl]pyrrolidin-2-he

Using a 5-methoxypyridine-2-carboxylic acid obtained in reference example 19, the target compound was obtained in the same manner as in example 53 (stage 2, stage 3), or in accordance with this method, or its combination with conventional pic the BOM.

1H-NMR (CDCl3) δ: 1,94 (2H, m), 2,35 (2H, m), 2,68 (3H, c), 3,30 (2H, m), of 3.94 (3H, c), 4,58 (2H, m), 7,14 (1/2N, c), 7,25-7,38 (2H, m), 7,45 (1/2N, c), 7,55 (1/2N, c), 7,74 (1/2N, c), 8,03 (1H, m), 8,28 is 8.38 (2H, m), of 8.47 (1/2H, m), 8,54 (1/2H, m), 10,7 (1/2H, m), 10,8 (1/2H, ush.).

ESI-MASS (m/e): 498 (M+H).

Example 223

1-[((2-(5-Methylpyridin-2-yl)-5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-1H-benzimidazole-6-yl)methyl]pyrrolidin-2-he

Using 6-methylpyridin-2-carboxylic acid, the target compound was obtained in the same manner as in example 53 (stage 2, stage 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,95 (2H, m), 2,33 (2H, m)2,60 (3H, c), 2,68 (3H, c), of 3.32 (2H, m), 4,58 (2H, c), 7,10-to 7.35 (2H+1/2H, m), 7,47 (1/2N, c), 7,56 (1/2N, c), of 7.75 (1H+1/2H, m), 8,03 (1H, m), 8,19 (1H, m), of 8.47 (1/2N, c), 8,54 (1/2N, c), or 10.9 (1H, ush.).

ESI-MASS (m/e): 482 (M+H).

Example 224

1-[(2-(6-Methoxypyridine-2-yl)-5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-1H-benzimidazole-6-yl)methyl]pyrrolidin-2-he

Using 6-methylpyridin-2-carboxylic acid, the target compound was obtained in the same manner as in example 53 (stage 2, stage 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,96 (2H, m), 2,34 (2H, m), 2,69 (3H, c)to 3.34 (2H, m), 4,03 (3/2N, c)4,07 (3/2H, c), 4,58 (2/2N, c), 4,59 (2/2N, c)6,86 (1H, d, J=8,2 Hz), 7,16 (1/2N, c), 7,32 (1H, m), 7,46 (1/2H c), to 7.61 (1/2N, c), 7,78 (1H+1/2H, m), of 7.96-of 8.06 (2H, m), 8,46 (1/2H, d, J=2,9 Hz), 8,54 (1/2H, d, J=2.5 Hz), 10,5 (1/2H, ush.), 10,6 (1/2H, ush..

ESI-MASS (m/e): 498 (M+H).

Example 225

Methyl 6-{5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-6-[(2-oxopyrrolidin-1-yl)methyl]-1H-benzimidazole-2-yl}nicotinate

Using 5-(methoxycarbonyl)pyridine-2-carboxylic acid, the target compound was obtained in the same manner as in example 53 (stage 2, stage 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,99 (2H, m), 2.40 a (2H, m), 2,69 (3H, c), the 3.35 (2H, m)4,00 (3H, c), br4.61 (2H, c), 7,19 (1/2N, c), 7,35 (1H, m), 7,53 (1/2N, c), 7,65 (1/2N, c), 7,80 (1/2N, c), with 8.05 (1H, m), to 8.45 (2H, m,), 8,48 (1/2H, d, J=3.0 Hz), 8,55 (1/2H, d, J=2.6 Hz), which 9.22 (1H, m), 10,8 (1/2H, ush.), 11,1 (1/2H, ush.).

ESI-MASS (m/e): 526 (M+H).

Example 226

1-[(2-(4-Methylpyridin-2-yl)-5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-1H-benzimidazole-6-yl)methyl]pyrrolidin-2-he

Using 4-methylpyridin-2-carboxylic acid, the target compound was obtained in the same manner as in example 53 (stage 2, stage 3), or in accordance with this method, or its combination with a customary method.

1H-NMR (CDCl3) δ: 1,94 (2H, m), 2,34 (2H, m), 2,46 (3/2H, c), 2,47 (3/2H, c), 2,68 (3H, c), of 3.32 (2H, m), 4,58 (2/2N, c), br4.61 (2/2N, c), 7,16 (1/2N, c), 7,72 (1H, d, J=4,7 Hz), 7,33 (1H, m), of 7.48 (1/2H c), EUR 7.57 (1/2N, c), to 7.77 (1/2N, c), with 8.05 (1H, m), 8,23 (1/2N, c), compared to 8.26 (1/2N, c), 8,49 (1H+1/2H, m), 8,55 (1/2H, d, J=2.7 Hz), and 10.8 (1H, ush.).

ESI-MASS (m/e): 482 (M+H).

Example 227

Triptorelin 3-hydroxy-1-[(5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-Ben is imidazol-6-yl)methyl]pyrrolidin-2-he

Stage 1. Obtain 3-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-2-it:

5 g dl-maleic-acid was dissolved in 20 ml of acetylchloride and stirred at 45°C for 3 hours. Acetylchloride evaporated under reduced pressure, the obtained crude product was dissolved in 30 ml of methanol and was stirred overnight. The solvent is evaporated under reduced pressure, obtaining of 5.3 g of 3-(atomic charges)-4-methoxy-4-oxobutanoic acid as a pale yellow oil. In a bath with ice, 10 ml of the complex borohydride-dimethyl sulfide (10M) was added to a solution of 5.3 g of 3-(atomic charges)-4-methoxy-4-oxobutanoic acid in tetrahydrofuran (25 ml) and stirred at room temperature for 24 hours. To the reaction liquid was added aqueous 10% solution of citric acid, was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure, obtaining of 5.1 g of methyl 2-(atomic charges)-4-hydroxybutanoic in the form of a colorless transparent oil.

In a bath with ice to 6.1 ml of triethylamine and 2.3 ml of methanesulfonamide was added to the solution at 2.59 g of methyl 2-(atomic charges)-4-hydroxybutanoic in chloroform (15 ml) and was stirred for 30 minutes. To the reaction liquid was added a saturated salt solution was extracted with chloroform and the organic layer was dried. The solvent you Aravali under reduced pressure, receiving of 2.54 g of methyl 2-(atomic charges)-4-[(methylsulphonyl)oxy]butanoate in the form of a brown liquid.

1,91 g of sodium azide was added to a solution of 2.54 g of methyl 2-(atomic charges)-4-[(methylsulphonyl)oxy]butanoate in dimethylformamide (10 ml) and stirred at 70°C for 8 hours. The reaction liquid was allowed to cool to room temperature and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried and the solvent evaporated under reduced pressure, getting 2.70 g of methyl 2-(atomic charges)-4-zidovudinee in the form of a brown oil.

2,53 g of potassium carbonate and 1 ml of water was added to the solution 2,47 g of methyl 2-(atomic charges)-4-zidovudinee in methanol (15 ml) and stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried. The solvent is evaporated under reduced pressure, receiving 591 mg of methyl 4-azido-2-hydroxybutanoic in the form of an orange oil.

692 mg of triphenylphosphine and 8 μl of water was added to a solution of 351 mg of methyl 4-azido-2-hydroxybutanoic in tetrahydrofuran (3 ml)was stirred at room temperature for 24 hours, then stirred overnight at 50°C. the Tetrahydrofuran is evaporated under reduced pressure and the mod what it was extracted with ethyl acetate, getting 255 mg of 3-hydroxypyrrolidine-2-it is in the form of a light brown oil.

In a bath with ice 300 mg of imidazole and 497 mg of tert-butyldimethylchlorosilane was added to a solution of 255 mg of 3-hydroxypyrrolidine-2-it is in dimethylformamide (2 ml) and was stirred for 1 hour. Added water to the reaction liquid was extracted with ethyl acetate and washed with hydrochloric acid (1 BC) and saturated salt solution. The organic layer was dried, getting 370 mg of crude product. 208 g of the product was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 2/8)to give 62 mg of the target compound in a solid white color.

Stage 2. Getting trifenatate 3-hydroxy-1-[(5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-6-yl)methyl]pyrrolidin-2-it:

In a bath with ice 36 μl of triethylamine and 14 μl of methanesulfonamide was added to a solution of 47 mg of the alcohol obtained in example 52 (stage 2), in tetrahydrofuran (1 ml) and was stirred for 30 minutes. To the reaction liquid was added a saturated salt solution was extracted with ethyl acetate and the organic layer was washed with saturated saline solution and dried. The solvent is evaporated under reduced pressure, obtaining 48 mg of crude product as a pale yellow oil.

In a bath with ice 62 mg of 3-{[tert-butyl(di is ethyl)silyl]oxy}pyrrolidin-2-it, obtained in stage 1, and 11 mg of sodium hydride (60%) was added to a solution of the above crude product in dimethylformamide (2 ml) and stirred at room temperature for 90 minutes. To the reaction liquid was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with water and saturated saline, and dried. The solvent is evaporated under reduced pressure and the residue was purified by thin-layer chromatography on a column of silica gel (manifesting solvent: chloroform/methanol = 9/1)to give 38 mg of the crude product as a yellow oil.

83 μl of tetrabutylammonium (1.0m solution in tetrahydrofuran) was added to a solution of 20 mg of the above crude product in tetrahydrofuran (0.2 ml) and was stirred over night at room temperature. The solvent is evaporated and 0.7 ml triperoxonane acid was added to the residue and stirred for 1 hour. Excess triperoxonane acid evaporated under reduced pressure and the residue was purified by high-performance liquid chromatography on a column of reverse phase (the solvent: water/acetonitrile = 9/1 to 1/9)to give 6 mg of the target compound as a colorless transparent oil.

1H-NMR (CD3OD) δ: 1,79-of 1.85 (1H, m), a 2.36 (1H, m), 2,69 (3H, c), 3,26-of 3.31 (1H, m), 3,39 (1H, d, J=6.5 Hz), 4,19 (1H, t, J=8,2 Hz),4,72-of 4.66 (2H, m), 7,49 (1H, c), 7,60 to 7.62 (1H, m), 7,66-to 7.68 (1H, m), a 7.85 (1H, c), 8,11-8,16 (2H, m), 8,29 (1H, d, J=8.0 Hz), 8,48 (1H, d, J=2.3 Hz), 8,86 (1H, d, J=4,7 Hz).

ESI-MASS (m/e): 484 (M+H).

Reference example 1

Getting 4-(methylsulphonyl)phenol

In a water bath of 18.5 ml under the conditions and 28.7 g of potassium carbonate were added to a solution of 25 g of 4-hydroxythiophenol in acetone (250 ml) and stirred at room temperature for 5 hours. Salt was removed by filtration, the solvent evaporated under reduced pressure, to the residue was added diethyl ether and was extracted with water 2 N. a solution of sodium hydroxide. The resulting aqueous layer was acidified aqueous 6 N. hydrochloric acid, was extracted with diethyl ether and the organic layer was washed with a saturated aqueous solution of sodium chloride. After drying, the solvent is evaporated under reduced pressure, obtaining of 27.3 g of 4-(methylsulfanyl)phenol in the form of a solid of light yellow color. In a water bath 67 ml of aqueous 30% solution of hydrogen peroxide gradually and dropwise added to a solution of 27.3 g of 4-(methylsulfanyl)phenol in acetic acid (130 ml). Once added, the mixture was gradually heated to 100°C and was stirred for 1 hour. The reaction liquid was allowed to cool to room temperature and neutralized with saturated aqueous sodium bicarbonate solution. Were extracted with ethyl acetate, washed with saturated aqueous BIK what rebonato sodium and saturated salt solution. After drying, the solvent is evaporated, receiving of 31.6 g of target compound in the form of a solid of light yellow color.

Reference example 2

Getting 4-(ethylsulfonyl)phenol

Using ethyliodide, the target compound was obtained in the same manner as in reference example 1 or in accordance with this method, or its combination with a customary method.

Reference example 3

Getting 6-(methylsulphonyl)-3-pyridinoland

6.6 g of bis(pinacolato)diboron, 5.9 g of potassium acetate and 980 mg of the complex (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II)-dichloromethane was added to a solution of 4.72 in g 3-bromo-6-(methylsulphonyl)pyridine in dimethyl sulfoxide (80 ml) and the reaction liquid was stirred at 80°C for 2 hours. To the reaction liquid were added ethyl acetate and water, the insoluble substance was removed by filtration through Celite and the organic layer was separated. The organic layer was washed with water and saturated saline, then was dried with anhydrous magnesium sulfate and the solvent evaporated under reduced pressure.

At 0°C to 60 ml of aqueous 5 n sodium hydroxide solution and 30 ml of aqueous 30% hydrogen peroxide was added to a solution of the obtained residue in tetrahydrofuran (200 ml) and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with diethyl shall FYROM and washed with water. The aqueous layer was acidified 5 N. hydrochloric acid and was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was washed with a mixture of chloroform and hexane, obtaining 1,17 g of target compound in a solid brown color.

Reference example 4

Getting 6-(ethylsulfonyl)-3-pyridinoland

Using 3-chloro-6-(ethylsulfonyl)pyridine, the target compound was obtained in the same manner as in reference example 3, or in accordance with this method, or its combination with a customary method.

Reference example 5

Obtain 3-chloro-4-(methylsulphonyl)phenol

48,3 ml of thionyl chloride was added to 108 ml methanesulfonic acid and heated under reflux for 1 hour. Was cooled to room temperature, was added 1,3-dichlorobenzene and 2.9 ml triptoreline acid and stirred at 120°C for 4 hours. After cooling to room temperature, the reaction liquid was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate and saturated saline solution. After drying, the solvent is evaporated under reduced pressure. The residue was recrystallized from a mixture of hexane/ethyl acetate, getting to 48.3 g of 2,4-dichlorophen is methylsulfone.

An aqueous solution (1 ml) 360 mg of potassium hydroxide was added to a solution of 1 g of 2,4-dichlorodimethylsilane in dimethyl sulfoxide (3 ml) and stirred at 100°C for 4 hours. The mixture was acidified aqueous 1 N. hydrochloric acid, was extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 2/1)to give 300 mg of 3-chloro-4-(methylsulphonyl)phenol.

Reference example 6

Getting trifenatate 6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinoland

Stage 1. Obtain 6-bromo-3-pyridinol:

While cooling on ice 435 ml isopropylacrylamide (2M solution in tetrahydrofuran) was added to a solution of 200 g of 2,5-dibromopyridine in tetrahydrofuran (800 ml) and stirred at room temperature for 1.5 hours. When cooled on ice was added a solution of 214 ml triisopropylsilane in tetrahydrofuran (200 ml) and was stirred over night at room temperature. While cooling on ice, the reaction liquid was gradually added to water (2.5 l) to a solution of 160 g of sodium hydroxide. Added 1 l of water and 1 l of hexane and extracted the aqueous layer. While cooling with ice and 150 ml of aqueous hydrogen peroxide (30%) gradually dobavlyali water layer, that took about 1 hour, and then stirred over night at room temperature. While cooling on ice, the reaction liquid was neutralized with concentrated hydrochloric acid, was extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure, receiving 130 g of target compound.

Stage 2. Obtain 2-bromo-5-(methoxyethoxy)pyridine:

73 ml of methoxyethylamine was added to a solution of 129 g of the obtained 6-bromo-3-pyridinol in tetrahydrofuran (1.3 l) was added 32 g of sodium hydride (with the addition of 30% liquid paraffin) so that the internal temperature could not exceed -10°C. was Added ice water, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = from 9.1 to 8/1)to give 105 g of the target compound as a colourless oil.

Stage 3. Getting 5-(methoxyethoxy)-2-pyridylcarbonyl:

88.9 g of cyanide of zinc and 29.1 g of tetrakis(triphenylphosphine)palladium(0) were added to a solution of 105 g of the obtained oil in dimethylformamide (1100 ml) and stirred at 105°C for 1 hour. Was cooled to room temperature, obavljale 1.5 l of ethyl acetate and 1.2 l of water and was extracted with ethyl acetate. The organic layer was washed with saturated saline and was dried, the solvent evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 8/1-7/1-2/1), receiving at 53.4 g of target compound.

Stage 4. Obtain 6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinol:

While cooling on ice 35.4 ml of hydroxylamine (50% aqueous solution) was added to a solution of 41 g of the obtained product in ethanol (400 ml) and stirred at room temperature for 30 minutes. Under ice cooling was added 1 l of water and was stirred for 1 hour. The resulting crystal was separated by filtration, receiving 39.5 g of product.

200 ml of acetic acid was added to 39.5 g of the obtained crystal and, with ice cooling, was added to 20.8 ml of acetic anhydride and stirred at room temperature for 1 hour. The mixture was also heated at 70°C and was stirred overnight. The reaction solvent evaporated under reduced pressure and the obtained solid substance brown added 100 ml triperoxonane acid and stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure and to the residue was added hexane/ethyl acetate = 20/1 and stirred. The obtained solid product was separated by filtration and dried, olucha to 57.1 g of target compound in the form of his trifenatate.

Reference example 7

Getting 4-(5-methyl-1,2,4-oxadiazol-3-yl)phenol

Stage 1. Getting 4-(methoxyethoxy)benzonitrile:

Using 4-cyanoprop, the target compound was obtained in the same manner as in reference example 6 (stage 2), or in accordance with this method, or its combination with a customary method.

Stage 2. 4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenol:

Using 4-(methoxyethoxy)benzonitrile, the target compound was obtained in the same manner as in reference example 6 (stage 4), or in accordance with this method, or its combination with a customary method.

Reference example 8

1-(4-hydroxyphenyl)pyrrolidin-2-he

Stage 1. Getting 1-iodine-4-(methoxyethoxy)benzene:

of 2.33 ml of N,N-diisopropylethylamine and 900 μl of methoxyethylamine was added to a solution of 2 g of 4-itfinal in chloroform (20 ml) and was stirred over night at room temperature. When cooled on ice was added a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate)to give 1.08 g of the target compound as a colourless oil.

Stage 2. Obtaining 1-(hydroxyphenyl)pyrrolidin-2-it :

5 μl of Ethylenediamine, 14,5 mg of copper iodide(I) and 321 mg of potassium phosphate was added to a solution (2 ml) 200 mg of the compound obtained in stage 1, and 70 μl of 2-pyrrolidone in 1,4-dioxane and stirred overnight in a nitrogen atmosphere at 110°C. When cooled on ice was added a saturated aqueous solution of ammonium chloride, diluted with ethyl acetate and the insoluble substance was removed by filtration through Celite. Were extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform/methanol)to give 174 mg of the intermediate.

250 μl of 4 n hydrochloric acid/dioxane and 10 ál of water was added to solution (1.0 ml) 80 mg of the obtained intermediate product in 1,4-dioxane and stirred at room temperature for 2.5 hours. After concentration of the mixture did azeotrope with chloroform and the residue was utverjdali diethyl ether, receiving 60.1 mg of target compound in a solid white color.

Reference example 9

Obtaining 1-(4-hydroxyphenyl)pyridine-2(1H)-it

A solution of 200 mg of the compound obtained in reference example 11 (stage 11), 72 mg of 2-hydroxypyridine, 29 mg of copper iodide(I), 210 mg of potassium carbonate and 22 mg of (1R,2R)-(-)-N,N dimethylcyclohexane-1,2-diamine in toluene (1 ml) was stirred overnight in a nitrogen atmosphere at 115°C. The mixture was diluted with chloroform, the insoluble substance was removed by filtration through Celite and the organic layer was washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform/methanol)to give 163 mg of the intermediate product.

80 mg of the obtained intermediate product was dissolved in 1.5 ml of water and 500 μl of chloroform was added 500 μl of 4 n hydrochloric acid/dioxane and 10 ál of water and stirred at room temperature for 40 minutes. After concentration of the mixture did azeotrope with chloroform and the residue was utverjdali simple ether, receiving 65,6 mg of target compound in a solid white color.

Reference example 10

5-Hydroxypyridine-2-carbonitril

This compound was obtained by combining stage 3 and stage 4 of reference example 6.

Reference example 11

6-(Methoxymethyl)pyridine-3-ol

Stage 1. Obtain 5-benzyloxy-2-methylpyridine:

140 g of 3-hydroxy-6-methylpyridine was dissolved in 1.4 l of dimethylformamide and cooled on ice was added 178 ml benzylchloride and was stirred over night at room temperature. The reaction liquid was poured into ice water, extracted with ethyl acetate and the organic is Loy was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 40/1 to 2/1)to give 246,7 g of target compound as an orange oil.

Stage 2. Obtain [5-(benzyloxy)pyridin-2-yl]methanol:

While cooling on ice 335,8 g of m-chloroperbenzoic acid was added to the solution 246,7 g of the obtained oil in chloroform (2.8 liters) and stirred for 1 hour. The reaction liquid is washed with aqueous 10% sodium carbonate solution and saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was recrystallized (hexane/ethyl acetate), obtaining 256,2 g of a light yellow crystal.

600 ml of acetic anhydride was added to 266 g of the obtained crystal was gradually heated and stirred at 120°C for 20 minutes. The solvent is evaporated under reduced pressure, to the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 50/1 to 2/1)to give 259 g of a brown oil.

259 g of the obtained oil was dissolved in 2 l of ethanol and 500 ml of water, was added 80 g of sodium hydroxide and heated under reflux for 30 minutes. The solvent is evaporated under reduced pressure, was added to the residue, 300 ml of water and was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. After drying, the solvent is evaporated under reduced pressure and the residue was recrystallized (diethyl ether), receiving 142,2 g of target compound as a brown crystal.

Stage 3. Getting 6-(methoxymethyl)pyridine-3-ol:

169 g of the obtained brown crystal was dissolved in 1.6 l of tetrahydrofuran and cooled on ice was added of 37.7 g of sodium hydride (with the addition of 30% liquid paraffin) and stirred at room temperature for 1 hour. While cooling on ice gradually dropwise added 53,7 ml iodomethane and was stirred over night at room temperature. When cooled on ice was added to ice water, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = from 60/1 to 21), getting 162,7 g orange oil. to 91.4 g of the obtained oil was dissolved in 900 ml of ethanol, was added 13 g of 10% palladium on coal and stirred in an atmosphere of hydrogen for 2 hours. After filtration the solvent is evaporated under reduced pressure and the residue was recrystallized (ethyl acetate/hexane)to give to 53.0 g of the target compound as a pale yellow crystal.

Reference example 12

6-(5-Methyl-1,3,4-oxadiazol-2-yl)pyridine-3-ol

This compound was obtained according to the method described in European Journal of Pharmaceutical Science, Vol.15, No.4, pp.367-378.

Reference example 13

6-(3-Methyl-1,2,4-oxadiazol-5-yl)pyridine-3-ol

This compound was obtained according to the method described in European Journal of Pharmaceutical Science, Vol.15, No.4, pp.367-378.

Reference example 14

6-(1-Methyl-1H-tetrazol-5-yl)pyridine-3-ol

Stage 1. Obtain 4-(benzyloxy)-N-methylbenzamide:

1.77 g of methylamine hydrochloride was added to a solution of 3 g of 4-benzyloxybenzyl acid in pyridine (60 ml), was added 5,04 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and stirred at room temperature. After the reaction, the solvent is evaporated under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was recrystallized from a mixture of hloroform/hexane and was separated by filtration, getting 2,272 g of target compound.

Stage 2. Getting 6-(1-methyl-1H-tetrazol-5-yl)pyridine-3-ol:

1 g of the obtained crystal was dissolved in 20 ml of toluene was added to 0.36 ml of thionyl chloride and stirred overnight at 90°C. the Solvent is evaporated under reduced pressure, was added 10 ml of acetonitrile, 0.54 g of sodium azide and 1.1 ml of chlorotrimethylsilane and was stirred over night at room temperature. The reaction liquid was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane-hexane/ethyl acetate = 1/1)to give 0.75 g of the intermediate product.

0.75 g of the obtained intermediate product was dissolved in 10 ml of ethanol was added 30 mg of palladium on coal and stirred in a hydrogen atmosphere at room temperature. After filtration the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: chloroform-chloroform/methanol = 5/1)to give 0.24 g of the target compound in the form of a crystal.

Reference example 15

6-(1,3-Oxazol-4-yl)pyridine-3-ol

Stage 1. Getting 4-(4-methoxyphenyl)-1,3-oxazole:

10 ml formiddable to 2 g of 2-bromo-4'-methoxyacetophenone and stirred at 180°C for 20 minutes. Was cooled to room temperature, diluted with ethyl acetate and washed with water and saturated salt solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane-hexane/ethyl acetate = 7/3)to give 0,76 g of target compound.

Stage 2. Getting 6-(1,3-oxazol-4-yl)pyridine-3-ol:

While cooling on ice, 12 ml of a 1M solution of boron TRIFLUORIDE/dichloromethane was added to a solution 0,76 g of the obtained compound in chloroform (8 ml) and was stirred for 4 hours. Added ice water, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate = 9/1 to 1/1)to give 0.36 g of the target compound.

Reference example 16

Obtain 6-(2-forfinal)pyridine-3-ol

An aqueous solution (1 ml) 127 mg of 2-ftorhinolonovy acid, 240 g of sodium carbonate and 53.4 mg dichlorobis(triphenylphosphine)palladium were added to a solution of 200 mg of 1-iodine-4-(methoxyethoxy)benzene obtained in reference example 11 (stage 1), in tetrahydrofuran (4 ml) and was stirred overnight in a nitrogen atmosphere while heating under reflux. When the OHL is a discussion on ice was added a saturated aqueous solution of ammonium chloride, was diluted with ethyl acetate and the insoluble substance was removed by filtration through Celite. Were extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated brine. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate)to give 135 mg of a colorless oil.

750 μl of 4 n hydrochloric acid/dioxane and 10 ál of water was added to a solution (3 ml) 67 mg of the obtained colorless oil in 1,4-dioxane and stirred at room temperature for 3 hours. After concentration of the mixture did azeotrope with chloroform, receiving of 53.7 mg of target compound in a solid white color.

Reference example 17

Getting 4-(2-methyl-2H-tetrazol-5-yl)phenol

This compound was obtained according to the method described in European Journal of Pharmaceutical Science, Vol.15, No.4, pp.367-378.

Reference example 18

Getting 5-herperidin-2-carboxylic acid

Stage 1. Getting 2-chloro-5-herperidin:

While cooling on ice and 16.3 ml of 42% terraforming acid was added to a solution of 5 g of 5-amino-2-chloropyridine in ethanol (50 ml), then gradually dropwise added an aqueous solution (10 ml) 2,95 g of sodium nitrite and stirred for 10 mi the ut. The obtained solid product was separated by filtration, getting to 9.9 g of solid yellow. Added 100 ml of heptane and heated under reflux. After the reaction was added aqueous sodium bicarbonate, extracted with diethyl ether and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/chloroform), receiving of 1.32 g of the target compound as a pale yellow oil.

Stage 2. Obtain ethyl 5-herperidin-2-carboxylate:

of 1.57 g of potassium carbonate, 0.34 g of 1,3-bis(diphenylphosphino)propane and 0.17 g of palladium acetate was added to a solution of 1 g of 2-chloro-5-herperidin in 8 ml of dimethylformamide and 8 ml of ethanol and stirred in an atmosphere of carbon monoxide at 90°C for 2 hours. The reaction liquid was filtered, the filtrate was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate)to give 0.97 g of the target compound as a white crystal.

Stage 3. Getting 5-herperidin-2-carboxylic acid:

2.4 ml of water and 2.5 n solution of hydroxy is sodium was added to a solution of 0.44 g of ethyl 5-herperidin-2-carboxylate in 5 ml of tetrahydrofuran and 2 ml of methanol and stirred at room temperature for 15 minutes. The mixture was neutralized aqueous 10% citric acid solution, extracted with ethyl acetate and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure, obtaining of 0.41 g of the target compound as a white crystal.

Reference example 19

Getting 5-methoxypyridine-2-carboxylic acid

100 mg of ethyl 5-herperidin-2-carboxylate obtained in reference example 18 (step 2), was dissolved in 1 ml of dimethylformamide and 1 ml of methanol, was added 163 mg of potassium carbonate and stirred at 90°C for 40 minutes. The mixture was neutralized aqueous 10% citric acid solution, was extracted with chloroform and the organic layer was washed with saturated saline solution. After drying, the solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (manifesting solvent: hexane/ethyl acetate), obtaining 46,5 mg of methyl 5-methoxypyridine-2-carboxylate as a white crystal.

The obtained ester compound was dissolved in 0.5 ml of methanol and 0.5 ml of tetrahydrofuran, was added 0,52 ml of aqueous 1 n sodium hydroxide solution and stirred at room temperature for 2 hours. The mixture was neutralized aqueous 10% citric acid solution, was extracted with chloroform and the organic layer was washed saturated the salt solution. After drying, the solvent is evaporated under reduced pressure, getting to 17.2 mg of the target compound as a white crystal.

Industrial applicability

Arylacetamides benzimidazole derivatives of the formula (I) and their pharmaceutically acceptable salts according to the invention have an excellent effect on the activation of glucokinase and can be used in the field of medicines for the treatment and/or prevention of diabetes, diabetic complications or obesity.

1. The compound of formula (I)

or its pharmaceutically acceptable salt, in which
R1and R2each independently represent a hydrogen atom, halogen atom, lower alkyl, hydroxyl group, cyano or lower alkoxy;
R3independently denotes a hydrogen atom, halogen atom, lower alkyl, lower alkoxy, hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano;
R4independently denotes a hydrogen atom, lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, hydroxyalkyl, optionally substituted lower alkyl, aminoalkyl, optionally substituted lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano;
Q denotes a nitrogen atom;
R5and R6each independently represent a hydrogen atom, lower alkyl, halogen atom, the lower the s alkylsulfonyl, lowest alkylsulfonyl, alkanoyl, formyl, aryl, mono - or di-(lower) allylcarbamate or mono - or di-(lower) alkylsulfonyl; or Q, R5and R6together can form the following:
(A) 5 - or 6-membered aliphatic nitrogen-containing heterocyclic group which may have a ring from 1 to 3 heteroatoms selected from the group consisting of nitrogen atom and oxygen atom, and having at least one nitrogen atom in addition to the heteroatoms; specified heterocyclic group may have one or two double bonds;
(B) a 5 - or 6-membered aromatic nitrogen-containing heterocyclic group which may have a ring from 1 to 3 heteroatoms selected from the group consisting of nitrogen atom and oxygen atom, and having at least one nitrogen atom in addition to the heteroatoms, or
(C) phenyl,
and aliphatic nitrogen-containing heterocyclic group, an aromatic nitrogen-containing heterocyclic group or phenyl can have from 1 to 3 groups selected from the following group of substituents α, and/or may have as a substituent 3-6-membered ring formed by the connection with each other associated groups selected from the group of substituents α, and/or may be condensed with a group of the formula (A):

in whichrepresents a simple bond or DV is you communication;
X1X2X3and X4each independently represent a carbon atom;
Z represents an oxygen atom or a sulfur atom;
Ar denotes an aryl or heteroaryl, optionally substituted groups a number from 1 to 3, selected from the following group of substituents β;
ring And denotes a 5 - or 6-membered nitrogen-containing heteroaromatic group of formula (III):

is pyrazinyl or pyridyl;
m denotes an integer from 1 to 6;
n denotes an integer from 0 to 3;
p denotes an integer from 0 to 2;
q represents 0 or 1;
the group of substituents α:
oxoprop, tocograph, lower alkyl, lower alkoxy, alkanoyl, formyl, hydroxyl group, carboxyl group, trifluoromethyl, hydroxyalkyl, optionally substituted lower alkyl, cyano, mono - or di-(lower) allylcarbamate, lower alkylsulfonyl, lower alkylsulfonyl and halogen atom;
the group of substituents β:
lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, lower alkylsulfonyl, lower alkylsulfanyl, lower alkylsulfonyl, cyano, aryl and heteroaryl having in the ring 1 to 3 heteroatoms selected from the group consisting of nitrogen atom and oxygen atom;
specified aryl and heteroaryl can have one or two groups selected from the following group of substituents γ;
group Deputy is stitely γ;
lower alkyl, lower alkoxy, halogen atom, hydroxyl group, lower alkylsulfonyl.

2. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) represented by the formula (1-2)

in which the symbols have the same meanings as defined above.

3. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) represented by the formula (1-3):

in which the symbols have the same meanings as defined above.

4. The compound or its pharmaceutically acceptable salt according to claim 1, in which m is from 1 to 4.

5. The compound or its pharmaceutically acceptable salt according to claim 1, in which Ar denotes phenyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, which may be substituted by a group selected from the group of substituents β.

6. The compound or its pharmaceutically acceptable salt according to claim 1, in which R5and R6each independently represents a hydrogen atom, lower alkyl, halogen atom, lower alkylsulfonyl, lower alkylsulfonyl, alkanoyl or formyl.

7. The compound or its pharmaceutically acceptable salt according to claim 1, in which a group of the formula (I-A)

in the Le (1-1) represents a group of the following formula

in which R11denotes a hydrogen atom or lower alkyl; and the other symbols have the same meanings as defined above.

8. The compound or its pharmaceutically acceptable salt according to claim 1, in which
R5and R6together with the nitrogen atom form a 5-or 6-membered aliphatic nitrogen-containing heterocyclic group which may have a ring from 1 to 3 heteroatoms selected from the group consisting of nitrogen atom and oxygen atom, and having at least one nitrogen atom in addition to the heteroatoms;
the specified 5 - or 6-membered aliphatic nitrogen-containing heterocyclic group may have one or two double bonds and may be mono - or disubstituted by identical or different groups selected from the following group of substituents α1;
m=1;
Z represents an oxygen atom;
Ar denotes phenyl or pyridyl, optionally mono - or disubstituted by identical or different groups selected from the following group of substituents β1;
R1and R2denote independently a hydrogen atom or lower alkyl,
the group of substituents α1:
oxoprop, tocograph, lower alkyl, lower alkoxy, alkanoyl, halogen atom, cyano, mono - or di-(lower) allylcarbamate;
the group of substituents β1:
lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, lower alkyl is sulfonyl, cyano, aryl or heteroaryl with the ring 2, or 3 heteroatoms selected from the group consisting of nitrogen atom and oxygen atom;
specified aryl and heteroaryl can have one or two groups selected from the group of substituents γ.

9. The compound or its pharmaceutically acceptable salt according to claim 1, in which Q, R5and R6together form a 5 - or 6-membered aromatic nitrogen-containing heterocyclic group having at least one nitrogen atom, optionally having in the ring 1 to 3 heteroatoms selected from the group consisting of nitrogen atom and oxygen atom in addition to the nitrogen atom, or phenyl;
specified aromatic heterocyclic group or phenyl can have from 1 to 3 groups selected from the following group of substituents α2;
Z represents an oxygen atom;
Ar denotes phenyl or pyridyl, optionally mono - or disubstituted by identical or different groups selected from the following group of substituents β1;
R1and R2denote independently a hydrogen atom or lower alkyl;
the group of substituents α2:
hydroxyl group, lower alkyl, lower alkoxy, alkanoyl, halogen atom, cyano or mono - or di-(lower) allylcarbamate;
the group of substituents β1:
lower alkyl, lower alkoxy, halogen atom, trifluoromethyl, lower alkylsulfonyl, cyano, aryl or heteroa is l, having in the ring 2, or 3 heteroatoms selected from the group consisting of nitrogen atom and oxygen atom;
specified aryl and heteroaryl can have one or two groups selected from the group of substituents γ.

10. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes
1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-5-thioxo-2-pyrrolidinone,
4-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}morpholine-3,5-dione,
3-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-thiazolane-2,4-dione,
3-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-thiazolin-2-it,
1-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione,
1-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-3-methylimidazolidine-2,5-dione,
2-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}isothiazolin-1,1-dioxide,
3-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyrazinyl)-1H-benzimidazole-6-yl]methyl}-2-oxazolidinone,
1-{[5-{[6-(ethylsulfonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione,
1-[(5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl)methyl]-2-pyrrolidinone,
N-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl}meth is l)-N-methylacetamide,
3-{[5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-oxazolidin-2,4-dione,
5-[4-(ethylsulfonyl)phenoxy]-6-((2-methyl-2H-tetrazol-5-yl)methyl)-2-(2-pyridinyl)-1H-benzimidazole,
5-[4-(ethylsulfonyl)phenoxy]-6-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-2-(2-pyridinyl)-1H-benzimidazole,
1-[(6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]pyrrolidin-2-he
or
4-(2,6-diferensial)-6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1H-benzimidazole.

11. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 1-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-5-thioxo-2-pyrrolidinone.

12. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 4-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}morpholine-3,5-dione.

13. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 3-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-thiazolane-2,4-dione.

14. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 3-{[5-[4-(methylsulphonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-thiazolin-2-it.

15. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 1-[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione.

16. The compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 1-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-3-methylimidazolidine-2,5-dione.

17. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) represents 2-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}isothiazolin-1,1-dioxide.

18. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 3-{[5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyrazinyl)-1H-benzimidazole-6-yl]methyl}-2-oxazolidinone.

19. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 1-{[5-{[6-(ethylsulfonyl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}pyrrolidin-2,5-dione.

20. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 1-[(5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)-3-pyridinyl]oxy}-2-(2-pyridinyl)-1H-benzimidazole-6-yl)methyl]-2-pyrrolidinone.

21. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes N-({5-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl} methyl)-N-methylacetamide.

22. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 3-{[5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)f is noxy]-2-(2-pyridinyl)-1H-benzimidazole-6-yl]methyl}-1,3-oxazolidin-2,4-dione.

23. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 5-[4-(ethylsulfonyl)phenoxy]-6-((2-methyl-2H-tetrazol-5-yl)methyl)-2-(2-pyridinyl)-1H-benzimidazole.

24. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 5-[4-(ethylsulfonyl)phenoxy]-6-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-2-(2-pyridinyl)-1H-benzimidazole.

25. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) denotes 1-[(6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyridin-2-yl-1H-benzimidazole-4-yl)methyl]pyrrolidin-2-it.

26. The compound or its pharmaceutically acceptable salt according to claim 1, in which formula (I) refers to 4-(2,6-diferensial)-6-{[6-(ethylsulfonyl)pyridine-3-yl]oxy}-2-pyrazin-2-yl-1H-benzimidazole.

27. A glucokinase activator comprising a compound or pharmaceutically acceptable salt according to any one of claims 1 to 26 as the active ingredient.

28. Therapeutic and/or prophylactic agent for the treatment and/or prevention of diabetes, containing the compound or pharmaceutically acceptable salt according to any one of claims 1 to 26 as the active ingredient.

29. Therapeutic and/or prophylactic agent for the treatment and/or prevention of obesity, containing the compound or pharmaceutically acceptable salt according to any one of claims 1 to 26 as the active ingredient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. Disclosed compounds have inhibitory effect on CDK1 kinase and can be used to prepare medicinal agents for treating diseases associated with abnormal cell cycle development. In formula I , R1 is hydrogen, -C(O)OR9 or R2-(X)n-; X is (lower)alkylene, hydroxy(lower)alkylene, cyclised(lower)alkylne or mono- or dihalogen(lower)alkylene; R2 is a group, where denotes a phenyl or a 5-6-member heteroaromatic ring containing 1-2 heteroatoms selected from a group comprising oxygen, sulphur and nitrogen atoms; R5, R6 and R7 are independently selected from a group comprising hydroxy, hydrogen, (lower)alkyl, halogen and (lower)alkoxy; R4 is a halogen, , (O)k(CH2CH2O)y-R10, , -S-R12 or -O-(CH2)tR14, where denotes a phenyl, a cycloalkyl ring containing 3-6 carbon atoms, a 4-6-member heterocycloalkyl containing 3-5 carbon atoms and 1-2 heteroatoms selected from a group comprising oxygen, nitrogen and sulphur atoms; R9, R11, R15 and R16 independently denote (lower)alkyl; R10 and R12 denote (lower)alkyl; R14 denotes perfluoro(lower)alkyl or -NR15R16; R17 and R18 independently denote hydrogen, , F, OCH3 and -C(=O)CH3; n and k are equal to 0 or 1; m, w, y and z are equal an integer from 0 to 3; and t equals an integer from 0 to 6.

EFFECT: invention also relates to a pharmaceutical composition having antiproliferative activity, containing one or more of the disclosed compounds.

65 cl, 1 tbl, 49 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I): wherein dashed lines present single or double bonds, and the values of radicals R1, R2, R3, R4 are described in cl. 1 of the patent claim. Besides the invention refers to application and a based pharmaceutical composition for prevention and treatment of neurodegenerative diseases and other diseases wherein cell dystrophy and/or cell loss (apoptosis) caused by free radicals act the main part.

EFFECT: production of new compounds and the based pharmaceutical composition which can find application in medicine for prevention and treatment of neurodegenerative diseases.

6 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit the properties of glycine carrier 1 (GlyT-1) inhibitors. In formula I , R1 represents -OR1', -SR1' or morpholinyl; R1' represents lower alkyl, halogen-substituted lower alkyl, or represents -(CH2)n-lower cycloalkyl; R2 represents -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; X1 represents CR3 or N; X2 represents CR3' or N; R3/R3' independently represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2, 3 or 4-yl, phenyl optionally substituted with one or two substitutes specified from the group consisting of NO2 or halogen, or represent halogen-substituted lower alkyl, or represent -C(O)-lower alkyl; n has a value of 0, 1 or 2. The invention also concerns a drug containing one or more compounds of the invention and pharmaceutically appropriate excipients.

EFFECT: preparation of the compounds exhibiting the properties of glycine carrier inhibitors.

20 cl, 1 tbl, 133 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on CDK1 kinase. In formula I , R1 is hydrogen or R2-(X)n-; X is a lower alkylene or cyclic lower alkylene; R2 denotes ; where denotes phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-member heterocycloalkyl ring having 3-5 carbon atoms and 1-2 oxygen atoms; R5, R6 and R7 are independently selected from a group containing hydrogen or halide; R4 is hydrogen or -(O)k(CH2CH2O)y-R10; R19 is hydrogen; R20 is hydrogen or -C(O)-R11; R10 and R11 is a lower alkyl; n and k are equal to 0 or 1; y is an integer from 0 to 3.

EFFECT: obtaining a pharmaceutical composition with inhibitory effect on CDK1 kinase, containing one or more of the disclosed compounds.

15 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK) of formula (I)

, where R0 denotes hydrogen; R1 is a saturated 6-member monocyclic or 10-member bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, which can be substituted with piperidinyl, (C1-C7)alkylpiperidinyl, hydroxy, (C1-C7)alkyl, piperazinyl, (C1-C7)alkylpiperazinyl; R2 and R3 together with the carbon or nitrogen atom to which they are bonded form a 5- or 6-member heterocycle containing one heteroatom selected from a nitrogen atom which is substituted with (C1-C7)alkyl and/or oxo- group, R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; halide, (C1-C7)alkoxy; carbamoyl which is unsubstituted or substituted with (C1-C7)alkyl; (C1-C7)alkoxy(C1-C7)alkoxy; 5- or 6-member heterocycle containing one or two heteroatoms independently selected from nitrogen or oxygen, and is unsubstituted or substituted with a substitute independently selected from hydroxy, (C1-C7)alkyl, mono- or di(C1-C7)alkylamino, 6-member heterocycle containing one or two nitrogen ring atoms which are unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle(C1-C7)alkoxy containing one nitrogen ring atom which is unsubstituted or substituted with (C1-C7)alkyl; R9 is hydrogen; R10 is hydrogen, halide or (C1-C7)alkoxy; or their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and use of formula (I) compounds.

EFFECT: obtaining novel compounds with inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK), having formula (I) .

7 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I in the form of salt where J means a C1-C2 alkylene; R1 means cyclopentane, cyclohexyl, phenyl or thiophenes; R2 means hydroxy; R3 means a cyclopentane, cyclohexyl, phenyl or thiophenes; with R1 and R3 are not identical, or -CR1R2R3 together form a group of the formula , where Ra means a chemical bond, and Rb means hydroxy; R4 means methyl; R5 means C1 alkyl substituted with -CO-NH-R6; R6 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur; or J means C1-C2 alkylene; R1 and R3 both mean phenyl; R2 means hydroxy; R4 means methyl, R5 means C1 alkyl substituted with -CO-NH-R9; and R9 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur. The invention also refers to pharmaceutical composition, to application of compound according to any of clauses 1-3, as well as to method for obtaining a compound of formula I according to clause 1.

EFFECT: obtaining new biologically active compounds having antagonistic activity against muscarinic receptor M3.

7 cl, 21 ex

Cytokine inhibitors // 2394029

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and acids. In formula (I) , Ar1 is an aromatic carbocycle substituted with one R1 and where Ar1 is independently substituted with two R2; R1 is J-N(Ra)-(CH2)m-, N(J)2-(CH2)m-, NH2C(O)-, J-N(Ra)-C(O)-, J-S(O)m-N(Ra)-, J-N(Ra)-S(O)m-; Q is CRP; Y is -N(Rx)-; where Ra, Rp, Rx and Ry each independently denotes hydrogen or (C1-C5)alkyl; X is O-; W is N or CH, m independently equals 0, 1 or 2; J is selected from (C1-C10)alkyl, optionally substituted Rb; R2 is selected from (C1-C6)alkyl or (C1-C4)alkoxy, optionally partially or completely halogenated; R3, R4 and R5 are each independently selected from hydrogen or (C1-C6)alkyl; R6 is optionally bonded in the ortho- or meta-position to the nitrogen atom of the said ring and is selected from a bond, -O-, O-(CH2)1-5-, -NH-, -C(O)-NH-, branched or straight (C1-C5)alkyl; and where each R6 is further optionally covalently bonded to groups selected from hydrogen, -NR7R8, (C1-C3)alkyl, heteroaryl(C0-C4)alkyl, where the heteroaryl is pyrimidine, and heterocyclyl(C0-C4)alkyl, where the heterocyclyl is selected form morpholine, pyrrolidine, piperazinyl, optionally substituted with (C1-C6)alkyl; R7 and R8 each independently denote hydrogen or branched or straight (C1-C5)alkyl; and Rb is selected from hydrogen, (C1-C5)alkyl, amino, (C1-C5)alkylamino, (C1-C5)dialkylamino. The invention also relates to a pharmaceutical composition containing a pharmaceutically effective amount of the formula (I) compound, to use of the disclosed compounds to prepare a pharmaceutical composition and to a method of obtaining formula (I) compounds.

EFFECT: disclosed compounds have cytokine inhibiting properties.

13 cl, 3 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: novel 1,2,4-triazole derivatives - protein kinase inhibitors of formula (I) are described, where X - N; Y - CH2, NH, NR or 0; R1 and R2 each independently denote hydrogen; R3 is phenyl, substituted with -CN, 6-member heteroaryl containing 1-2 N atoms, possibly substituted with a 7-member heterocyclyl containing 2 nitrogen atoms, which in turn is substituted with C1-6alkylcarbonyl; R4 is hydrogen; R5 is hydrogen or -CN; and R is a C1-6alkyl group, C1-6alkylcarbonyl group substituted with -CN, or a C3-6cycloalkyl group, a method of inhibiting FLT-3 or c-KIT protein kinase.

EFFECT: obtaining novel compounds and their use in making a medicinal agent for treating or relieving acute myelogenic leucosis.

11 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts , involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK) of formula (I)

, where R0 denotes hydrogen; R1 is a saturated 6-member monocyclic or 10-member bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, which can be substituted with piperidinyl, (C1-C7)alkylpiperidinyl, hydroxy, (C1-C7)alkyl, piperazinyl, (C1-C7)alkylpiperazinyl; R2 and R3 together with the carbon or nitrogen atom to which they are bonded form a 5- or 6-member heterocycle containing one heteroatom selected from a nitrogen atom which is substituted with (C1-C7)alkyl and/or oxo- group, R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; halide, (C1-C7)alkoxy; carbamoyl which is unsubstituted or substituted with (C1-C7)alkyl; (C1-C7)alkoxy(C1-C7)alkoxy; 5- or 6-member heterocycle containing one or two heteroatoms independently selected from nitrogen or oxygen, and is unsubstituted or substituted with a substitute independently selected from hydroxy, (C1-C7)alkyl, mono- or di(C1-C7)alkylamino, 6-member heterocycle containing one or two nitrogen ring atoms which are unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle(C1-C7)alkoxy containing one nitrogen ring atom which is unsubstituted or substituted with (C1-C7)alkyl; R9 is hydrogen; R10 is hydrogen, halide or (C1-C7)alkoxy; or their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and use of formula (I) compounds.

EFFECT: obtaining novel compounds with inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK), having formula (I) .

7 cl, 155 ex

Up!