Using ep4 receptor ligands in treatment of il-6-mediated diseases

FIELD: medicine.

SUBSTANCE: invention relates to using antagonist of EP4 receptors in preparing a medicinal preparation used in treatment of IL-6-mediated disease chosen from the group including alcoholic cirrhosis, amyloidosis, atherosclerosis, cardiac disease, sclerosis and responses in transplantation of organs.

EFFECT: valuable medicinal properties of ligands.

6 cl, 8 dwg, 380 ex

 

The scope of the invention

The present invention relates to new methods of using the ligands of the receptor EP4. The invention also includes methods of identifying agents that affect the activation of cells of peripheral whole blood, and specific methods of identifying compounds that affect the secretion of IL-6 by these cells in peripheral whole blood, by modulating the activity, mediated by PGE2. The present invention also relates to new methods of using antagonists of the receptor EP4. The methods of this invention include methods for analysis of cell activation in peripheral whole blood by interacting with connections and PGE2, which can identify cellular activity by measuring the production of IL-6.

Background of the invention

Prostaglandin E2 (PGE2) is an important modulator involved in the pathogenesis of arthritis. PGE2 binds at least four subtypes of PGE receptor, designated as EP1, EP2, EP3 and EP4. Molecular studies showed that all subtypes are 7-transmembrane receptors, passing through the bilayer, which belong to the superfamily of receptors associated with G-protein (Robert et al., Am. Soc. Pharm. Exp. Ther. 46:205-29,1994). Activation of EP1 stimulates the release of intracellular calcium by a mechanism mediated G-protein; both P2 and EP4, stimulating the G-proteins that activate adenylate cyclase, but differ with regard to specific ligands; EP3 inhibit adenylate cyclase, inhibition of G-proteins (Robert et al., supra, Negishi et al., Biochimica Biophys. Acta 1259:109-20,1995).

It was hypothesized that increased levels of interleukin-6 (IL-6), a pleiotropic cytokine inflammation contributes to many pathological disorders, such as rheumatoid arthritis, autoimmune diseases and atherosclerosis.

Interleukin-6 (IL-6) is a key cytokine required for the induction of plasma cell, secretion of Titel, growth of B-cells, activation of acute phase protein synthesis, activation of T-cells, the growth of hematopoietic stem cells and maintain optimal immune system function. The activity of this cytokine provides the activation and maintenance functions of the immune system during infections and in response to other inflammatory stimuli. It was described that IL-6 plays an important role in the development and maintenance of chronic inflammatory diseases such as rheumatoid arthritis, in a mammal. In a recent clinical studies have shown that antibodies to the receptor of IL-6 holocaut strength of the joint, reduce pain and swelling in patients with rheumatoid arthritis (Yoshizaki et al., Springer Semin Immunopathol. Vol. 20,247-259, 1998). This fact, suggesting that regulation of IL-6 may influence n the course of the disease, is a promising strategy for the treatment of chronic inflammatory diseases.

Atherosclerosis is a complex disease characterized by the deposition of cholesterol and macrophage infiltration of the subendothelial space, which leads to the formation of foam cells (Ross R. (1993) Nature 362:801-809). The presence of macrophages and T-lymphocytes in atherosclerotic damage speaks about the important role of the immune system and the inflammatory process in the pathogenesis of atherosclerosis (Libby et al.(1993) Curr. Opin. Lipidol. 4:355-363).

The man in the atherosclerotic lesions were identified mRNA transcripts of IL-6 (Seine et al. Cytokine. 1994, 6, 87-91). These observations confirmed and expanded immunohistochemistry, which showed the joint localization of protein expression of IL-6 and macrophage, and smooth muscle cells in the atherosclerotic plaques of human (Kishikawa H. et al., Virchows. Arch. A Pathol. Anat. Histopathol. 1992, 423, 433-442). Moreover, it was shown that IL-6 has a significant impact on the types of cells that are components of atherosclerotic plaques. IL-6 can premirovat macrophage cells THP-1, which increases the amount of production of tumor necrosis factor in response to lipopolysaccharide (LPS) (Cochran FR et al., Immunopharmacology, 1992, 23, 97-103), thus suggesting that IL-6 may play a role in stimulation of macrophages for the achievement of their maximum inflammatory activity. It was shown that IL-6 stimulates the growth of smooth muscle cells under the action of platelet growth factor (Ikeda U. et al., Am. J. Physio. 1991, 260, H1713-H1717). Recent research has shown that mice with a "knockout" apolipoprotein E is developing atherosclerosis, similar to atherosclerosis person (Bourassa P-AK et al., Proc. Natl. Acad Sci USA 1996, 93, 10022-10027; K. Kauser et al., J. Vasc. Res, 1996, 33 (suppl 1) 48, Abstract). The secretion of IL-6, isolated from the aorta of mice with knockout apoE showed a positive correlation with the area of lesions in the aorta of mice with knockout apoE, and immunohistochemical staining showed that macrophages predominantly produce IL-6 (Sukovich, D. A. et al., Arterioscler Thromb Vase Biol. 1998, 18, 1498-1505). Thus, it seems that IL-6 plays a critical role in the development of atherosclerosis.

On the other hand, recent research prove the hypothesis of the inflammatory nature of atherosclerosis (Ross, R., et al., Nature, 1993, 362, 801-809; Alexander, R. W., et al., N. Engl. J. Med., 1994, 331, 468-469), and studies of inflammatory markers show a link between increased inflammation and risk of myocardial infarction (Rider, P. M. et al., N. Engl. J. Med., 1997, 336, 973-979; Liuzzo, G. et al., N. Engl. J. Med., 1994, 331, 417-424). The gap plaques, leading to thrombosis is a key event of heart attack, and it was shown that the gap associated with an increasing in the plaque inflammation (van der Wal. A. C., et al., Circulation, 1994, 89, 36-44). Moreover, the reduction of the inflammatory response may be with Asano with a reduced risk of subsequent ischemic manifestations (Rider, P. M. et al., N. Engl. J. Med., 1997,336, 973-979), and an assumption was made that the effective action of aspirin, an inhibitor of cyclooxygenase, reducing the risk of myocardial infarction associated with anti-inflammatory action. These facts indicates that, in addition to cytokines and growth factors, prostaglandins, apparently, also play a significant role in atherosclerosis.

Prostaglandins are usually produced by the enzyme cyclooxygenase-1 (COX-1), which constituitive is expressed by the vascular endothelium, platelets, kidney and in other places (Monkada, S. et al., Nature, 1976, 263, 663-665). In addition, in various cell types was selected cytokine-inducible the cyclooxygenase, COX-2. The expression of COX-2 is limited to the basic conditions and not under control inflammation, such as rheumatoid arthritis (Needeleman, P. et al., J. Rheumatol, 1997, 24 (suppl 49), 6-8). In atherosclerotic lesions in humans COX2 was detected in macrophages, in some smooth muscle cells and endothelial cells (Christopher, S. R., et al., Arterioscler Thromb. Vasc. Biol. 1999, 19, 646-655; Stemme, V. et al., Eur. J. Vasc. Endovasc, Surg., 2000, 20, 146-152). Since the activation of COX2 produced prostaglandin E2and I2that is well known as a key and positive factors of inflammation, such as PGE2 and/or PGI2then COX2 can play an important role in atherosclerotic disease.

On the basis of the data series can be deleteregvalue, that prostaglandins and IL-6 produced by macrophages in inflammation or atherosclerotic damage are related to the development and maintenance of the disease. In fact, it was previously reported that simultaneous stimulation of monocytes in human peripheral blood PGE2 and particles of titanium PGE2 enhances the production of IL-6 to its maximum limit (Blaine, T. A. et al, J. Bone Joint Surgery, 1997, 10, 1519-1528). In this study the authors of this patent, it was shown that PGE2 increases the production of IL-6 in the processing concanavalin A (ConA) mononuclear cells of peripheral blood (PBMC). The authors of this patent unexpectedly found that selective antagonists of the receptor subtype EP4 inhibit the production of IL-6 in PBMC and in peripheral whole blood, while stimulation of PGE2 and ConA (see detailed description of the invention).

Brief description of the invention

The present invention relates to methods of use of the EP4 receptor ligand in the manufacture of a medicine for the treatment of diseases mediated by IL-6. Preferably, the disease mediated by IL-6, selected from the group including cirrhosis with alcoholism, amyloidosis, atherosclerosis, heart disease, such as angina, myocardial infarction, myocardiopathy and myocarditis, multiple sclerosis, such as multiple sclerosis, and reactions when transportation is antali bodies.

In accordance with another aspect of the present invention relates to a method of treating diseases mediated by IL-6, in mammals, including humans, which consists of introducing an effective amount of an EP4 receptor ligand. Preferably, the disease mediated by IL-6, selected from the group including cirrhosis with alcoholism, amyloidosis, atherosclerosis, heart disease, such as angina, myocardial infarction, myocardiopathy and myocarditis, multiple sclerosis, such as multiple sclerosis, and reactions by transplantation of organs.

In accordance with an additional aspect of this invention relates to a pharmaceutical composition consisting of EP4 receptor ligand for use in the treatment of diseases mediated by IL-6.

Preferably, the disease mediated by IL-6, selected from the group consisting of cirrhosis with alcoholism, amyloidosis, atherosclerosis, heart disease, such as angina, myocardial infarction, myocardiopathy and myocarditis, multiple sclerosis, such as multiple sclerosis, and reactions by transplantation of organs.

Preferably, the EP4 receptor ligand used in this invention is a selective EP4 receptor antagonist.

In accordance with another preferred aspect of the ligand (antagonist) receptor EP4 represents aryl or het is Roheline condensed imidazole compound of the following formula I

or its pharmaceutically acceptable salt,

where Y1, Y2, Y3and Y4independently selected from N, CH or C(L);

R1represents H, C1-8alkyl, C2-8alkenyl, C2-8quinil, C3-7cycloalkyl, C1-8alkoxy, halogen-substituted C1-8alkoxy, C1-8alkyl-S(O)m-, Q1-pyrrolidinyl, piperidyl, oxopyrrolidin, oxopiperidin, amino, mono - or di-(C1-8alkyl)amino, C1-4alkyl-C(=O)-N(R3)or C1-4alkyl-S(O)m-N(R3)-where the specified C1-8alkyl, C2-8alkenyl and C2-8quinil optionally substituted with halogen, C1-3by alkyl, hydroxy, oxo, C1-4alkoxy, C1-4alkyl-S(O)m-, C3-7cycloalkyl-, cyano, indenolol, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthalene, pyrrolidinium, piperidino, oxopyrrolidin, oxopiperidine, Q1-, Q1-C(=O)-, Q1-O-, Q1-S(O)m-, Q1-C1-4alkyl-O-, Q1-C1-4alkyl-S(O)m-, Q1-C1-4alkyl-C(O)-N(R3)-, Q1-C1-4alkyl-N(R3)or C1-4alkyl-C(O)-N(R3)-;

Q1represents a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4the alkyl, guy is Roxie, C1-4alkoxy, halogen-substituted C1-4alkoxy, C1-4alkylthio, nitro, amino, mono - or di-(C1-4alkyl)amino, cyano, HO-C1-4the alkyl, C1-4alkoxy-C1-4the alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyls(=O)-, HO(O=)C-, C1-4alkyl-O(O=)C-, R3N(R4)C(=O)-, C1-4alkylsulfonyl, C3-7cycloalkyl, R3C(=O)N(R4)- or-NH2(HN=)C-;

A is a 5-6-membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, where the specified 5-6-membered monocyclic aromatic ring optionally substituted by up to 3 substituents selected from halogen, C1-4of alkyl, halogen-substituted C1-4of alkyl, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, C1-4alkylthio, nitro, amino, mono - or di-(C1-4alkyl)amino, cyano, HO-C1-4of alkyl, C1-4alkoxy-C1-4of alkyl, C1-4alkylsulfonyl, aminosulfonyl, acetyl, R3N(R4)C(=O)-, HO(O=)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl, C3-7cycloalkyl, R3C(=O)N(R4)and NH2(HN=)C-;

B represents a halogen-substituted C1-6alkylene, C3-7cycloalkyl, C2-6albaniles, C2-6akinyan, -O-C1-5alkylene, C1-2alkylen-O-C1-2alkylene or C1-6alkylen, neobythites is but replaced by oxopropoxy or C 1-3by alkyl;

W represents NH, N-C1-4alkyl, O, S, N OR5or a covalent bond;

R2represents H, C1-4alkyl, OH or C1-4alkoxy;

Z represents a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, where the specified 5-12-membered monocyclic or bicyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4the alkyl, C1-4alkenyl, C1-4the quinil, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, C1-4alkylthio, nitro, amino, mono - or di-(C1-4alkyl)amino, cyano, HO-C1-4the alkyl, C1-4alkoxy-C1-4the alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyls(=O)-, R3C(=O)N(R4)-, HO(O=)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl, C3-7cycloalkyl, NH2(HN=)C-, Q2-S(O)m-, Q2-O-, Q2-N(R3)- or Q2-;

L represents halogen, C1-4alkyl, halogen-substituted C1-4alkyl, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, C1-4alkylthio, nitro, amino, mono - or di-(C1-4alkyl)amino, cyano, HO-C1-4alkyl, C1-4alkoxy-C1-4alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyls(=O)-, HO(=)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl, C3-7cycloalkyl, R3C(=O)N(R4)-, NH2(HN=)C-, R3N(R4)C(=O)-, R3N(R4)S(O)m-, Q2-, Q2-C(=O)-, Q2-O-, Q2-C1-4alkyl-O-, or two adjacent L groups are optionally joined together with formation of alkalinous chain containing 3 or 4 members in which one or two (lesosecnyh) carbon atoms neobyzantine semenary atoms of oxygen;

m is 0, 1 or 2;

R3and R4independently selected from H and C1-4of alkyl;

R5represents H, C1-4alkyl, C1-4alkyl-(O=)C -, or C1-4alkyl-O-(O=)C-; and

Q2represents a 5-12 membered monocyclic or bicyclic aromatic ring, or 5-12-membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, where the specified 5-12-membered monocyclic or bicyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4the alkyl, C1-4alkenyl, C1-4the quinil, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, C1-4alkylthio, nitro, amino, mono - or di-(C1-4alkyl)amino, cyano, HO-C1-4the alkyl, C1-4alkoxy-C1-4the alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyl-(O=)C-, R3(R4)C(=O)N-, HO(THE)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl, C3-7cycloalkyl, C1-4-alkyl-C(=O)NH - or-NH2(HN=)C-.

In accordance with another preferred aspect of the ligand (antagonist) of the EP4 receptor, which is described in WO 00/16760, represents aryl or jerrilee condensed imidazole compound of the following formula II

or its pharmaceutically acceptable salt,

where R1represents lower alkyl, substituted hydroxy, protected carboxy or carboxy; carboxy; protected carboxy, carbarnoyl; heterocyclic group; cyano; halogen(lower)alkylsulfonate; lower alkoxy, substituted hydroxy or carbamoyl; aryl, substituted carboxy, protected carboxy, carbamoyl or heterocyclic group; or amino, optionally substituted by protected carboxy or lower alkylsulfonyl,

R2represents hydrogen or lower alkyl,

R3represents aryl, optionally substituted with halogen,

R4represents aryl, optionally substituted with halogen,

Q represents[where-A1- represents a single bond or lower alkylene,represents a cyclo(C5-C9)alkene, cyclo(C3-C9)Alka is, bicyclo(C6-C9)alkene or bicyclo(C5-C9)alkane, and-A3- represents a single bond or lower alkylene], and X represents O, NH or S.

In accordance with another aspect of this invention relates to a method, which includes the cultivation of whole peripheral blood with a test compound; and determining the effect of compounds on PGE2-induced activation of cells of whole blood. Preferably, as measured by changes in cellular activity is increased release of cytokines. Preferably, the action of the compounds is determined by comparing with the action on the control culture in the absence of a connection.

In accordance with another aspect of this invention relates to a method, which includes the activation of the cells of whole peripheral blood by a combination of PGE2 and other stimulating agents, such as concanavalin A, CD3 or titanium.

The person skilled in the art will be completely understandable terms used here in the description and the attached claims, describe the present invention. However, if not stated otherwise, the following terms such as described immediately below.

Under "disease mediated by IL-6" understand the disease induced IL-6, in which IL-6 activate and maintain the function of the immune system during the AI infectious diseases.

Examples of such diseases mediated by IL-6, include cirrhosis with alcoholism, amyloidosis, atherosclerosis, heart disease, such as angina, myocardial infarction, myocardiopathy and myocarditis, multiple sclerosis, such as multiple sclerosis, and reactions by transplantation of organs.

By "ligand receptor EP4" understand the connection that binds to a receptor EP4, including a stereoisomer of the compound, pharmaceutically acceptable salt of this compound, or a stereoisomer, a prodrug of the compound or stereoisomer, or pharmaceutically acceptable salt of the prodrug. It is also clear that any additional pharmaceutically active compound used in combination with the EP4 receptor ligand may be a stereoisomer of this additional active compound, the salt of this additional active compound or its stereoisomer, prodrug additional compound or its stereoisomer, or salt of the prodrug.

By "antagonist of the EP4 receptor" understand chemical compound that reduces or blocks the biological activity of the receptor EP4. Such antagonists may include proteins, such as anti-EP4 antibodies, nucleic acids, amino acids, peptides, carbohydrates, small molecules (organic or inorganic), or any other connection is tion or composition, reducing the activity of the receptor EP4 or by reducing present in the cell number of the EP4 receptor, either by reducing binding or signaling activity of the receptor EP4.

Used here, the term "alkyl" denotes a straight or branched saturated monovalent hydrocarbon radical, including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl, neopentyl and the like.

Used herein, the term "alkenyl" denotes a hydrocarbon radical containing at least one double bond, including, but not limited to, ethynyl, propenyl, 1-butenyl, 2-butenyl and the like.

Used here, the term "quinil" denotes a hydrocarbon radical containing at least one triple bond, including but not limited to, ethinyl, PROPYNYL, 1-butynyl, 2-butynyl and the like.

Used herein, the term "halogen" refers to F, Cl, Br or I, preferably F or Cl.

Used here, the term "cycloalkyl" means a saturated hydrocarbon radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl and the like.

Used here, the term "alkoxy" denotes an O-alkyl group, where "alkyl" as defined is use.

Used here, the term "monocyclic aromatic ring" refers to monocyclic aromatic carbocyclic or heterocyclic ring (containing 0-4 heteroatoms selected from O, N and S), including, but not limited to, phenyl, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolin, triazolyl, furutani and the like.

Used here, the term "bicyclic aromatic ring" refers to monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring (containing 0-4 heteroatoms selected from O, N and S), including, but not limited to, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophene, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazoles, benzimidazoles, hinely, ethanolic, cinnoline, phthalazine, hintline, honokalani and the like.

Used here, the term "alkylene" denotes a saturated hydrocarbon (straight or branched chain), where the hydrogen atom is removed from each end of the carbon, such as methylene, ethylene, propylene, butylene, pentile, hexylen and the like.

Used here, the term "cycloalkyl" refers to a bivalent cycloalkyl group, including, but their is s limited to, cyclopropyl, cyclobutene, cyclopentene, cyclohexene and cycloheptene and the like.

Used here, the term "albaniles" denotes the intermediate radical is straight or branched hydrocarbon chain containing at least one double bond, including, but not limited to, -CH=CH-, -CH=CHCH-, -CH=CHCH(CH3)and the like.

Used here, the term "akinyan" denotes the intermediate radical is straight or branched hydrocarbon chain containing at least one triple bond, including but not limited to, -C≡,-C-C≡H2-,-C≡CH(CH3)and the like.

Used here, the term "tricyclic ring" means a saturated hydrocarbon radical, including, but not limited to, substituted, tricyclo [5.2.1.02,6]decane and the like.

Used here, the term "two adjacent L groups are optionally joined together with formation of alkalinous chain containing 3 or 4 members in which one or two (lesosecnyh) a carbon atom optionally replaced by oxygen atoms" means, but is not limited to, -O-CH2-O-, -CH2-O-CH2-, -O-CH2CH2-, -CH2CH2-O-, -O-CH2CH2-O-, -CH2CH2CH2-O-, -O-CH2CH2CH2-, -CH2-O-CH2CH2-, -CH2CH2-O-CH2 - and the like.

Used here, the term "aryl" denotes aromatic radicals, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl and the like.

Used here, the term "protective group" means a hydroxy or aminosidine group selected from conventional hydroxy or aminosidine groups described in Protective Groups in Organic Synthesis edited by T. W. Greeneet al. (JohnWiley & Sons, 1991);

Used herein, the term "treatment" refers to the reversion, facilitation, inhibition of the development or prevention of a disorder or condition that applies to this term, or one or more symptoms of the disorder or condition. Used the verb "treatment" refers to the act of treatment, where "treatment" is defined directly above.

Other features and advantages of this invention will be understood from the following detailed description and from the claims. Although the invention is described in connection with specific embodiments, it will be understood that within the scope of this invention and within the attached claims may also be made of changes and modifications. This invention includes all equivalents, variants, application or device according to this invention, which are, in General, in principle, danagoulian, including deviations from the descriptions that were consistent with the known or customary practice in this area. Additional guidance regarding the receipt and use of the nucleic acids and polypeptides can be obtained from conventional textbooks on molecular biology, protein chemistry and immunology (see, for example, Davis et al.,Basic Methods in Molecular Biology, Elsevir Sciences Publishing, Inc., New York, NY, 1986; Hames et al.,Nucleic Acid Hybridization, IL Press, 1985;Molecular Cloning, Sambrook et al.,Current Protocols in Molecular Biology, Eds. Ausubel et al., John Wiley and Sons;Current Protocols in Human Genetics, Eds. Dracopoli et al., John Wiley and Sons;Current Protocols in Protein Science, Eds. John E. Coligan et al., John Wiley and Sons; andCurrent Protocols in Immunology, Eds. John E. Coligan et al., John Wiley and Sons). All publications are hereby incorporated by reference in full.

Description of figures

The figure 1 presents a histogram showing the secretion of IL-6 upon stimulation of PGE2 ConA-treated human PBMC (shaded band) and ConA-raw human PBMC (shaded band).

The figure 2 presents a histogram showing the relation between the stimulation of the secretion of IL-6 RVMS person on the concentration of PGE2 with and without ConA stimulation, and inhibition effect of the EP4 antagonist, compound A (N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide). In PBMC, processed ConA, compound A significantly inhibited the secretion of IL-6.

<> The figure 3 presents a histogram showing the effect of the EP4 antagonist, compound A and compound B (3-{[1S)-2-(4,5-diphenyl-1,3-oxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid) in the inhibition of the secretion of IL-6 in RVMS processed ConA.

The figure 4 presents a histogram showing the effect on the production of IL-6 in the application of PGE2 on whole human blood.

The figure 5 presents a graph showing the effects of EP2 (butaprost), EP4 (11-deoxy-PGE1) and EP1/EP3 (sulprostone) on the production of IL-6 in HWB.

The figure 6 presents a graph showing the effect of compound B (320-40000 nm) on the production of IL-6 in HWB-stimulated PGE2.

The figure 7 presents a graph showing the effect of PGE2 on the production of IL-6 in whole blood (HWB), ConA stimulated.

The figure 8 presents a graph showing the effect of compound C(N-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide) (16-50000 nm) on the production of IL-6 in HWB, ConA stimulated and PGE2.

Detailed description of the invention

The present invention relates to the use of ligand receptor EP4 when getting medicines for the treatment of diseases mediated by IL-6. This invention is based on the observation of the relative resistance to the development of symptoms of arthritis in mice with "knockout" EP4 after induction of the disease antibodies to collagen type II (experimental model of rheumatoid arthritis).

This invention also describes methods of screening to identify agents that inhibit the activity EP4in vivofor example, for use as a drug for the treatment of rheumatoid arthritis.

Therapeutic methods

The agent, identified as a ligand of the receptor EP4, was administered in a dose effective for the treatment of diseases mediated by IL-6, selected from the group consisting of cirrhosis with alcoholism, amyloidosis, atherosclerosis, heart disease, multiple sclerosis and reactions in organ transplantation. Such therapeutically effective amounts can be determined using conventional optimization methods, based on the specific condition, the treatment for which it is assumed that the condition of the patient, route of administration, the composition, the physician's recommendation and other factors evident to the experts in this field in the light of this description.

An agent that inhibits the activity EP4, can be entered in the form therapeutic compositions. Such ligands of the receptor EP4 may include small molecules, nucleic acids such as antisense nucleic acids EP4, amino acids, peptides, hydrocarbons and antibodies against EP4. Preferably, such agents together with a pharmaceutically acceptable transport agent or carrier. Examples of antibodies against EP4 include, for example the EP, polyclonal, monoclonal, humanized, anti-idiotopes, chimeric or antibodies, single chain, Fab, F(ab')2and Fab from a library of fragments of the expression of scFV molecules and fragments thereof that bind the epitope. Antisense oligonucleotide which inhibits expression of a gene or EP4 mRNA produced in accordance with standard methods (see, for example, Agrawal et al. Methods in Molecular Biology: Protocols for Oligonucleotides and Analogs, Vol. 20 (1993)).

As used here, the pharmaceutically acceptable carrier includes solvents, dispersion medium, coating agents, antibacterial and antifungal agents and isotonic agents and agents that delay absorption, compatible with pharmaceutical administration.

The carrier may also include other active or inert components, and/or may be focused on the tissue of the joint, due to its structure.

therapeutic composition was such that it was compatible for the intended route of administration. Unlimited examples of routes of administration include parenteral, for example intravenous, percutaneous, subcutaneous, oral (e.g., intake or inhalation), transdermal (topical), through the mucosa and rectal route. Solutions or suspensions can be obtained as described inRemington's Pharmaceutical Sciences(18thed., Gennaro, ed., Mack Publishing Co. Easton, PA, (1990)).

Therapeutic efficacy of such inhibitors EP4 can be determined in the light of this description standard therapeutic methods in cell cultures or experimental animals, for example to determine the ED50(the dose therapeutically effective in 50% of the population).

Data obtained from cell culture assays and animal studies can be used to determine the dose range in humans. The dose may vary depending on the composition and route of administration. For any inhibitor EP4 used in the method according to this invention, therapeutically effective dose can be determined in experiments on cell culture. The dose can be determined in animal models to achieve the level of concentration of circulating plasma, which includes IC50as defined in experiments on cell culture. These data can be used for more accurate determination of effective doses of the person. Levels in plasma may be measured, for example using high-performance liquid chromatography.

The person skilled in the art it will be clear that certain factors can affect the dose and the time required for effective treatment of mammals, including, but not limited to, the seriousness of the disease or disorder, RA is its treatment, General health status and/or age of the mammal and the presence of other diseases. Moreover, treatment of a mammal a therapeutically effective amount of an inhibitor EP4 can include a single treatment or, preferably, can include a periodic courses of treatment.

In the case of antibodies against EP4 preferred dose is usually 10 mg/kg to 20 mg/kg of body weight. Usually partially humanized antibodies and exclusively human antibodies have a great time half-life in humans compared with other antibodies. Consequently, it is possible to use lower doses and do not so often. To stabilize antibodies and to increase absorption and absorption in tissue is possible to apply modifications, such as lipidization. How lipidization antibodies described by Cruikshank et al. (J. Acquired Immune Deficiency = MKD Syndromes Hum. Retrovirol. 14:193, 1997).

The ligands of the receptor EP4 (e.g., antagonists)that can be entered are the ligands of formula I and described below, and described in provisional application U.S. 60/241825, filed October 19, 2000, and Akiyoshi et al., for a non-provisional application U.S. filed approximately October 10, 2001 and referred to as "Aryl or Heteroaryl Fused Imidazole Compound as Anti-Inflammatory and Analgesic Agents", presented here as a reference. The application was published as WO 02/32900. In this application WO 02/32900 provided in the floor of the second volume as a reference. Other EP4 inhibitors that can be entered include the inhibitors described in EP0985663, WO 00/15608, WO 00/03980, WO 98/55468, WO 01/62708, WO 01/42281, WO 01/02855, WO 01/10426, WO 99/47497, WO 00/16760, WO 00/18744, WO 00/16760, WO 00/21532, WO 00/18405, EP 0855389, GB 2330307, GB 2342799 and GB 2075503.

This invention includes both General and specific descriptions of the above links.

An example of A

Stimulation of PGE2 secretion of IL-6 in RVMS person treated with ConA

The incubation of PBMC with 5 μg/ml ConA for 24 hours increased the secretion of IL-6 (figure 1). If cells PBMC competitive stimulated with ConA and various concentrations of PGE2 for 24 hours, the secretion of IL-6, in addition, increased 3.5, 5.7 and 10.1 times upon stimulation with 10, 100 and 1000 M PGE2, respectively, compared with the secretion of IL-6 upon stimulation with ConA without PGE2 (figure 1). In contrast, stimulation of 10-1000 nm PGE2 RUMS, not treated with ConA, did not affect the secretion of IL-6. PBMC were stimulated with 5 µg/ml only Con A or with 10 nm to 1000 nm PGE2 at 37°C within 24 hours. IL-6, secreted in culture was measured using ELISA. Data were expressed as the mean ± s.d. (figure 1).

The effect of EP4 antagonists on the secretion of IL-6 in PBMC

The dependence of secretion of IL-6 by PBMC cells of a person depending on the concentration of PGE2 and without together with ConA stimulation and inhibitory effect of compound A. PBMC stimulated with 5 µg/ml only concanavalin A or with 10 nm - 1000 nm PGE2 at 37°C in 5% CO 2within 24 hours. In order to see the effect of the compound A, simultaneously with the addition of ConA and PGE2 was added 50 μm compound A, and incubated for 24 hours. Data in parentheses Express the percent of control activity of mitochondrial dehydrogenase (figure 2).

Compound a inhibited the production of IL-6 increased at all concentrations of PGE2 (10-1000 nm) (figure 2). However, in order to ensure that 50 μm of compound A are non-toxic to PBMC, after 24 hours incubation PBMC was examined cell viability by the colorimetric method, using a set to count cells. Cells treated with compound A, had similar viability with viability of untreated cells, which means that the inhibitory effect of compound A on the secretion of IL-6 is not a result of cytotoxicity. The figure 3 shows the dose/response for compound A and compound B in stimulation of PBMC 5 μg/ml ConA and 100 nm PGE2 for 24 hours. The production of IL-6 inhibited depending on the dose of the compound, and connections with values IC50equal to 13 and 32 nm, respectively. Compound a and compound B inhibited the secretion of IL-6 in RVMS treated with ConA (figure 3). PBMC were incubated with 5 μg/ml Con A, 100 nm PGE2 and different doses of EP4 antagonists at 37°C for 24 hours. The secretion of IL-6 in culture medium was measured using the ELISA. Data are expressed as the mean ± s.d.

Example B: Obtaining cultures of whole human blood (HWB) andactivation of PGE2

Ways:

Whole peripheral blood (HWB) was collected from healthy volunteers in test tubes for samples (nine volumes to one volume of 3.8% trinacria citrate, Becton Dickinson) and cooled at 4°C prior to the experiment. HWB (50 μl) were placed in the experimental die and mixed for 10 seconds using a stirrer to die (with intensity level 4, TAITAC, Micromixer). The samples were left for 3 minutes at room temperature, then added to 45 µl of the environment AIM and mixed for 10 seconds using a stirrer to die (level 4). Within 3 minutes the samples were at room temperature. The samples were added to the mixture (100 μl) 10-10000 nm PGE2 and 100 μm argatroban and was stirred for 10 sec stirrer to die (level 4). Samples were incubated in 5% CO2at 37°C for 24 hours. Then the samples were mixed and centrifuged at 200g for 10 minutes. Supernatant were collected, and the amount of conc. IL-6 was measured using a kit for carrying out ELISA (cyto-screening).

The results:

In this experiment, the authors present invention was implemented method PGE2-induced production of IL-6 using whole human blood (HWB). For sight is brasenia synthesis of fibrin to the culture medium was added argatroban, thrombin inhibitor. The addition of 100 μm argatroban inhibited the formation of fibrin in blood samples within 24 hours of incubation and did not affect the amount of production of IL-6. If the blood samples stimulated with 10, 100 and 1000 nm PGE2, the concentration of IL-6 in the experiment was 1.5 ˜ 10 ng/ml, 3 ˜ 15 ng/ml and 4.5 ˜ 20 ng/ml, respectively (figure 4). Diluted samples of whole human blood stimulated 10-10000 nm PGE2 and incubated 37°C for 24 hours. Conc. IL-6 in the supernatant were determined using ELISA. The results are presented as the mean ± s.d. one typical experiment, conducted in three identical copies.

Example C: the Impact of EP agonists on the production of IL-6 in HWB

Ways:

Whole peripheral blood (HWB) was collected from healthy volunteers in test tubes for samples (nine volumes to one volume of 3.8% trinacria citrate, Becton Dickinson) and cooled at 4°C prior to the experiment. HWB (50 μl) were placed in the experimental die and mixed for 10 seconds using a stirrer to die (with intensity level 4, TAITAC, Micromixer). The samples were left for 3 minutes at room temperature, then added to 45 µl of the environment AIM and mixed for 10 seconds using a stirrer to die (level 4). Within 3 minutes the samples were at room temperature is E. The samples were added to the mixture (100 μl) 10-10000 nm of each EP and 100 μm argatroban and was stirred for 10 sec stirrer to die (level 4). Samples were incubated in 5% CO2at 37°C for 24 hours. Then the samples were mixed and centrifuged at 200g for 10 minutes. Supernatant were collected, and the amount of conc. IL-6 was measured using a kit for carrying out ELISA (cyto-screening).

The results:

Introduction 1-10 μm butaprost, EP2 agonist, increased the production of IL-6 (figure 5). 11-Deoxy-PGE1 (1-10 μm), the EP4 agonist, increased the production of IL-6, whereas sulprostone (agonist EP1/EP3) did not increase the concentration up to 10 μm (figure 5). We measured the effects of EP2 agonists (butaprost), EP4 (11-deoxy-PGE1) and EP1/EP3 (sulprostone) in respect of the production of IL-6 in HWB, respectively. Each agonist was added to the HWB and incubated in 5% CO2at 37°C within 24 hours. The results are presented as the mean ± s.d. results in three identical copies. This experiment was carried out for samples taken from 3 people, and 3 people got similar results.

Example D: the Effect of EP4 antagonists on the production of IL-6 in HWB-stimulated PGE2

Materials and methods:

Whole peripheral blood (HWB) was collected from healthy volunteers in test tubes for samples (nine volumes to one volume of 3.8% trinacria citrate, Becton Dickinson) and a cooling gap is Ali at 4° C prior to the experiment. Compound (5 μl) or medium (environment AIM, containing 0.2% DMSO) were added to 96-well culture plate. HWB (50 μl) were placed in the experimental die and mixed for 10 seconds using a stirrer to die (with intensity level 4, TAITAC, Micromixer). The samples were left for 3 minutes at room temperature, then added to 45 µl of the environment AIM and mixed for 10 seconds using a stirrer to die (level 4). Within 3 minutes the samples were at room temperature. The samples were added to the mixture (100 μl) of 100 nm each PGE2 and 100 μm argatroban and was stirred for 10 sec stirrer to die (level 4). Samples were incubated in 5% CO2at 37°C for 24 hours. Then the samples were mixed and centrifuged at 200g for 10 minutes. Supernatant were collected, and the amount of conc. IL-6 was measured using a kit for carrying out ELISA (cyto-screening).

The results:

Compound B inhibited the production of IL-6, depending on the dose (figure 6). The effect of compound B (320-40000 nm) on the production of IL-6 HWB-stimulated PGE2. The diluted samples of whole human blood containing compound B, stimulated 10-10000 nm PGE2 and incubated at 37°C for 24 hours. conc. IL-6 in the supernatant were determined using ELISA. The results were presented as mean LVEF is giving ± s.d. results in three identical copies.

Example E: the Production of IL-6 in whole blood of man, stimulated by the joint introduction of ConA and PGE2

Ways:

Compound B (50 ml), ConA and PGE2 (50 μl, 1:1) was diluted with environment AIM (Gibco) in appropriate concentrations (conc.) and placed in 96-well culture plates (dies for analysis). Peripheral blood was collected from healthy volunteers (nine volumes in one volume of 3.8% trinacria citrate, Becton Dickinson). Samples of whole human blood was diluted with the same volume environment AIM and analyzed the die was placed 100 μl of the diluted blood samples. The final concentration of DMSO in the test mixtures were made of 0.25%. The investigated mixtures were incubated in 5% CO2at 37°C for 24 hours. Then the analyzed mixture was stirred and centrifuged at 200g for 10 minutes. Supernatant were collected, and the amount of conc. IL-6 was measured using a kit for carrying out ELISA (cyto-screening).

The results:

PGE2 depending on the dose of 10-1000 nm increased the production of IL-6 (figure 7). If blood samples stimulated with 10, 100 and 1000 nm PGE2, the concentration of IL-6 in the tested mixtures was 1.8˜to 10.8 ng/ml, 4˜20 ng/ml and 5.8˜23 ng/ml, respectively. The concentration of PGE2 (10-1000 nm) gave sufficient production of IL-6 to determine the IC50EP4 antagonists. The most important observation from the data was that the factor is, connection C has inhibitory activity in a dose-dependent (figure 8). Connection C concurrence with PGE2 inhibited the production of IL-6. The pA2 values of the connection C of the three people was 6.3, about 6.4 and 7.1. Diluted samples of human blood stimulated with 5 μg/ml ConA and three different concentrations of PGE2 (10-1000 nm). Conc. IL-6 in the supernatant was determined after 24 hours incubation at 37°C. Diluted whole blood of a person simultaneously stimulated with 5 μg/ml ConA and 100 nm PGE2 and incubated at 37°C for 24 hours. Conc. IL-6 in the supernatant were determined using ELISA.

Pharmaceutically acceptable salts of the ligands of the receptor EP4 (e.g., antagonists)mentioned in this invention include their salts of addition of acids and bases (including dioli). Suitable salt of the added acid are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate, camsylate, citrate, Etisalat, Eilat, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, phosphate, isetionate, D - and L-lactate, malate, maleate, malonate, mesilate, methyl sulfate, 2-napsylate, nicotinate, nitrate, orotate, palmoate, phosphate, saharat, stearate, succinate, sulfate, D - and L-tartrate and tosylate. Suitable salts of the bases are formed from the basis of any, which form non-toxic salts. Examples include aluminium salts, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc. An overview of suitable salts described in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002). Pharmaceutically acceptable salt of the ligand receptor EP4 (e.g., antagonists)mentioned in this invention can be easily obtained by mixing solutions of ligando receptor EP4 (e.g., antagonists)mentioned in this invention, and desired a suitable acid or base. Salt can precipitate in the solution and can be collected by filtration or may be recovered by evaporation of the solvent. Pharmaceutically acceptable solvate in accordance with this invention include hydrates and solvate, where the solvent used in the crystallization may be isotopically substituted, e.g., D2Oh, d6-acetone, d6-DMSO. Also within this invention are the clathrates, connection, inclusion of the drug in the host organism, where, in contrast to the above solvate, the drug and host are in nestekhiometricheskikh quantities. An overview of such complexes are described in J. Pharm. Sci., 64 (8), 1269-1288 by Haleblian (August 1975). Hereinafter in this application with all ylki on the ligands of the receptor EP4 (for example, antagonists) include links to their salts and solvate and clathrates ligand receptor EP4 (e.g., antagonists)mentioned in this application, and their salts. The invention includes all polymorphs of the ligands of the receptor EP4 (e.g., antagonists)mentioned in this proposal, as defined above. Also within the present invention are the so-called "prodrugs" of the ligands of the receptor EP4 (e.g., antagonists)mentioned in this invention. Thus, some derivatives of ligands EP4 receptor (for example, antagonists)mentioned in this invention, which themselves have little pharmacological activity or do not have pharmacological activity, can metabolizes after introduction into the body or applied to the body to give the ligand receptor EP4 (e.g., antagonists)mentioned in this invention with the desired activity. These derivatives are referred to as "prodrugs". Prodrugs in accordance with this invention can, for example, be obtained by substitution of the appropriate functional groups present in the ligand receptor ER (e.g., antagonists)mentioned in this invention, certain groups known to the person skilled in the art as "programmy", as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

Finally, certain ligands of the receptor E is 4 (for example, antagonists)mentioned in this invention may themselves act as prodrugs of other ligands of the receptor ER (e.g., antagonists) mentioned in this invention. The ligands of the receptor ER (e.g., antagonists)mentioned in this invention, containing one or more assimetrichosti of carbon atoms can exist as two or more optical isomers. If the ligands of the receptor EP4 (e.g., antagonists)mentioned in this invention contain alkenilovyh or alkenylamine group, it is possible geometricCIS/TRANS(or Z/E) isomers, and if the ligands of the receptor ER (e.g., antagonists)mentioned in this invention include, for example, ketogroup or oxime, can meet the tautomeric isomerism ("tautomerism"). Thus, one connection can exist in more than one isomeric form. In the framework of the present invention are all optical isomers, geometric isomers and tautomeric forms of the ligands of the receptor ER (e.g., antagonists)mentioned in this invention, including compounds that exist in more than one isomeric form and mixtures of one or more forms.CIS/TRANSthe isomers can be separated by conventional methods known to the person skilled in the art, such as fractional crystallization and chromatography. Conventional venture is the event of receiving the separate stereoisomers include the conversion of a suitable optically pure precursor, the dissolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral HPLC or fractional crystallization diastereoisomeric salts obtained by the interaction of the racemate with a suitable optically active acid or base, for example tartaric acid.

The present invention also includes all pharmaceutically acceptable isotopically types of ligands of the receptor ER (e.g., antagonists)mentioned in this invention. Isotopic species are defined as species with at least one atom is replaced with an atom with the same atomic number, but an atomic weight differs from the atomic weight, usually found in nature.

Examples of isotopes suitable for inclusion in the ligands of the receptor ER (e.g., antagonists)mentioned in this invention include isotopes of hydrogen, such as2H and3H, carbon, such as13C and14C, nitrogen, such as15N, oxygen, such as17O and18Oh, phosphorus, such as32P, sulfur, such as35S, fluorine, such as18F, and chlorine, such as36Cl.

The substituents of the ligands of the receptor ER (e.g., antagonists)mentioned in this invention, with isotopes such as deuterium, i.e2H, may have certain therapeutic advantages, due to the greater metabolic stability, for example b is lesego time half-life of in vivoor lower the required dose, and that may be preferable in some circumstances.

Certain isotopic variations of the ligands of the receptor ER (e.g., antagonists)mentioned in this invention, for example, which introduced a radioactive isotope, effective drug and/or study the distribution of the substrate in the tissue. Radioactive isotopes tritium,3H, and carbon-14, that is,14C, are preferably used for this purpose due to the simplicity of their introduction and the ease of its discovery. Isotopic variants of ligands of the receptor ER (e.g., antagonists)mentioned in this invention can generally be obtained by conventional methods known to the person skilled in the art, or by methods similar to them, are described in the accompanying examples and the examples of compositions using appropriate isotopic variations of suitable agents.

The ligands of the receptor ER (e.g., antagonists)mentioned in this invention can be dried by freezing, by sputtering or evaporation to obtain a solid residue, powder or film of crystalline or amorphous material. For this purpose, can be used drying using microwave or radio frequency drying. The ligands of the receptor ER (e.g., antagonists)mentioned in this invented and, can be administered alone or in combination with other drugs and is usually introduced in the form of a composition in combination with one or more pharmaceutically acceptable excipients. Examples of these medications are COX-2 selective, COX-1 selective or non-selective NSAID (non-steroidal anti-inflammatory drugs, opioids, anticonvulsants, antidepressant, local anesthetics, disease modifying Antirheumatic drugs and steroid drugs. The combination with a COX-2 selective NSAID is especially preferred when applying for the prevention and treatment of pain, arthritis, cirrhosis with alcoholism, amyloidosis, atherosclerosis, heart disease, such as angina, myocardial infarction, myocardiopathy and myocarditis, multiple sclerosis, such as multiple sclerosis and reactions in organ transplantation. Examples of COX-2 selective NSAID are nimesulide, celecoxib, rofecoksib, valdecoxib. The term "excipient" is used herein to describe any ingredient other than the ligands of the receptor ER (e.g., antagonists)mentioned in this invention. The choice of excipient from a wide variety depends on the specific method of administration.

Oral administration

The ligands of the receptor ER (e.g., antagonists)mentioned in this invention, the can is to be oral. Oral administration may include swallowing, so that the connection into the gastrointestinal tract, or can be used hominids or sublingual introduction, with which the connection enters the blood stream directly from the mouth. Compositions suitable for oral administration include solid compositions such as tablets, capsules, containing particles, liquids or powders, cakes (including liquid-filled), gum, multi - and nanoparticles, gels, films (including mucoadhesive), ovule, sprays and liquid composition. Liquid compositions include suspensions, solutions, syrups and elixirs. Such compositions can be used as fillers in soft or hard capsules and usually contain a carrier, for example water, ethanol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspendida agents. Liquid compositions can also be obtained by reduction of solid product, for example, from Sasha.

The ligands of the receptor ER (e.g., antagonists)mentioned in this invention can also be used in the instant, bystrodeistviya dosage forms, such as dosage forms described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, Liang and Chen (2001). The typical composition of the tablets in accordance with data from Britanie may include:

Ingredient% wt./mass.
The ligands of the receptor ER (e.g., antagonists)mentioned in this invention10,00*
Microcrystalline cellulose64,12
Lactose21,38
Crosscarmellose sodium3,00
Magnesium stearate1,50

* The number established in accordance with drug activity

Typical tablet can be obtained using conventional methods known to the pharmacist, for example by direct compression, granulation (dry, wet or melt), the solidification of the melt or extrusion. The composition is in the form of tablets may contain one or more layers and may or may not be prokritee. Examples of excipients suitable for oral administration include media such as cellulose, calcium carbonate, dioskouroi calcium phosphate, lures and sodium citrate, granulation binders such as polyvinylpyrrolidine, hydroxypropylcellulose, hypromellose and gelatin, a disintegrator such as sodium starch glycolate and silicates, lubricants such as magnesium stearate and stearic acid, wetting agents, for example the lauryl sulfate is the atrium, preservatives, antioxidants, flavors and dyes. Solid compositions for oral administration can be obtained as a composition with immediate and/or modified release. Composition with modified release include deferred, continuous, pulse, bilateral control, targeted and programmed release. Learn more about the ways of obtaining adequate modified release, such as high energy dispersions, osmotic and coated particles, see Verma et al., Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). Other composition with modified release described in U.S. patent No. 6106864.

Parenteral administration

The ligands of the receptor ER (e.g., antagonists)mentioned in this invention can also be injected directly into the blood stream, muscles or internal organs. Suitable methods of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intranasal, intracranial, intramuscular and subcutaneous. A suitable device for parenteral administration include syringes with a needle (including microgame), without needle syringes and accessories for infusion. Parenteral compositions typically depict ablaut an aqueous solution, which may contain excipients such as salts, hydrocarbons and buffering agents (preferably to a pH from 3 to 9), but, in some cases, more preferably, compozitizia were obtained in the form of a sterile non-aqueous solution or as a dried form to use in mixture with a suitable carrier, such as sterile pyrogen free and no water. Receiving parenteral compositions in sterile conditions, for example by lyophilization, can be easily managed using standard pharmaceutical methods, well known to the person skilled in the art. The solubility of the ligands of the receptor ER (e.g., antagonists)mentioned in this invention, used in the preparation of parenteral solutions may be increased depending on how appropriate processing, for example, with the use of high-energy dispersions, dried by spraying (see WO 01/47495), and/or use of appropriate methods of obtaining compositions, such as the use of agents that enhance solubility. Compositions for parenteral administration can be obtained as a composition with immediate and/or modified release. Composition with modified release include deferred, continuous, pulse, bilateral controlled, targeted and theprogram the new release.

Local application

The ligands of the receptor ER (e.g., antagonists)mentioned in this invention can also be applied topically applying to the skin or mucous membranes, or skin, or percutaneous. Conventional compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, apadravya powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Can also be used liposomes. Common carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin and propylene glycol. Can be introduced agents, Uzlovaya penetration, see, for example, J. Pharm. Sci., 88 (10), 955-958 by Finnin and Morgan (October, 1999). Other methods of topical application include the introduction of the use of iontophoresis, electroporation, phonophoresis, sonophoresis and without needle injection or by injection microgame. Compostie for ostogo can be obtained as a composition with immediate and/or modified release. Composition with modified release include deferred, continuous, pulse, bilateral controlled, targeted and programmed release. Thus, the ligands of the receptor ER (e.g., antagonists)mentioned in this invention can be obtained in more than the solid form for administration as an implanted depot, providing prolonged release of the active connection.

Introduction ingalatore/intranasal

The ligands of the receptor ER (e.g., antagonists)mentioned in this invention can also be administered intranasally or ingalatore, usually in the form of a dry powder (either alone or as a mixture, for example, as a dry blend with lactose, or as a mixture of particles, for example, mixed with phospholipids), using the inhaler for dry powders or aerosol sprays from the container with high pressure, pump, spray, atomizer (preferably electrohydrodynamic spray to obtain a fine mist), or nebulizer, with or without the use of a suitable propellant, such as DICHLOROFLUOROMETHANE. Container with high pressure, pump, spray, atomizer or spray bottle containing a solution or suspension of the active compounds containing, for example, ethanol (optional, an aqueous solution of ethanol) or other suitable agent for dispersing, solubilisation or increase release of the active substance, the propellant(s) as solvent and, optionally, surface-active substances, such as trioleate sorbitol or oligobrachia acid. Before use of the composition as a dry powder or suspension of the drug is crushed to the size of the RA, suitable for introduction via nebulizer (usually less than 5 microns). This can be accomplished by any suitable grinding method, such as the mill, spiral emissions, jet mill, fluidized bed, ways with supercritical environment, with the formation of nanoparticles, homogenization under high pressure or spray drying. A suitable composition is in the form of a solution for use in a spray bottle, using electrohydrodynamic spray to obtain a fine mist may contain from 1 μg to 10 mg of ligand receptor ER (e.g., antagonists)mentioned in this invention, by activating, and the effective amount can vary from 1 μl to 100 μl. Conventional compositions may contain ligands of the receptor ER (e.g., antagonists)mentioned in this invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerin and polyethylene glycol. Capsules, blisters and cartridges (made, for example, from gelatin or HPMC) for use in an inhaler or duvalle can be obtained with a content of powder mixtures of ligands of the receptor ER (e.g., antagonists)mentioned in this invention, a suitable powder base such as lactose or edge is small, and effective modifier, such as 1-leucine, mannitol, or magnesium stearate. In the case of dry powder inhalers and aerosols single dose is determined by using a valve that releases a metered amount. Single dose in accordance with this invention are usually installed for introducing a metered quantity or "zilch". The composition of the input ingalatore/intranasally can be obtained as a composition with immediate and/or modified release. Composition with modified release include deferred, continuous, pulse, bilateral controlled, targeted and programmed release.

Rectal/intravaginal introduction

The ligands of the receptor ER (e.g., antagonists)mentioned in this invention may be administered rectally or vaginally, for example, in the form of suppositories, uterine rings or enemas. The traditional base for the suppository is cocoa butter, but if it is appropriate, can be used for various other reasons. Compositions for rectal/vaginal injection can be obtained as a composition with immediate and/or modified release. Composition with modified release include deferred, continuous, pulse, duster is nee controlled, targeted and programmed release.

Introduction to the eyes/ears

The ligands of the receptor ER (e.g., antagonists)mentioned in this invention can also be injected directly into the eye or ear, typically in the form of drops microtrenching suspension or solution in isotonic, sterile saline solution with a defined pH. Other compositions suitable for introduction into the eyes and ears include ointments, biodegradable (for example, absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, plates, lenses and systems of particles or bubbles, such as Nozomi or liposomes. Polymer, such as polyacrylic acid crosslinking, polyvinyl alcohol, hyaluronic acid, cellulose polymer, such as hypromellose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymer such as gum Helena, can be introduced together with preservatives, such as chloride benzalconia. Such compositions can also be entered using iontophoresis. Compositions for the eye/ear of the introduction can be obtained as a composition with immediate and/or modified release. Composition with modified release include deferred, continuous, pulse, bilateral controlled,targeted and programmed release.

Enabling technologies

The ligands of the receptor ER (e.g., antagonists)mentioned in this invention can be combined with suitable macromolecular substances such as cyclodextrin or polymers containing polyethylene glycol, to improve their solubility, dissolution rate, taste improvement, bioavailability and/or stability. It was found that the complexes of the drug-cyclodextrin, for example, as a rule, effective in most dosage forms and routes of administration. Can be used as complexes of introduction, and other complexes. Alternatively, for direct formation of a complex with the drug, cyclodextrin can ispolzovatsa as an auxiliary additive, that is, as a carrier, diluent or solubilizer. Most often used for this purpose alpha-, beta - and gamma-cyclodextrins, examples of which can be found in international patent application no WO 91/11172, WO 94/02518 and WO 98/55148.

Dosing

The ligands of the receptor ER (e.g., antagonists)mentioned in this invention can be applied in a mammal orally, parenterally or topically. Usually, these compounds are most preferably administered to humans in doses ranging from 0.1 mg to 3000 mg, preferably 1 mg to 500 mg, which may be administered in a single dose or doses of the th, separated for the reception during the day, although depending on the weight and condition of the subject treated, the condition of the disease, the affected, and the specific route of administration will have variances. These doses were calculated based on the average patient with a mass of about 65-70 kg physician will easily be able to determine doses for patients whose weight is off limits, such as children and the elderly. For example, the dose, which is in the range from 0.01 mg to 10 mg per kg of body weight per day is most desirable for use in the treatment of pain associated with inflammation.

EP4 antagonists: condensed Aryl and heteroaryl compounds of imidazoleformula I

Aryl and heteroaryl condensed imidazole compounds of formula I have the following formula:

or its pharmaceutically acceptable salt.

In the compounds of formula I

Y1, Y2, Y3and Y4preferably independently selected from N, CH and C(L);

L represents halogen, C1-4alkyl, galatarasay C1-4alkyl, hydroxy, C1-4alkoxy, mono - or di-(C1-4alkyl)amino, galatarasay C1-4alkoxy, cyano, HO-C1-4alkyl, C1-4alkoxy-C1-4alkyl, C1-4alkylsulfonyl, am noulton, C1-4alkyl, C(=O)-, HO(O=)C-, C1-4alkyl-O(O=C-), C1-4alkylsulfonyl, C3-7cycloalkyl, R3C(=O)N(R4)-, R3N(R4)C(=O)-, R3N(R4)S(O)m-, Q2-, Q2-C(=O)-, Q2-O-, Q2-C1-4alkyl-O-, or two adjacent L groups are optionally joined together with formation of alkalinous chain containing 3 or 4 members in which one or two (non-adjacent) carbon atoms optionally replaced by oxygen atoms;

m is 0 or 2;

R3and R4independently selected from H and C1-4of alkyl; and

Q2represents 5 - or 6-membered monocyclic or bicyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from N and S, where the aforementioned 5-or 6-membered monocyclic or bicyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4the alkyl, C1-4alkenyl, C1-4quinil, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, C1-4alkylthio, mono - or di-(C1-4alkyl)amino, cyano, HO-C1-4the alkyl, C1-4alkoxy-C1-4the alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyl-(O=)C-, R3(R4)C(=O)N-, HO(O=)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl, C3-7cycloalkyl or C1-4lcil-C(=O)NH-, more preferably Y1, Y2, Y3and Y4independently selected from N, CH and C(L);

L represents halogen, C1-4alkyl, halogen-substituted C1-4alkyl, hydroxy, C1-4alkoxy, mono - or di-(C1 - alkyl)amino, halogen-substituted C1-4alkoxy, cyano, HO-C1-4alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyl, C(=O)-, HO(O=)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl, C3-7cycloalkyl, R3C(=O)N(R4)-, R3N(R4)C(=O)-, R3N(R4)S(O)m-, Q2-, Q2-C(=O)-, Q2-O-, Q2-C1-4alkyl-O-, or two adjacent L groups are optionally joined together with formation of alkalinous chain comprising 3 or 4 members in which one or two (messenia) atom optionally replaced by oxygen atoms;

m is 0 or 2;

R3and R4independently selected from H and C1-4of alkyl; and

Q2represents 5 - or 6-membered monocyclic aromatic ring or a 8-12 membered tricyclic ring containing up to 3 heteroatoms selected from N and S, where the aforementioned 5 - or 6-membered monocyclic aromatic ring optionally substituted with halogen, more preferably Y1, Y2, Y3and Y4independently selected from N, CH and C(L);

m is 0 or 2;

R3and R4independently selected from H and C1-4of alkyl; and

2represents 5 - or 6-membered monocyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing 1 sulfur atom, where the aforementioned 5 - or 6-membered monocyclic aromatic ring optionally substituted with halogen, more preferably Y1, Y2, Y3and Y4independently selected from N, CH and C(L);

L represents halogen, C1-4alkyl, galatarasay C1-4alkyl, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, cyano, HO-C1-4alkyl, acetyl, R3N(R4)C(=O)-, R3N(R4)S(O)m-, Q2-, Q2-C(=O)-, Q2-O-, Q2-C1-4alkyl-O-, or two adjacent L groups are joined to each other, with the formation of methylenedioxy group;

R3and R4independently selected from H and C1-4of alkyl; and

Q2represents 5 - or 6-membered monocyclic aromatic ring system, more preferably, Y1, Y2, Y3and Y4independently selected from N, CH and C-L;

L represents chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C(=O)NH2cryptometrics, methanesulfonyl, or 1-hydroxy-1-methylethyl, or two adjacent L groups are joined to each other, form methylenedioxy group, more preferably, Y1, Y2, Y3and Y4selected from g is PI, consisting of

a) Y1and Y3represent C(L), Y2represents CH and Y4represents N;

b) Y1represents CH, Y2and Y3represent C(L) and Y4represents N;

c)Y1, Y2and Y3represent C(L) and Y4represents N;

d) Y1and Y3represent C(L), Y2represents N and Y4represents CH;

e) Y1represents C(L) and Y2, Y3and Y4represent CH;

f) Y1, Y3and Y4are CH and Y2represents C(L);

g) Y1, Y2and Y3are CH and Y4represents C(L);

h) Y1and Y2represent C(L) and Y3and Y4represent CH;

i) Y1and Y3represent C(L) and Y2and Y4represent CH;

j) Y1and Y4are CH and Y2and Y3represent C(L);

k) Y1and Y2are CH, Y3represents C(L) and Y4represents N;

l) Y1and Y3are CH, Y2represents C(L) and Y4represents N;

m) Y1, Y2, Y3and Y4represent CH;

n) Y1and Y2represent C(L), Y3p is ecstasy a CH and Y 4represents N;

o) Y1, Y2and Y4are CH and Y3represents C(L);

p) Y1and Y2represent C(L), Y3represents N and Y4represents CH;

q) Y1and Y3represent C(L) and Y2and Y4represent N;

r) Y1represents C(L), Y2and Y3are CH and Y4represents N;

s) Y2represents C(L), Y1and Y3are CH and Y4represents N; and

t) Y1, Y2and Y3represent C(L) and Y4represents CH;

L represents chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C(=O)NH2cryptometrics, methanesulfonyl, or 1-hydroxy-1-methylethyl, or two adjacent L groups are joined to each other, form methylenedioxy group, most preferably, Y1, Y2, Y3and Y4selected from the group consisting of

a) Y1and Y3represent C(L), Y2represents CH and Y4represents N;

b) Y1represents CH, Y2and Y3represent C(L) and Y4represents N;

c) Y1, Y2and Y3represent C(L) and Y4represents N;

d) Y1and Y3present is a C(L), Y2represents N and Y4represents CH;

e) Y1represents C(L) and Y2, Y3and Y4represent CH;

f) Y1, Y3and Y4are CH and Y2represents C(L);

g) Y1, Y2and Y3are CH and Y4represents C(L);

h) Y1and Y2represent C(L) and Y3and Y4represent CH;

i) Y1and Y3represent C(L) and Y2and Y4represent CH;

j) Y1and Y4are CH and Y2and Y3represent C(L); and

k) Y1, Y2and Y3represent C(L) and Y4represents CH;

L represents chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C(=O)NH2cryptometrics, methanesulfonyl or 1-hydroxy-1-methylethyl, or two adjacent L groups are joined to each other, form methylenedioxy group.

In the compounds of formula I

R1preferably represents H, C1-8alkyl, C2-8alkenyl, C2-8quinil, C3-7cycloalkyl, C1-8alkoxy, halothamnus1-8alkoxy, C1-8alkyl-S(O)m-, Q1-pyrrolidinyl, piperidyl, oxopyrrolidin, oxopiperidin, amino, mono - or di-(C1-8alkyl)amino, C1-4alkyl-C(=O)-N(R3)or C1-4 alkyl-S(O)m-N(R3)-where the specified C1-8alkyl, C2-8alkenyl and C2-8quinil optionally substituted with halogen, C1-3by alkyl, hydroxy, oxo, C1-4alkoxy, C1-4alkyl-S(O)m-, C3-7cycloalkyl-, cyano, indenolol, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthalene, pyrrolidinium, piperidino, oxopyrrolidin, oxopiperidine, Q1-, Q1-C(=O)-, Q1-O-, Q1-S(O)m-, Q1-C1-4alkyl-O-, Q1-C1-4alkyl-S(O)m-, Q1-C1-4alkyl-C(O)-N(R3)-, Q1-C1-4alkyl-N(R3)or C1-4alkyl-C(O)-N(R3)-;

Q1represents a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4by alkyl, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, C1-4alkylthio, nitro, amino, mono - or di-(C1-4alkyl)amino, cyano, HO-C1-4the alkyl, C1-4alkoxy - C1-4the alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyls(=O)-, HO(O=)C-, C1-4alkyl-O(O)C-, R3N(R4)C(=O)-, C1-4alkylsulfonyl, C3-7cycloalkyl, R3C(=O) N(R4)- or-NH2(HN=) -;

m is 0 or 2; and

R3represents H or C1-4alkyl, more predpochtite is) R1represents H, C1-8alkyl, C2-8alkenyl, C2-8quinil and C3-7cycloalkyl, Q1-pyrrolidinyl, piperidyl, oxopyrrolidin, oxopiperidin, amino, mono - or di-(C1-8alkyl)amino, where the specified C1-8alkyl optionally substituted with halogen, C1-3by alkyl, hydroxy, oxo, C1-4alkoxy, C1-4alkyl-S(O)m-, C3-7cycloalkyl-, cyano, indenolol, pyrrolidinium, piperidino, oxopyrrolidin, oxopiperidine, Q1-, Q1-C(O)-, Q1-O-, Q1-S -, or Q1-C1-4alkyl-O-, or C1-4alkyl-C(O)-N(R3)-;

Q1represents a 5-12 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S, and optionally substituted with halogen, C1-4the alkyl, C1-4alkylsulfonyl and C1-4alkyls(=O)-; and

m is 0 or 2, more preferably R1represents H, C1-8alkyl, C2-8alkenyl, C2-8quinil, C3-7cycloalkyl, Q1or mono - or di-(C1-8alkyl)amine where the specified C1-8alkyl optionally substituted with halogen, C1-3by alkyl, hydroxy, oxo, C1-4alkoxy, C1-4alkyl-S(O)m-With3-7cycloalkyl-, cyano, indenolol, pyrrolidinium, piperidino, oxopyrrolidin, oxopiperidine, Q1-, Q1-C(=O)-, Q1-O-, Q1-S-, Qsup> 1-C1-4alkyl-O-, or C1-4alkyl-C(O)-N(H)-;

Q1represents 5 - or 6-membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S; and

m is 0 or 2, more preferably R1represents a C1-5alkyl, C3-7cycloalkyl, or Q1-, mono - or di-(C1-8alkyl)amino, where the specified C1-5alkyl optionally substituted C1-3by alkyl, hydroxy, oxo, pyrrolidinium, piperidino, oxopyrrolidin, oxopiperidine, Q1-, or C1-4alkyl-C(O)-N(H)-; and

Q1represents a 5-12 membered monocyclic aromatic ring system, optionally containing up to 2 heteroatoms selected from N and S, more preferably, R1represents a C1-5alkyl, mono - or di-(C1-8alkyl)amino, pyrrolidinyl or pyridyl, optionally substituted C1-3by alkyl, hydroxy, oxo, 5 - or 6-membered monocyclic aromatic ring, where the aforementioned 5 - or 6-membered monocyclic aromatic ring containing 1 or 2 heteroatoms selected from N and S, or C1-4alkyl-C(O)-N(H)-, most preferably, R1represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, triazolylmethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl or 1-acetylamino-1-methylethyl.

In compounds is ormula I

R2 preferably represents H or C1-4alkyl, most preferably is H.

In the compounds of formula I

A preferably represents a 5-6-membered monocyclic aromatic ring optionally containing up to 2 heteroatoms selected from O, N and S, where the specified 5-6-membered monocyclic aromatic ring optionally substituted up to 2 substituents selected from halogen, C1-4of alkyl, halogen-substituted C1-4of alkyl, hydroxy, C1-4alkoxy and halogen-substituted C1-4alkoxy, more preferably 5-6 membered monocyclic aromatic ring, optionally substituted with halogen, C1-4the alkyl or C1-4alkoxy, more preferably 5-6 membered monocyclic aromatic ring system, optionally substituted with halogen or C1-4the alkyl, more preferably 5-6 membered monocyclic aromatic ring system, most preferably phenyl or pyridyl.

In the compounds of formula I

B preferably represents C3-7cycloalkyl or C1-6alkylene, optionally substituted oxopropoxy or C1-3the alkyl, more preferably C1-3alkylene, optionally substituted C1-3the alkyl, more preferably C1-2alkylene, optionally substituted stands, most is preferable, ethylene or propylene.

In the compounds of formula I

W preferably represents NH, N-C1-4alkyl, O or N-OH, more preferably NH, N-C1-2alkyl or O, most preferably NH, N-CH3or O.

In the compounds of formula I

Z preferably represents a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N, O and S, where the specified 5-12-membered monocyclic or bicyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4the alkyl, C1-4alkenyl, hydroxy, C1-4alkoxy, nitro, amino, cyano, HO-C1-4the alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyls(=O)-, R3C(=O)N(R4)-, HO(O=)C-, C1-4the alkyl-O(O=)C-, C1-4alkylsulfonyl, C1-4alkyl-C(=O)NH-, Q2-S(O)m-, Q2-Oh,

Q2-N(R3)- or Q2-;

m is 0 or 2;

R3and R4independently selected from H and C1-4of alkyl; and

Q2represents a 5-12 membered monocyclic or bicyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, where the specified 5-12-membered monocyclic or bicyclic aromatic ring, optionally substituted, halogeno is, C1-4by alkyl, halogen-substituted C1-4the alkyl, C1-4alkenyl, C1-4the quinil, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, C1-4alkylthio, mono - or di-(C1-4alkyl)amino, cyano, HO-C1-4the alkyl, C1-4alkoxy-C1-4the alkyl, C1-4alkylsulfonyl, aminosulfonyl,1-4alkyl-(O=)C-, R3(R4)C=(O)N, HO(O=)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl, C3-7cycloalkyl or C1-4alkyl-C(=O)NH-, more preferably, Z represents a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, where the specified 5-12-membered monocyclic or bicyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4the alkyl, C1-4alkenyl, C1-4alkoxy, nitro, amino, cyano, R3C(=O)N(R4)-, C1-4alkyl-O(O=)C-, Q2-S(O)m, Q2"Oh, Q2-N(R3)- or Q2-;

m is 0 or 2;

R3and R4independently selected from N and C1-4of alkyl; and

Q2represents 5 - or 6-membered monocyclic aromatic ring or a 8-12 membered tricyclic ring containing up to 3 heteroatoms selected from N and S, where the aforementioned 5 - or 6-membered monocyclic aromatic ring is not battelino substituted with halogen, more preferably, Z represents a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, where the specified 5-12-membered monocyclic or bicyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4the alkyl, C1-4alkenyl, C1-4alkoxy, nitro, amino, cyano, R3C(=O)N(R4)-, C1-4alkyl-O(O=)C-, Q2-S(O)m-, Q2-O-, Q2-N(R3)- or Q2;

m is 0 or 2;

R3and R4independently selected from H and C1-4of alkyl; and

Q2represents 5 - or 6-membered monocyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing 1 sulfur atom, where the aforementioned 5 - or 6-membered monocyclic aromatic ring optionally substituted with halogen, more preferably, Z represents a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, where the specified 5-12-membered monocyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, nitro, R3C(=O)N(R4)- or Q2-;

R3and R4independently selected from H and C1-4of alkyl; and

Q2represents 5 - or 6-membered mono is clichesque aromatic ring system, more preferably, Z represents a 5-10 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, where the specified 5-10-membered monocyclic aromatic ring optionally substituted by chlorine, bromine, stands, nitro, CH3C(=O)NH-, tBuC(=O)NH -, or phenyl, most preferably, Z represents a phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothiazyl where specified phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl optionally substituted from one to three substituents, independently selected from chlorine, bromine, methyl, acetylamino, paulolino, nitro and phenyl.

A preferred group of compounds of formula I includes compounds where

Y1, Y2, Y3and Y4independently selected from N, CH and C(L);

R1represents H, C1-8alkyl, C2-8alkenyl, C2-8quinil, C3-7cycloalkyl, C1-8alkoxy, galatarasay C1-8alkoxy, C1-8alkyl-S(O)m-, Q1-pyrrolidinyl, piperidyl, oxopyrrolidin, oxopiperidin, amino, mono - or di-(C1-8alkyl)amino, C1-4alkyl-C(=O)-N(R3)or C1-4alkyl-S(O)m-N(R3)-where the specified C1-8alkyl, C2-8alkenyl and C2-8quinil optionally substituted with halogen, C1-3by alkyl, hydroxy, oxo, C1-4 alkoxy, C1-4alkyl-S(O)m-, C3-7cycloalkyl-, cyano, indenolol, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthalene, pyrrolidinium, piperidino, oxopyrrolidin, oxopiperidine, Q1-, Q1-C(=O)-, Q1-O-, Q1-S(O)m-, Q1-C1-4alkyl-O-, Q1-C1-4alkyl-S(O)m-, Q1-C1-4alkyl-C(=O)-N(R3)or C1-4alkyl-C(=O)-N(R3)-;

Q1represents a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4by alkyl, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, C1-4alkylthio, nitro, amino, mono - or di-(C1-4alkyl)amino, cyano, HO-C1-4the alkyl, C1-4alkoxy-C1-4the alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyls(=O)-, HO(O=)C-, C1-4alkyl-O(O)C-, R3N(R4)C(=O)-, C1-4alkylsulfonyl, C3-7cycloalkyl, R3C(=O)N(R4)- or-NH2(HN=)C-;

A is a 5-6-membered monocyclic aromatic ring optionally containing up to 2 heteroatoms selected from O, N and S, where the specified 5-6-membered monocyclic aromatic ring optionally substituted up to 2 substituents selected from halogen, C1-4of alkyl, halogen is umestnogo C 1-4of alkyl, hydroxy, C1-4alkoxy and halogen-substituted C1-4alkoxy;

Represents a C3-7cycloalkyl or C1-6alkylene, optionally substituted oxopropoxy or C1-3by alkyl;

W represents NH, N-C1-4alkyl, or N-IT;

R2represents N or C1-4alkyl;

Z represents a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, where the specified 5-12-membered monocyclic or bicyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4the alkyl, C1-4alkenyl, hydroxy, C1-4alkoxy, nitro, amino, cyano, HO-C1-4the alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyls(=O)-, R3C(=O)N(R4)-, HO(O=)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl, C1-4alkyl-C(=O)NH-, Q2-S(O)m-, Q2-O-, Q2-N(R3)- or Q2-;

L represents halogen, C1-4alkyl, galatarasay C1-4alkyl, hydroxy, C1-4alkoxy, mono - or di-(C1-4alkyl)amino, galatarasay C1-4alkoxy, cyano, HO-C1-4alkyl, C1-4alkoxy-C1-4alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyls(=O)-, HO(O=)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl the Ino, C3-7cycloalkyl, R3C(=O)N(R4)-, R3N(R4)C(=O)-, R3N(R4)S(O)m-, Q2-, Q2-C(=O)-, Q2-O-, Q2-C1-4alkyl-O-, or two adjacent L groups are not necessarily attached to each other with the formation of alkalinous chain containing 3 or 4 members in which one or two (lesosecnyh) a carbon atom optionally replaced by oxygen atoms;

m is 0 or 2;

R3and R4independently selected from H and C1-4of alkyl; and

Q2represents a 5-12 membered monocyclic or bicyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, where the specified 5-12-membered monocyclic or bicyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4the alkyl, C1-4alkenyl, C1-4the quinil, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, C1-4alkylthio, mono - or di-(C1-4alkyl)amino, cyano, HO-C1-4the alkyl, C1-4alkoxy-C1-4the alkyl, C1-4alkylsulfonyl, aminosulfonyl,1-4alkyl-(O=)C-, R3(R4)C(=O)N-, HO(O=)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl, C3-7cycloalkyl or C1-4alkyl-C(=O)NH-.

Another preferred group of compounds of formula I includes all the I connection where

Y1, Y2, Y3and Y4independently selected from N, CH and C(L);

R1represents H, C1-8alkyl, C2-8alkenyl, C2-8quinil, C3-7cycloalkyl, Q1-pyrrolidinyl, piperidyl, oxopyrrolidin, oxopiperidin, amino, mono - or di-(C1-8alkyl)amino, where specified With1-8alkyl optionally substituted with halogen, C1-3by alkyl, hydroxy, oxo, C1-4alkoxy, C1-4alkyl-S(O)m-, C3-7cycloalkyl-, cyano, indenolol, pyrrolidinium, piperidino, oxopyrrolidin, oxopiperidine, Q1-, Q1-C(O)-, Q1-O-, Q1-S-, Q1-C1-4alkyl-O -, or C1-4alkyl-C(O)-N(R3)-;

Q1represents a 5-12 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S, and optionally substituted with halogen, C1-4the alkyl, C1-4alkylsulfonyl and C1-4alkyls(=O)-;

A is a 5-6-membered monocyclic aromatic ring, optionally substituted with halogen, C1-4the alkyl or C1-4alkoxy;

B represents a C3-7cycloalkyl or C1-6alkylene, optionally substituted oxopropoxy or C1-3by alkyl;

W represents NH, N - C1-4alkyl, O or N-OH;

R2represents H or C1-4alkyl;

Z represents a 5-12-the Lenna monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from, N and S, where the specified 5-12-membered monocyclic or bicyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4the alkyl, C1-4alkenyl, C1-4alkoxy, nitro, amino, cyano, R3C(=O)N(R4)-With1-4alkyl-O(O=)C-, Q2-S(O)m-, Q2-O-, Q2-N(R3)- or Q2-;

L represents halogen, C1-4alkyl, halogen-substituted C1-4alkyl, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, mono - or di-(C1-4alkyl)amino, cyano, HO-C1-4alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyls(=O)-, HO(O=)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl, C3-7cycloalkyl, R3C(=O)N(R4)-, R3N(R4)C(=O)-, R3N(R4)S(O)m-, Q2-, Q2-C(=O)-, Q2-O-, Q2-C1-4alkyl-O-, or two adjacent L groups are optionally linked to each other to form alkalinous chain containing 3 or 4 members in which one or two (lesosecnyh) a carbon atom optionally replaced by oxygen atoms;

m is 0 or 2;

R3and R4independently selected from H and C1-4of alkyl; and

Q2represents 5 - or 6-membered monocyclic aromatic ring or a 8-12 membered tricyclic ring, optional is about containing up to 3 heteroatoms, selected from N and S, where the aforementioned 5 - or 6-membered monocyclic aromatic ring, be sure substituted with halogen.

Another preferred group of compounds of formula I includes compounds where

Y1, Y2, Y3and Y4independently selected from N, CH and C(L);

R1represents H, C1-8alkyl, C2-8alkenyl,C2-8quinil or C3-7cycloalkyl where the specified C1-8alkyl optionally substituted with halogen, C1-3by alkyl, hydroxy, oxo, C1-4alkoxy, C1-4alkyl-S(O)m-, C3-7cycloalkyl-, cyano, indenolol, pyrrolidinium, piperidino, oxopyrrolidin, oxopiperidine, Q1-, Q1-C(=O)-, Q1-O-, Q1-S-, Q1-C1-4alkyl-O -, or C1-4alkyl-C(O)-N(R3)-;

Q1represents 5 - or 6-membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S;

A is a 5-6-membered monocyclic aromatic ring system, optionally substituted with halogen or C1-4by alkyl;

Represents a or C3-7cycloalkyl or C1-6alkylene, optionally substituted oxopropoxy or C1-3by alkyl;

W represents NH, N - C1-4alkyl, O or N-OH;

R2represents H or C1-4alkyl;

Z represents a 5-12-clenn the e monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from N and S, where the specified 5-12-membered monocyclic or bicyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, halogen-substituted C1-4the alkyl, C1-4alkenyl,1-4alkoxy, nitro, amino, cyano, R3C(=O)N(R4)-, C1-4alkyl-O(O=)C-, Q2-S(O)m-, Q2-O-, Q2-N(R3)- or Q2-;

L represents halogen, C1-4alkyl, halogen-substituted C1-4alkyl, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, cyano, HO-C1-4alkyl, C1-4alkylsulfonyl, aminosulfonyl, C1-4alkyls(=O), HO(O=)C-, C1-4alkyl-O(O=)C-, C1-4alkylsulfonyl, C3-7cycloalkyl, R3C(=O)N(R4)-, R3N(R4)C(=O)-, R3N(R4)S(O)m-, Q2-, Q2-C(=O)-, Q2-O-, Q2-C1-4alkyl-O-, or two adjacent L groups are optionally joined together with formation of alkalinous chain containing 3 or 4 members in which one or two (lesosecnyh) a carbon atom optionally replaced by oxygen atoms;

m is 0 or 2;

R3and R4independently selected from H and C1-4of alkyl; and

Q2is a 5-6-membered monocyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing 1 sulfur atom, where the specified 5-6-member of the second monocyclic aromatic ring optionally substituted with halogen.

Another preferred group of compounds of formula I includes compounds where

Y1, Y2, Y3and Y4independently selected from N, CH and C(L);

R1represents a C1-5alkyl or C3-7cycloalkyl where the specified C1-5alkyl optionally substituted C1-3by alkyl, hydroxy, oxo, pyrrolidinium, piperidino, oxopyrrolidin, oxopiperidine, Q1or C1-4alkyl-C(O)-N(H)-;

Q1represents a 5-12 membered monocyclic aromatic ring system, optionally containing up to 2 heteroatoms selected from N and S,

A is a 5-6-membered monocyclic aromatic ring system;

B represents a C1-3alkylene, optionally substituted C1-3by alkyl;

W represents NH, N-C1-2alkyl or O;

R2represents H;

Z represents a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, where the specified 5-12-membered monocyclic aromatic ring optionally substituted with halogen, C1-4by alkyl, nitro, R3C(=O)N(R4)- or Q2-;

L represents halogen, C1-4alkyl, halogen-substituted C1-4alkyl, hydroxy, C1-4alkoxy, halogen-substituted C1-4alkoxy, cyano, H - C 1-4alkyl, acetyl, R3N(R4)C(=O)-, R3N(R4)S(O)m-, Q2-, Q2-C(=O)-, or two adjacent L groups are joined to each other, form methylenedioxy group;

R3and R4independently selected from H and C1-4of alkyl; and

Q2represents 5 - or 6-membered monocyclic aromatic ring system.

Another preferred group of compounds of formula I includes compounds where

Y1, Y2, Y3and Y4independently selected from N, CH and C-L;

R1represents a C1-5alkyl, optionally substituted C1-3by alkyl, hydroxy, oxo, 5 - or 6-membered monocyclic aromatic ring, where the aforementioned 5 - or 6-membered monocyclic aromatic ring containing 1 or 2 heteroatoms selected from N and S, or C1-4alkyl-C(O)-N(R3)-;

A represents phenyl;

B represents a C1-2alkylene, optionally substituted stands;

W represents NH, N-CH3or O;

R2represents H;

Z represents a 5-10 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, where the specified 5-10-membered monocyclic aromatic ring optionally substituted by chlorine, bromine, stands, nitro, CH3C(=O) NH-, tBuC(=O) NH -, or phenyl; and

L represents chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C(=O)NH2cryptometrics, methanesulfonyl or 1-hydroxy-1-methylethyl, or two adjacent L groups are joined to each other, form methylenedioxy group.

Another preferred group of compounds of formula I includes compounds where

Y1, Y2, Y3and Y4independently selected from N, CH and C-L;

R1represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, triazolylmethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl or 1-acetylamino-1-methylethyl;

A represents phenyl;

B represents ethylene or propylene;

W represents NH, N-CH3or O;

R2represents H;

Z represents phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothiazyl where specified phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl optionally substituted from one to three substituents, independently selected from chlorine, bromine, methyl, acetylamino, paulolino, nitro and phenyl; and

L represents chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C(=O)NH2cryptometrics, methanesulfonyl or 1-hydroxy-1-methylethyl, or two adjacent L groups are joined to each other, form methylenedioxy group.

Another pre is respectful group of compounds of formula I includes compounds where Y1, Y2, Y3and Y4selected from the group consisting of

a) Y1and Y3represent C(L), Y2represents CH and Y4represents N;

b) Y1represents CH, Y2and Y3represent C(L) and Y4represents N;

c) Y1, Y2and Y3represent C(L) and Y4represents N;

d) Y1and Y3represent C(L), Y2represents N and Y4represents CH;

e) Y1represents C(L) and Y2, Y3and Y4represent CH;

f) Y1, Y3and Y4are CH and Y2represents C(L);

g) Y1, Y2and Y3are CH and Y4represents C(L);

h) Y1and Y2represent C(L) and Y3and Y4represent CH;

i) Y1and Y3represent C(L) and Y2and Y4represent CH;

j) Y1and Y4are CH and Y2and Y3represent C(L);

k) Y1and Y2are CH, Y3represents C(L) and Y4represents N;

1) Y1and Y3are CH, Y2represents C(L) and Y4represents N;

m) Y1, Y2, Y3and Y4represent Cobain;

n) Y1and Y2represent C(L), Y3represents CH and Y4represents N;

o) Y1, Y2and Y4are CH and Y3represents C(L);

p) Y1and Y2represent C(L), Y3represents N and Y4represents CH;

q) Y1and Y3represent C(L) and Y2and Y4represent N;

r) Y1represents C(L), Y2and Y3are CH and Y4represents N; and

s) Y2represents C(L), Y1and Y3are CH and Y4represents N;

R1represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, triazolylmethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl or 1-acetylamino-1-methylethyl;

A represents phenyl;

B represents ethylene or propylene;

W represents NH, N-CH3or O;

R2represents H;

Z represents phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothiazyl where specified phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl optionally substituted from one to three substituents, independently selected from chlorine, bromine, methyl, acetylamino, paulolino, nitro and phenyl; and

L represents chlorine, methyl, trip ormetal, hydroxy, methoxy, cyano, acetyl, -C(=O)NH2cryptometrics, methanesulfonyl or 1-hydroxy-1-methylethyl, or two adjacent L groups are joined to each other, form methylenedioxy group.

Another preferred group of compounds of formula I includes compounds where

Y1, Y2, Y3and Y4selected from the group consisting of

a) Y1and Y3represent C(L), Y2represents CH and Y4represents N;

b) Y1represents CH, Y2and Y3represent C(L) and Y4represents N;

c) Y1, Y2and Y3represent C(L) and Y4represents N;

d) Y1and Y3represent C(L), Y2represents N and Y4represents CH;

e) Y1represents C(L) and Y2, Y3and Y4represent CH;

f) Y1, Y3and Y4are CH and Y2represents C(L);

g) Y1, Y2and Y3are CH and Y4represents C(L);

h) Y1and Y2represent C(L) and Y3and Y4represent CH;

i) Y1and Y3represent C(L) and Y2and Y4represent CH; and

j) Y1and Y4are CH and Y2and Y3represent C();

R1represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, triazolylmethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl or 1-acetylamino-1-methylethyl;

A represents phenyl;

B represents ethylene or propylene;

W represents NH, N-CH3or O;

R2represents H;

Z represents phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothiazyl where specified phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl optional someseni from one to three substituents, independently selected from chlorine, bromine, methyl, acetylamino, paulolino, nitro and phenyl; and

L represents chlorine, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, -C(=O)NH2cryptometrics, methanesulfonyl or 1-hydroxy-1-methylethyl, or two adjacent L groups are joined to each other, form methylenedioxy group.

Specific preferred compounds of formula I are:

3-(4-{2-[({[(5-chloro-1,3-dimethyl-1N-pyrazole-4-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

3-(4-{2-[({[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

N-[5-({[({2-[4-(2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amine is)carbonyl]amino}sulfonyl)-1,3,4-thiadiazole-2-yl]ndimethylacetamide;

6-ethyl-5-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5N-[1,3]dioxolo[4,5-f]benzimidazole;

6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole;

2-ethyl-5,7-dimethyl-3-(4-{2-[methyl({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3N-imidazo[4,5-b]pyridine;

2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]propyl}phenyl)-3N-imidazo[4,5-b]pyridine;

2-[4-(2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethyl(4-were)sulfonylurea;

5,7-dimethyl-3-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-propyl-3N-imidazo[4,5-b]pyridine;

2-isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3N-imidazo[4,5-b]pyridine;

2-butyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3N-imidazo[4,5-b]pyridine;

2-isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3N-imidazo[4,5-b]pyridine;

5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-neopentyl-3N-imidazo[4,5-b]pyridine;

5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3N-imidazo[4,5-b]pyridine;

3-4-[2-({[(4 biphenylmethanol)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

2-ethyl-5,7-dimethyl-3-{4-[2-({[(1-naphthylmethyl)amino]carbonyl}amino)ethyl]phenyl}-3N-imidazo[4,5-b]pyridine;

2-ethyl-5,7-dimethyl-3-{4-[2-({[(2-naphthylmethyl)amino]carbonyl}amino)ethyl]phenyl}-3N-imidazo[4,5-b]pyridine;

2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3N-imidazo[4,5-b]pyridine;

3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

3-(4-{2-[({[(4,5-dichloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

3-{4-[2-({[(1-bestien-2-ylsulphonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3N-imidazo[4,5-b]pyridine;

5,6-dichloro-2-ethyl-3-(4-{2-[([(4-were)sulfonyl)amino}carbonyl)amino]ethyl}phenyl)-3N-imidazo[4,5-b]pyridine;

5-chloro-2-ethyl-7-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3N-imidazo[4,5-b]pyridine;

6-cyano-2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfon the l]amino}carbonyl)amino]ethyl}phenyl)-3 N-imidazo[4,5-b]pyridine;

2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-imidazo[4,5-c]pyridine;

4-methyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-benzimidazole;

7-chloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-benzimidazole;

5-methoxy-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-benzimidazole;

5-acetyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-benzimidazole;

5-cyano-2-ethyl-1-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole;

2-ethyl-5-hydroxy-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole;

2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

4,6-dimethyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-benzimidazole;

5,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole;

5,6-dichloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole;

2-[4-(5,6-dichloro-2-ethyl-1N-benzimidazole-1-yl)phenyl]ethyl-(4-were)sulfonylurea;

6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole;

4-(6-chloro-2-ethyl-5-trifluoromethyl-1N-benzimidazole-1-yl)phenethyl-(4-were)sulfonylurea;

5-chloro-6-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole;

6-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole-5-carboxamide;

2-ethyl-3-{4-[2-({[({3-[hydroxy(oxido)amino]phenyl}sulfonyl)amino]carbonyl}amino)-ethyl]phenyl}-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

3-(4-{2-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

N-[4-({[({2-[4-(2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)phenyl]-2,2-dimethylpropanamide;

3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

3-(4-{2-[({[(3-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

3-(4-{2-[({[(5-bromo-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

3-(4-{2-[({[(2-bromophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

3-{4-[2-({[({4-chloro-3-nitrophenyl}su is hanil)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3 N-imidazo[4,5-b]pyridine;

2-[4-(2-ethyl-4,6-dimethyl-1N-imidazo[4,5-c]pyridine-1-yl)phenyl]ethyl(4-were)sulfonylurea;

2-{4-[5,7-dimethyl-2-(methylamino)-3N-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl(4-were)sulfonylurea;

N-{[(2-{4-[5,7-dimethyl-2-(methylamino)-3N-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1N-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole-5-carboxamide;

2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(2-chlorophenyl)sulfonylurea;

2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]-2-pyridinyl}ethyl(4-were)sulfonylurea;

2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(5-methyl-2-pyridinyl)sulfonylurea;

2-{4-[6-chloro-2-(1N-pyrazole-3-yl)-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

N-{[(2-{4-[6-chloro-2-ethyl-5-(methylsulphonyl)-1NBenson Gasol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

2-{4-[6-chloro-2-ethyl-5-(methylsulphonyl)-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

N-[({2-[4-(2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]-2-thiophenesulfonyl;

2-[4-(4,6-dimethyl-2-phenyl-1N-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfonylurea;

2-[4-(2-butyl-4,6-dimethyl-1N-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfonylurea;

2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(5-chloro-1,3-dimethyl-1N-pyrazole-4-yl)sulfonylurea;

2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1N-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-were)sulfonylurea;

2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}-1-methylethyl(4-were)sulfonylurea;

2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]-3-pyridinyl}ethyl(4-were)sulfonylurea;

N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

N-{[(2-{4-[5,7-dimethyl-2(1N-pyrazole-3-yl)-3N-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1N-imidazo[4,5-c]feast the DIN-1-yl]phenyl}ethyl(4-were)sulfonylurea;

2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole-5-carboxamide;

and their salts.

Specific preferred compounds of formula I are:

6-ethyl-5-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl)phenyl)-5N-[1,3]dioxolo[4,5-f]benzimidazole;

6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole;

2-[4-(2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethyl(4-were)sulfonylurea;

5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3N-imidazo[4,5-b]pyridine;

2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3N-imidazo[4,5-b]pyridine;

3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine;

2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3N-imidazo[4,5-b]pyridine;

5,6-dichloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3N-imidazo[4,5-b]pyridine;

2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]and the Ino}carbonyl)amino]ethyl}phenyl)-1 N-imidazo[4,5-c]pyridine;

5-methoxy-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-benzimidazole;

5-acetyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-benzimidazole;

5-cyano-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole;

2-ethyl-5-hydroxy-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole;

2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole;

4-(6-chloro-2-ethyl-5-trifluoromethyl-1N-benzimidazole-1-yl)phenethyl-(4-were)sulfonylurea;

6-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole-5-carboxamide;

2-[4-(2-ethyl-4,6-dimethyl-1N-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfonylurea;

2-{4-[5,7-dimethyl-2-(methylamino)-3N-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl(4-were)sulfonylurea;

N-{[(2-{4-[5,7-dimethyl-2-(methylamino)-3N-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1N-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole-5-carboxamid is;

2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(2-chlorophenyl)sulfonylurea;

2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]-2-pyridinyl}ethyl(4-were)sulfonylurea;

2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(5-methyl-2-pyridinyl)sulfonylurea;

2-{4-[6-chloro-2-(1N-pyrazole-3-yl)-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

N-{[(2-{4-[6-chloro-2-ethyl-5-(methylsulphonyl)-1N-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

2-{4-[6-chloro-2-ethyl-5-(methylsulphonyl)-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

N-[({2-[4-(2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]-2-thiophenesulfonyl;

2-[4-(4,6-dimethyl-2-phenyl-1-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfonylurea;

2-[4-(2-butyl-4,6-dimethyl-1N-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfonylurea;

2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(5-chloro-1,3-dimethyl-1N-pyrazole-4-yl)sulfanilyl the Mat;

2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1N-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-were)sulfonylurea;

2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}-1-methylethyl(4-were)sulfonylurea;

2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1N-benzimidazole-1-yl]-3-pyridinyl}ethyl(4-were)sulfonylurea;

N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

N-{[(2-{4-[5,7-dimethyl-2-(1N-pyrazole-3-yl)-3N-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;

2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1N-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-were)sulfonylurea;

2-4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1N-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea;

6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1N-benzimidazole-5-carboxamide; and their salts.

The synthesis of compounds of formula I.

Typical compounds of the formula I compounds and methods of synthesis of compounds of formula 1 are described in the following examples 1-380. For more General scheme of synthesis described in the preliminary statements of the e 60/241825, filed October 19, 2000, and Akiyoshi et al., non-provisional application filed approximately 10 October 2001 and called "Aryl or Heteroaryl Fused Imidazole Compounds as Anti-Inflammatory and Analgesic Agents".

Unless otherwise stated, all manipulations described in the examples below were carried out at room temperature or at ambient temperature, which was in the field from 18 to 25°C; evaporation of solvent was carried out on a rotary evaporator under reduced pressure with a bath temperature equal to 60°C; interaction was controlled by thin-layer chromatography (TLC)and reaction times are given only as an example; the melting point (TPL) was not specified (the difference of the melting temperatures may be the result of polymorphism); structure and purity of all selected compounds were evaluated by at least one of the following techniques: TLC (silica gel 60 TLC plates coated F254, Merck), mass spectrometry, nuclear magnetic resonance (NMR), infrared spectroscopy (IR) or microanalysis. The output is presented only for illustrative purposes. Column flash chromatography on a column was carried out using Merck silica gel 60 (230-400 mesh mesh ASTM). The data of the mass spectrum with a low-resolution (EI) were obtained on a mass spectrometer Automass 120 (JEOL). The data of the mass spectrum with a low-resolution (ESI) were obtained on mA is with the spectrometer Quattro II (Micromass) or aZMD (Micromass). These NMR was determined at 270 MHz (spectrometer JEOL JNM-LA 270) or at 300 MHz (spectrometer JEOL JNM-LA300), using as solvent datarecovery chloroform (99,8% D) or dimethylsulfoxide (99.9% of D), unless otherwise stated, relative to the internal standard tetramethylsilane (TMS) ppm (ppm); used conventional abbreviations: s = singlet, d= doublet, t = triplet, q = Quartet, quint = quintet, m = multiplet, user. = broadened, and the like. The IR spectrum was measured by an infrared spectrometer (Shimazu (IR-470). Chemical symbols have their usual meanings; BP. (boiling point), TPL (melting point), l (liter), ml (milliliters), g (grams)mg (milligrams), mol (moles), mmol (mmol), the coding gain. (equivalents), colwid (quantitative yield).

Example 1

2-Ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 4,6-Dimethyl-3-nitro-2(1H)-pyridinone

A mixture of ethylnitrosourea (80,0 g, 601 mmol) in ammonium hydroxide (25% NH3in water, 400 ml) was stirred at room temperature for 3 days and then the solution was concentrated, drying in the air. The residue was dissolved in water (450 ml). To the solution was added 2,4-pentanedione (73,1 g, 730 mmol), pyridine (16.2 ml, 200 mmol) and acetic acid (11,4 ml, 200 mmol) and the mixture was stirred for another 7 days. The precipitate was collected p is the filtration and was dried under reduced pressure to get 35,0 g (35%) compound specified in the header, in the form of a yellow solid:1H-NMR (DMSO-d6) δ to 12.44 (1H, Shir, (C), the 6.06 (1H, s), are 2.19 (3H, s)to 2.13 (3H, s).

Stage 2. 2-Chloro-4,6-dimethyl-3-nitropyridine

A mixture of 4,6-dimethyl-3-nitro-2(1H)pyridinone (stage 1, 10.0 g, 29.7 mmol) in phosphorus oxychloride (35 ml, 187,3 mmol) was stirred at 95°C for 3 hours, then cooled to 45°C. the Excess phosphorus oxychloride was removed by distillation under reduced pressure at 45°C. the Residue was cooled to room temperature and was diluted with dichloromethane (75 ml). The resulting solution was cooled to 0°C and the solution was added dropwise 2 N. hydrochloric acid (50 ml). The organic layer was separated and washed 2 N. hydrochloric acid (4 x 25 ml), 2 N. aqueous NaOH (2 x 50 ml) and saturated saline (50 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure to obtain 10.0 g (90%) of the compound indicated in the title, in the form of a white solid:1H-NMR (CDCl3) δ 7,07 (1H, s), of 2.56 (3H, s)to 2.35 (3H, s).

Stage 3. 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

A mixture of 2-chloro-4,6-dimethyl-3-nitropyridine (stage 2, 1.3 g, 7.0 mmol) and 4-aminophenylacetamido alcohol (1.4 g, 10.2 mmol) were placed in a sealed tube and heated at 150°C for 3 hours. The reaction mixture was cooled and purified using flash chromatography on a column of the silica gel, elwira hexane/ethyl acetate (2:1) to give 1.6 g (80%) of the compound indicated in the title, in the form of an orange solid:1H-NMR (CDCl3) δ of 9.55 (1H, Sirs), EUR 7.57 (2H, d, J=8,4 Hz), 7,20 (2H, d, J=8,4 Hz), of 6.52 (1H, s), a-3.84 (2H, t, J=6.4 Hz), 2,85 (2H, t, J=6.4 Hz), of 2.54 (3H, s), 2,42 (3H, s).

Stage 4. 2-{4-[(3-Amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol

To a stirred solution of 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 3, 1.6 g, 5.6 mmol) in ethyl acetate (15 ml) was added 10% Pd-C (160 mg). The mixture was stirred at room temperature for 6 hours in an atmosphere of hydrogen. The palladium catalyst was removed by filtration and washed with ethanol (100 ml). The filtrate was concentrated under reduced pressure to obtain 1.3 g (92%) of the compound indicated in the title, in the form of a light yellow solid:1H-NMR (CDCl3) δ 7,10 (4H, s), is 6.61 (1H, s), 3,81 (2H, t, J=6.4 Hz), 2,80 (2H, t, J=6.4 Hz), a 2.36 (3H, s), are 2.19 (3H, s).

Stage 5. 2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropane

To a stirred suspension of 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4, 1.3 g, 5.1 mmol) in toluene (30 ml) was added dropwise propionate (990 mg, about 10.7 mmol) at 0°C and the reaction mixture is boiled under reflux for 2 hours. After cooling, the mixture was poured into water (50 ml) and was extracted with ethyl acetate (100 ml). The body is ical layer was washed 2 N. aqueous NaOH (50 ml) and saturated saline (50 ml), then dried (MgSO4). Removal of solvent gave 1.8 g (colwid) the connection specified in the header, in the form of a brown solid:1H-NMR (CDCl3) δ 7,41 (2H, d, J=8,4 Hz), 7,33 (2H, d, J=8,4 Hz), make 6.90 (1H, s), 4,37 (2H, t, J=6.9 Hz), totaling 3.04 (2H, t, J=6.9 Hz), 2,82 (2H, q, J=7,6 Hz), 2,65 (3H, s), 2,52 (3H, s)to 2.35 (2H, q, J=7,6 Hz), 1.27mm (3H, t, J=7,6 Hz)to 1.14 (3H, t, J=7,6 Hz).

Stage 6. 2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

To a solution of 2-{4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropylamine (stage 5, of 1.75 g, 5.1 mmol) in methanol/THF (V/V, 1:1, 28 ml) was added 4 N. aqueous LiOH solution (4.6 ml, 18.4 mmol) and the resulting mixture was stirred at room temperature. After 3 hours the mixture was concentrated. The residue was dissolved in water (30 ml) and was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated saline (50 ml), dried (MgSO4) and concentrated. Was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (gradient elution from 2:1 to 0:1), to obtain 1.3 g (86%) of the compound indicated in the title, in the form of a light brown solid:1H-NMR (CDCl3) δ 7,40 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,4 Hz)6,91 (1H, s), 3,81 of 3.75 (2H, m), 3,47 (1H, Sirs), of 2.92 (2H, t, J=6.9 Hz), of 2.81 (2H, q, J=7,6 Hz)to 2.66 (3H, s), of 2.51 (3H, s)of 1.27 (3H, t, J=7,6 Hz).

Stage 7. 3-[4-(2-Chloro what Teal)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 6, 2.2 g, 7.4 mmol) in toluene (40 ml) was added thionyl chloride (2.0 ml, 23.6 mmol) and the resulting mixture was stirred at 80°C for 3 hours. Volatile components were removed under reduced pressure and the residue was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (gradient elution from 2:1 to 1:1), to obtain 2.1 g (90%) of the compound indicated in the title, in the form of a white solid:1H-NMR (CDCl3) δ 7,41 (2H, d, J=8,4 Hz), 7,35 (2H, d, J=8,4 Hz), make 6.90 (1H, s), of 3.78 (2H, t, J=7,4 Hz)and 3.15 (2H, t, J=7.4 Hz), and 2.83 (2H, q, J=7,6 Hz), 2,71 (3H, s)to 2.54 (3H, s)of 1.28 (3H, t, J=7,6 Hz).

Stage 8. 2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

To a stirred solution of 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 7, 2.8 g, 9.0 mmol) and KI (1.5 g, 9.0 mmol) in DMF (50 ml) was added sodium azide (1.2 g, 18.0 mmol), and then the resulting mixture was stirred over night at 100°C. the Reaction mixture was poured into water (100 ml) and was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml) and saturated saline (50 ml), then dried (Na2SO4). After removal of solvent the crude product was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (1:1), to obtain 2.35 g (8%) compound specified in the header, in the form of a white solid:1H-NMR (CDCl3) δ 7,41 (2H, d, J=8,4 Hz), 7,35 (2H, d, J=8,4 Hz), make 6.90 (1H, s)and 3.59 (2H, t, J=7,1 Hz)to 2.99 (2H, t, J=7,1 Hz), and 2.83 (2H, q, J=7,6 Hz), 2,65 (3H, s), 2,52 (3H, s)of 1.27 (3H, t, J=7,GC).

Stage 9. 2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)fenretinide (stage 8, 2,35 g, 7,3 mmol) in methanol (50 ml) was added 10% Pd-C (200 mg). The resulting mixture was stirred for 4 hours in hydrogen atmosphere. The mixture was filtered through a thick layer of celite and the filtrate was concentrated. The residue was purified using flash chromatography on a column of silica gel, elwira dichloromethane/methanol/triethylamine (100:5:1), with a 2.01 g (94%) of the compound indicated in the heading in the form of a white solid:1H-NMR (CDCl3) δ 7,39 (2H, d, J=8,4 Hz), 7,32 (2H, d, J=8,4 Hz), make 6.90 (1H, s), 3,05 (2H, t, J=7,3 Hz), 2,88-2,78 (4H, m), 2,65 (3H, s), of 2.51 (3H, s)of 1.28 (3H, t, J=7,6 Hz).

Stage 10. 2-Ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-3H-imidazo[4,5-b]pyridine

To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 9, 1.2 g, 4.0 mmol) in dichloromethane (15 ml) was added p-toluensulfonate (805 mg, 4.0 mmol). The resulting mixture was stirred at room temperature for 3 hours. After removal of solvent the residue was purified is using flash chromatography on a column of silica gel, elwira dichloromethane/methanol (20:1), to obtain 1.10 g (56%) of the compound indicated in the title, in the form of a white solid:1H-NMR (CDCl3) δ a 7.85 (2H, d, J=8,2 Hz), 7,32 (2H, d, J=8,2 Hz), 7.23 percent (2H, d, J=8,4 Hz), 7,16 (2H, d, J=8,4 Hz)6,91 (1H, s), 6,12 (1H, Sirs), 3,55-of 3.46 (2H, m), 2,85 (2H, t, J=6.3 Hz), 2,74-of 2.64 (5H, m), 2,42 (3H with), to 2.41 (3H, s)to 1.21 (3H, t, J=7,6 Hz).

Example 2

Sodium salt of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

To a solution of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (example 1, 5.0 g, 10.2 mmol) in methanol (20 ml) was added 2 N. aqueous NaOH (5.1 ml, 10.2 mmol). The resulting mixture was stirred at room temperature for 5 minutes and concentrated. The residue solid was collected by filtration and dried under reduced pressure at 50°C connection is specified in the header, in the form of a white solid:1H-NMR (DMSO-d6) δ of 7.60 (2H, d, J=8,2 Hz), 7,31-7,39 (4H, m), 7,14 (2H, d, J=8,2 Hz), of 6.96 (1H, s)and 3.15 (2H, Sirs), 2,66 is 2.75 (4H, m), of 2.53 (3H, s), is 2.40 (3H, s), of 2.28 (3H, s)of 1.20 (3H, t, J=7,6 Hz).

Example 3

2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl (4-were)sulfonylureas

To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 6 of example 1, 300 mg, 1.0 mmol) in dichloromethane (10 ml) was added p-that is wilsonfelician (237 mg, 1.2 mmol). The resulting mixture was stirred at room temperature overnight. After removal of solvent the residue solids papercraftantonella from ethyl acetate to obtain 454 mg (92%) of the compound indicated in the title, in the form of a white solid:1H-NMR (CDCl3) δ to 7.93 (2H, d, J=8,4 Hz), 7,33 (2H, d, J=8,4 Hz), 7,22 (4H, s), 6,92 (1H, s), to 4.87 (1H, Sirs), 4,35 (2H, t, J=6.6 Hz), 2,96 (2H, t, J=6.6 Hz), 2,78 (2H, q, J=7,7 Hz)to 2.66 (3H, s)of 2.50 (3H, s), 2,43 (3H, s)of 1.24 (3H, t, J=7,7 Hz).

Example 4

2-Ethyl-5,7-dimethyl-3-(4-{2-[({methyl[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (example 1, 200 mg, 0.41 mmol) in THF (10 ml) was added dropwise a solution of diisopropylamide lithium (LDA) (2,0 N. in heptane/hexane/ethyl benzene, 0.8 ml, 1.6 mmol)while cooling on ice for 10 minutes. After complete addition, stirring was continued for another 20 minutes at the same temperature. To the mixture was added dropwise MeI (0.5 ml) at 0°C and was stirred at room temperature for 15 hours. The mixture was poured into a solution of phosphate buffer (100 ml) and was extracted with dichloromethane (100 ml). The organic layer was washed with saturated saline (50 ml), dried (Na2SO4) and concentrated. The residue was purified by flashamature on silica gel, elwira dichloromethane/methanol (10:1), to obtain 10 mg (5%) of the compound indicated in the title, in the form of a colorless oil:1H-NMR (CDCl3) δ to 7.64 (2H, d, J=8,3 Hz), 7,53-of 7.25 (7H, m), 6.89 in (1H, s), 3,65-3,55 (2H, m), 3,14 (3H, s), 2,96 (2H, t, J=6,7 Hz), 2,82 (2H, q, J=7,6 Hz)to 2.66 (3H, s)of 2.50 (3H, s), is 2.40 (3H, s), 1,25 (3H, t, J=7,6 Hz).

Example 5

2-Ethyl-5,7-dimethyl-3-(4-{2-[methyl({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. N-{2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenylethyl}-N-methylamine

A mixture of 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 7 example 1,627 mg, 9.0 mmol), a solution of methylamine (40% in methanol, 6 ml) and water (6 ml) were placed in a sealed tube and heated overnight at 130°C. the Reaction mixture was distributed between dichloromethane (50 ml) and water (50 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic extracts were washed with saturated brine (50 ml) and dried (Na2SO4). After removal of solvent the crude product was purified flash chromatography on a column of silica gel, elwira dichloromethane/methanol (5:1), with 523 mg (85%) of the compound indicated in the title, in the form of a white solid:1H-NMR (CDCl3) δ 7,41 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,3 Hz), make 6.90 (1H, s), to 4.73 (1H, Sirs), with 2.93 (4H, s), 2,82 (2H, q, J=7.5 Hz), 2,65 (3, C)of 2.51 (3H, s), 2.49 USD (3H, s)of 1.28 (3H, t, J=7.5 Hz).

Stage 2. 2-Ethyl-5,7-dimethyl-3-(4-{2-[methyl({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

To a solution of N-{2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}-N-methylamine (stage 1, 523 mg, 1.7 mmol) in dichloromethane (10 ml) and triethylamine (2 ml) was added p-toluensulfonate (400 mg, 2.0 mmol). The resulting reaction mixture was stirred at room temperature for 6 hours. After removal of solvent the residue was purified using flash chromatography on a column of silica gel, elwira dichloromethane/methanol (10:1), to obtain 358 mg (42%) indicated in the title compounds as white solids:1H-NMR (CDCl3) δ to 7.93 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,3 Hz), 7,14 (2H, d, J=8,4 Hz), 6,92 (1H, s), 3,66-to 3.49 (2H, m), 3,51 (3H, s), 2,93-2,70 (4H, m), 2,65 (3H, s)of 2.50 (3H, s), 2,38 (3H, s)of 1.24 (3H, t, J=7.2 Hz).

Example 6

2-Ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]propyl}phenyl-3-imidazo[4,5-b]pyridine

Stage 1. 1-(4-AMINOPHENYL)-2-propanol

A mixture of 1-(4-nitrophenyl)-2-propanol (Schadt, F.L.; et al.J. Am. Chem. Soc., 1978, 100, 228., 2.2 g, 12.3 mmol), iron powder (3.3 grams, to 59.1 mmol), ammonium chloride (370 mg, 6,9 mmol), ethanol (48 ml) and water (24 ml) was boiled under reflux for 2 hours. The mixture was cooled and filtered through a thick layer of celette concentrated. The residue was diluted with ethyl acetate (200 ml) and washed with water (2 x 100 ml). The organic layer was dried (MgSO4) and concentrated. Was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (1:1), to obtain 1.45 g (78%) of the compound indicated in the title, in the form of a yellow oil:1H-NMR (CDCl3) δ 7,00 (2H, d, J=8.6 Hz), only 6.64 (2H, d, J=8,8 Hz), 3,99-to 3.89 (1H, m), of 3.60 (2H, Shir. C)2,72-2,52 (2H, m)to 1.22 (3H, d, J=6.2 Hz).

Stage 2. 1-{4-[(4,6-Dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-propanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 1-(4-AMINOPHENYL)-2-propanol (step 1) and 2-chloro-4,6-dimethyl-3-nitropyridine (stage 2 of example 1).

1H-NMR (CDCl3) δ 9,59 (1H, Shir. C)7,58 (2H, d, J=8,4 Hz), 7,20 (2H, d, J=8,4 Hz), 6,53 (1H, s), 4,13-4,01 (1H, m), 2,82-of 2.64 (2H, m)to 2.55 (3H, s), is 2.44 (3H, s), 1,25 (3H, d, J=6.2 Hz).

Stage 3. 1-{4-[(3-Amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}-2-propanol

A mixture of 1-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-propanol (step 2, 500 mg, from 1.66 mmol), iron powder (440 mg, 7,88 mmol), ammonium chloride (80 mg, 1.5 mmol) in ethanol/water (vol./about., 31:8, 39 ml) was boiled under reflux for 2 hours. The mixture was cooled and filtered through a thick layer of celite. The filtrate was concentrated. The residue was diluted with dichloromethane (200 ml) and washed with water (2 x 100 ml). Organizes the second layer was dried (MgSO 4) and concentrated. Removal of solvent gave 450 mg (amounts.) the connection specified in the header, in the form of a brown solid: TLC Rf of 0.10 (hexane/ethyl acetate = 1:1).

Stage 4. 2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethylamine

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 1-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}-2-propanol (stage 3) and propionitrile.

TLC Rf= 0,30 (hexane/ethyl acetate = 1:1).

Stage 5. 1-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-2-propanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethylamine (stage 4).1H-NMR (CDCl3) δ 7,40 (2H, d, J=8.0 Hz), 7,33 (2H, d, J=8.0 Hz), 6,91 (1H, s), 4,16-4,07 (1H, m), 2,90 was 2.76 (4H, m)to 2.66 (2H, s), 2,52 (3H, s), 1.32 to-1,22 (6H, m).

Stage 6. 3-[4-(2-Chloropropyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 1-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-2-propanol (stage 5).

TLC Rf = 0.50 in (hexane/ethyl acetate = 1:1).

Stage 7. 2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylacylate

Connect the tion, specified in the header received in accordance with the method described for stage 8 of example 1 from 3-[4-(2-chloropropyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 6).

1H-NMR (CDCl3) δ 7,40 (2H, d, J=8,4 Hz), 7,34 (2H, d, J=8,4 Hz)6,91 (1H, s), 3,81-3,74 (1H, m), 2.95 and-and 2.79 (4H, m)to 2.66 (3H, s), 2,52 (3H, s)of 1.35 (3H, d, J=6.6 Hz), of 1.27 (3H, t, J=7.5 Hz).

Stage 8. 1-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-2-propanamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylatropine (stage 7).

1H-NMR (CDCl3) δ 7,40-7,31 (4H, m), 6.90 to (1H, s), 3,31-3,20 (1H, m), 2,87-2,77 (3H, m), 2,66-of 2.58 (4H, m), 2,52 (3H, s)of 1.28 (3H, t, J=8,3 Hz)to 1.19 (3H, d, J=6,8 Hz).

Stage 9. 2-Ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]propyl}phenyl)-3H-imidazo[45-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl-2-propanamine (stage 8).

TPL 128 C; MS (ESI) m/z 506,19 (M+H)+;

1H-NMR (CDCl3) δ 7,74 (2H, d, J=8,3 Hz), 7,30-7,19 (6H, m), 6.90 to (1H, s), 4,08-was 4.02 (1H, m), 2,84-of 2.72 (4H, m), 2,65 (3H, s), 2,48 (3H, s), 2,32 (3H, s), 1,20-of 1.13 (6H,m).

Example 7

2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 1-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-2-propanol (stage 5 example 6).

TPL 108 C; MS (ESI) m/z 507,18 (M+H)+;

1H-NMR (CDCl3) δ to $ 7.91 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,3 Hz), 7.23 percent (4H, s)6,91 (1H, s), 5,10-5,04 (1H, m), 2.95 and was 2.76 (4H, m), 2,65 (3H, s)of 2.50 (3H, s)to 2.41 (3H, s), 1,28-to 1.21 (6H, m).

Example 8

5,7-Dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-propyl-3H-imidazo[4,5-b]pyridine

Stage 1. 2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl butyrate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of example 1) and butyryl chloride.

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,2 Hz), 7,32 (2H, d, J=8,2 Hz), 6,92 (1H, s), 4,39 (2H, t, J=6.4 Hz), to 3.09 (2H, t, J=6.4 Hz), 2,77, (2H, t, J=7,7 Hz)to 2.66 (3H, s), 2,52 (3H, s), 2,32 (2H, t, J=7,7 Hz), 1,81 is 1.58 (4H, m), 1.00 and is 0.86 (6H, m).

Stage 2. 2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl butyrate (stage 1).

1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8.0 Hz), 7,32 (2H, d, J=8.0 Hz), 6.90 to (1H, s), 4,00-to 3.89 (2H, m), of 2.97 (2H, t, J=6.4 Hz), 278 (2H, t, J=7.8 Hz), 2,65 (3H, s), of 2.51 (3H, s), 1,80-of 1.64 (2H, m)to 0.92 (3H, t, J=7,4 Hz).

Stage 3. 3-[4-(2-Chloroethyl)phenyl]-5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 2).

MS (EI) m/z 327(M+).

Stage 4. 2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine (stage 3).

MS (EI) m/z 334 (M+);1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,4 Hz), 7,34 (2H, d, J=8,4 Hz)6,91 (1H, s), of 3.60 (2H, t, J=7,2 Hz)of 3.00 (2H, t, J=7.2 Hz), 2,77 (2H, t, J=7.8 Hz), 2,65 (3H, s), 2,52 (3H, s), 1,75-of 1.62 (2H, m)of 0.90 (3H, t, J=7,4 Hz).

Stage 5. 2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 4).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), to 6.88 (1H, s)to 3.89 (2H, Shir. C)3,18 (2H, t, J=6.8 Hz), a 3.01 (2H, t, J=6.8 Hz), a 2.75 (2H, t, J=7.5 Hz), of 2.64 (3H, s), 2,48 (3H, s), 1,78-to 1.63 (2H, m)of 0.90 (3H, t, J=7,3 Hz).

Stage 6. 5,7-Dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-about the Il-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 5).

1H-NMR (CDCl3) δ 7,86 (2H, d, J=8,3 Hz), 7,30 (2H, d, J=8,3 Hz), 7.23 percent (2H, d, J=8,3 Hz), 7,16 (2H, d, J=8,3 Hz), make 6.90 (1H, s), 6,10 (1H, Shir. C)to 3.58-of 3.46 (2H, m), 2,87 (2H, t, J=6.4 Hz), 2,71 at 2.59 (5H, m), 2,42 (3H, s), is 2.40 (3H, s), 1,74-to 1.61 (2H, m)to 0.89 (3H, t, J=7,0 Hz).

Example 9

2-Isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 5-Bromo-4,6-dimethyl-3-nitro-2-pyridinol

To a solution of 5-bromo-4,6-dimethyl-3-nitro-2-pyridinylamino (Heitsch, H.; et al.Bioorg. Med. Chem. 1997, 5, 673., 2.0 g, 8.1 mmol) in triperoxonane acid/water (vol./about., 2:1,30 ml) in small portions was added sodium nitrite (1.1 g, 16 mmol) at room temperature and then the reaction mixture was stirred over night. The precipitate was collected by filtration, washed with water and dried under reduced pressure to obtain 2.2 g (colwid) the connection specified in the header.

1H-NMR (CDCl3) δ of 2.53 (3H, s), of 2.38 (3H, s).

Stage 2. 3-Bromo-6-chloro-2,4-dimethyl-5-nitropyridine

The connection specified in the header received in accordance with the method described for stage 2 of example 1, starting from 5-bromo-4,6-dimethyl-3-nitro-2-pyridinol (stage 1).

1H-NMR (CDCl3 ) δ of 2.72 (3H, s)to 2.41 (3H, s).

Stage 3. 2-{4-[(5-Bromo-4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 3-bromo-6-chloro-2,4-dimethyl-5-nitropyridine (stage 2) and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 8,66 (1H, Shir. C)7,51 (2H, d, J=8,4 Hz), 7,22 (2H, d, J=8,4 Hz), 3,90-of 3.77 (2H, m), is 2.88 (2H, t, J=6.5 Hz), 2,65 (3H, s)at 2.59 (3H, s).

Stage 4. 2-{4-[(3-Amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 2-{4-[(5-bromo-4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 3).

1H-NMR (CDCl3) δ for 7.12 (4H, s), 6,21 (1H, s)to 3.38 (1H, Shir. C), 3,82 (2H, t, J=6.5 Hz), 2,80 (2H, t, J=6.5 Hz), of 2.54 (3H, s), of 2.38 (3H, s).

Stage 5. 2-[4-(6-Bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)ethyl 2-methylpropanoate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4) and isobutyryl chloride.

MS (EI) m/z 457 (M+).

Stage 6. 2-[4-(6-Bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example , on the basis of 2-[4-(6-bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl 2-methylpropanoate (stage 5).

1H-NMR (CDCl3) δ was 7.45 (2H, d, J=8,3 Hz), 7,30 (2H, d, J=8,3 Hz), of 3.96 (2H, t, J=7,3 Hz), 3,15-3,03 (1H, m), of 2.97 (2H, t, J=7,3 Hz), was 2.76 (3H, s)to 2.67 (3H, s)of 1.34 (6H, d, J=6,8 Hz).

Stage 7. 6-Bromo-3-[4-(2-chloroethyl)phenyl]-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(6-bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 6).

1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8,3 Hz), 7,32 (2H, d, J=8,3 Hz), 3,81 (2H, t, J=7,3 Hz), 3,19 (2H, t, J=7,3 Hz), 3,15-to 3.02 (1H, m), was 2.76 (3H, s)to 2.66 (3H, s)of 1.33 (6H, d, J=6,9 Hz).

Stage 8. 2-[4-(6-Bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-bromo-3-[4-(2-chloroethyl)phenyl]-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 7).

MS (EI) m/z 412 (M)+;1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), of 3.60 (2H, t, J=6.5 Hz), 3,16-to 3.02 (1H, m), to 3.02 (2H, t, J=6.5 Hz), 2,77 (3H, s), 2,68 (3H, s)of 1.33 (6H, d, J=6,9 Hz).

Stage 9. [4-(2-Isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 8).

1H-NMR (CDCl3) δ 7,49 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), 6,93 (1H, s), 6,60 (2H, Shir. C), 3,32 is 3.00 (5H, m), 2,65 (3H, s), 2,48 (3H, s)is 1.31 (6H, d, J=6,8 Hz).

Stage 10. 2-Isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from [4-(2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 9).

1H-NMR (CDCl3) δ 7,87 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,3 Hz), 7.23 percent (2H, d, J=8,4 Hz), 7,17 (2H, d, J=8,4 Hz)6,91 (1H, s), between 6.08 (1H, Shir. C)3,56-of 3.43 (2H, m), 3,02-2,89 (1H, m), 2,85 (2H, t, J=6.3 Hz), to 2.67 (3H, s)to 2.41 (6H, s)of 1.26 (6H, d, J=6,8 Hz).

Example 10.

Sodium salt of 2-isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described in example 2 from 2-isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (example 9).

MS (EI) m/z 506(M+N)+.

Example 11.

2-Butyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 2-[4-(6-Bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpentane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[3-amino-5-bromo-4,6-dimethyl-pyridinyl)amino]phenyl}ethanol (step 4 of example 9) and pentanolide.

MS (EI) m/z 485 (M+);1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,3 Hz), 4,37 (2H, t, J=6.9 Hz), 3,05 (2H, t, J=6.9 Hz), and 2.79 (2H, t, J=7,7 Hz)of 2.75 (3H, s)to 2.67 (3H, s), of 2.33 (2H, t, J=7.5 Hz), 1,75-and 1.54 (4H, m), 1,40-1,20 (4H, m)of 0.91 (3H, t, J=7,3 Hz), is 0.84 (3H, t, J=7,3 Hz).

Stage 2. 2-[4-(6-Bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(6-bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpentane (stage 1).

MS (EI) m/z 401(M+).

Stage 3. 6-Bromo-2-butyl-3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(6-bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 2).

MS (EI) m/z 419(M+).

Stage 4. 2-[4-(6-Bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-bromo-2-butyl-3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 3).

MS (EI) m/z 426 (M+);1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8,4 Hz), 7,33 (2H, d, J=8,4 Hz), 3,61 (2H, t, J=7.2 Hz), a 3.01 (2H, t, J=7,2 Hz), and 2.79 (2H, t, J=7.9 Hz), a 2.75 (3H, s)to 2.67 (3H, s), a 1.75-to 1.60 (2H, m), 1,36 is 1.20 (2H, m), is 0.84 (3H, t, J=7,3 Hz).

Stage 5. 2-[4-(2-Butyl-5,7-dimethyl-3H-it is dazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(6-bromo-2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 4).

1H-NMR (CDCl3) δ to 7.59 (2H, d, J=8,3 Hz), 7,35 (2H, d, J=8,3 Hz), make 6.90 (1H, s), 3,52-up 3.22 (4H, m), 3,01 (2H, Shir. C)2,90 (2H, t, J=7,7 Hz), is 2.74 (3H, s), of 2.56 (3H, s), 1,79-of 1.62 (2H, m), 1.41 to to 1.23 (2H, m), is 0.84 (3H, t, J=7.5 Hz).

Stage 6. 2-Butyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 5).

1H-NMR (CDCl3) δ 7,86 (2H, d, J=8,2 Hz), 7,31 (2H, d, J=8,2 Hz), 7,22 (2H, d, J=8,3 Hz), 7,14 (2H, d, J=8,3 Hz)6,91 (1H, s)6,09 (1H, Shir. C)3,56-3,44 (2H, m), 2,84 (2H, t, J=6.4 Hz), 2,70 at 2.59 (5H, m), 2,42 (3H, s)to 2.41 (3H, s), 1,69 was 1.43 (2H, m), 1.30 and of 1.18 (2H, m)to 0.80 (3H, t, J=7,3 Hz).

Example 12. Sodium salt of 2-butyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described in example 2 from 2-butyl-5,7-dimethyl-3-(4-{2-[(I[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (example 11).

MS (ESI) m/z 520 (M+H)+.

Example 13. 2-Isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-were)Sul who were radioactive]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl 3-methylbutanoate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of example 1) and isovaleryl chloride.

MS (EI) m/z 407(M+).

Stage 2. 2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl 3-methylbutanoate (stage 1).

MS (EI) m/z 323 (M+).

Stage 3. 3-[4-(2-Chloroethyl)phenyl]-2-isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 example 1 from 2-[4-(2-isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 2).

MS (EI) m/z 341 (M+);1H-NMR (CDCl3) δ 7,41 (2H, d, J=8,2 Hz), 7,33 (2H, d, J=8,2 Hz), make 6.90 (1H, s), 3,80 (2H, t, J=6.5 Hz), 3,18 (2H, t, J=6.5 Hz), 2,68 (2H, d, J=7.5 Hz), to 2.66 (3H, s), of 2.51 (3H, s), 2,14 is 1.96 (1H, m)0,86 (6H, d, J=6,6 Hz).

Stage 4. 2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 example 1 from 3-[4-(2-chloroethyl)phenyl]-2-isobutyl-57-dimethyl-3H-imidazo[4,5-b]pyridine (stage 3).

MS (EI) m/z 348 (M+);1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,4 Hz)6,91 (1H, s), of 3.60 (2H, t, J=6.5 Hz), of 3.00 (2H, t, J=6.5 Hz), 2,69 (2H, d, J=7.5 Hz), 2,65 (3H, s), 2,52 (3H, s), 2,08-to 1.98 (1H, m)of 0.87 (6H, d, J=6,7 Hz).

Stage 5. 2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 4).

1H-NMR (CDCl3) δ 7,40 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz)6,91 (1H, s)to 3.09 (2H, t, J=6.4 Hz), with 2.93 (2H, t, J=6.4 Hz), 2,80 (2H, Shir. C), 2,68 (2H, d, J=7.5 Hz), to 2.66 (3H, s), of 2.53 (3H, s), 2,18 is 2.00 (1H, m)to 0.88 (6H, d, J=6,8 Hz).

Stage 6. 2-Isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 5).

1H-NMR (CDCl3) δ a 7.85 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), 7,21 (2H, d, J=8,3 Hz), 7,12 (2H, d, J=8,3 Hz)6,91 (1H, s), 6,14 (1H, Shir. C), 3,55-of 3.42 (2H, m), 2,82 (2H, t, J=6.3 Hz), 2,65 (3H, s), 2,53 (2H, d, J=7,3 Hz)to 2.41 (3H, s), 2,39 (3H, s), 2,10-of 1.92 (1H, m), 0,81 (6H, d, J=6,6 Hz).

Example 14

Sodium salt of 2-isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection is shown in the header, received in accordance with the method described in example 2 from 2-isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (example 13).

MS (ESI) m/z 520 (M+N+)

Example 15

5,7-Dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-neopentyl-3H-imidazo[4,5-b]pyridine

Stage 1. 2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl 3,3-dimethylbutanoate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of example 1) and tert-butylacetamide.

MS (EI) m/z 435 (M+).

Stage 2. 2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl 3,3-dimethylbutanoate (stage 1).

MS (EI) m/z 337 (M+).

Stage 3. 3-[4-(2-Chloroethyl)phenyl]-2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 2).

1H-NMR (CDCl3) δ 7,41 (2H, d, J=8,2 G is), 7,30 (2H, d, J=8,2 Hz), 6.89 in (1H, s), 3,81 (2H, t, J=6.5 Hz), 3,18 (2H, t, J=6.5 Hz), and 2.79 (2H, s)to 2.66 (3H, s), of 2.51 (3H, s)to 0.89 (9H, s).

Stage 4. 2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 3-[4-(2-chloroethyl)phenyl]-2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 3).

MS (EI) m/z 362 (M+); 1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,3 Hz)6,91 (1H, s), 3,62 (2H, t, J=6.5 Hz), to 3.02 (2H, t, J=6.5 Hz), 2,78 (2H, s), 2,68 (3H, s), of 2.53 (3H, s), 0.88 to (9H, s).

Stage 5. 2-[4-(2-Neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 4).

MS (EI) m/z 336 (M+).

Stage 6. 2-Neopentyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-neopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 5).

1H-NMR (CDCl3) δ 7,86 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,3 Hz), 7,22 (2H, d, J=8,3 Hz), 7,14 (2H, d, J=8,3 Hz)6,91 (1H, s), 6,18 (1H, Shir. C)3,56-of 3.46 (2H, m), 2,85 (2H, t, J=6.4 Hz), 2,65 (3H, s), 2,60 (2H, s)to 2.41 (3H, s), is 2.40 (3H, s)of 0.87 (9H, s).

Example TIA salt of 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-neopentyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described in example 2 of 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-neopentyl-3H-imidazo[4,5-b]pyridine (example 15).

MS (ESI) m/z 534 (M+H)+.

Example 17. 5,7-Dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine

Stage 1. N-[4-(2-Chloroethyl)phenyl]-N-(4,6-dimethyl-3-nitro-2-pyridinyl)amine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 3 of example 1).

1H-NMR (CDCl3) δ 9,46 (1H, Shir. C)8,29 (1H, d, J=8,8 Hz), 7,42 (1H, d, J=l,7 Hz), 7,35 (2H, d, J=8,3 Hz), 7,22 (2H, d, J=8,3 Hz), 6,97 (1H, DD, J=8,8, 1.7 Hz), of 3.77 (2H, t, J=7.2 Hz), of 3.13 (2H, t, J=7.2 Hz).

Stage 2. N2-[4-(2-Chloroethyl)phenyl]-4,6-dimethyl-2,3-pyridinediamine

The connection specified in the header received in accordance with the method described for stage 3 of example 6, on the basis of N-[4-(2-chloroethyl)phenyl]-N-(4,6-dimethyl-3-nitro-2-pyridinyl)amine (stage 1).

MS (EI) m/z 383 (M+).

Stage 3. 3-[4-(2-Chloroethyl)phenyl]-5,7-dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine

To a mixture of N2-[4-(2-chloroethyl)phenyl]-4,6-dimethyl-2,3-pyridinediamine (stage 2, 276 mg, 1.0 mmol) and 3-(1,3-thiazol-2-yl)propanoic acid (157 mg ,0 mmol) in dichloromethane (10 ml) in one portion was added the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) (192 mg, 1.0 mmol). The reaction mixture was stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure. The residue is suspended in toluene (20 ml) and was heated at 150°C for 5 hours. The reaction mixture was poured into water (50 ml), the organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases were washed with saturated brine (50 ml) and dried (Na2SO4). After removal of solvent the crude product was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (1:1) to obtain 210 mg (53%) of the connection specified in the header:

MS (EI) m/z 396 (M+);1H-NMR (CDCl3) δ 7,63 (1H, d, J=3,4 Hz), 7,39 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), to 7.15 (1H, d, J=3,4 Hz), 6,93 (1H, s), of 3.78 (2H, t, J=7.4 Hz), 3,69-3,50 (2H, m), 3,39-3,20 (2H, m)and 3.15 (2H, t, J=7,4 Hz), to 2.66 (3H, s), of 2.53 (3H, s).

Stage 4. 2-(4-{5,7-Dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine-3-yl}phenyl)utilized

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine (stage 3).

MS (EI) m/z 403 (M+);1H-NMR (CDCl3) δ 7,63 (1H, d, J=3.5 Hz), 7,38 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), to 7.15 (1H, d, J=3.5 Hz), 6,93 (1H, s), 3,63-of 3.54 (4H, m), 3,34-3,26 (2H, m), 2,98 (2H, t, J=7.4 Hz), 2,68 (3H, s), 2,53 (3H with).

u> Stage 5. 2-(4-{5,7-Dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine-3-yl}phenyl)ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-(4-{5,7-dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine-3-yl}phenyl)utilised (stage 4).

MS (EI) m/z 377 (M+).

Stage 6. 5,7-Dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-(4-{5,7-dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine-3-yl}phenyl) - ethylamine (stage 5).

MS (ESI) m/z 575 (M+H)+;1H-NMR (CDCl3) δ 7,83 (2H, d, J=8,3 Hz), to 7.61 (1H, d, J=3.5 Hz), 7,32 (2H, d, J=8,3 Hz), 7,19-to 7.15 (3H, m), 7,07 (2H, d, J=8,2 Hz), 6,91 (1H, s), 6,21 (1H, Shir. C), 3,52 is 3.40 (4H, m), 3,20-3,13 (2H, m), of 2.81 (2H, t, J=6,1 Hz), 2,65 (3H, s), is 2.44 (3H, s)to 2.41 (3H, s).

Example 18

3-{4-[2-({[(4-Biphenylmethanol)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Stage 1. Phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate

To a stirred solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 9 of example 1, 1.55 g, 5.3 mmol) and triethylamine (0,80 ml, 5.8 mmol) in dichloromethane (26 ml), cooled in an ice bath, was added dropwise vanillaroma the t (0,69 ml, 5.5 mmol) and the mixture was stirred at ambient temperature. After 30 minutes the reaction mixture was distributed between saturated aqueous sodium bicarbonate (30 ml) and dichloromethane (30 ml). The organic layer was separated and the aqueous phase was extracted with dichloromethane (30 ml). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was recrystallized from dichloromethane/hexane to obtain 1.90 g (87%) of the compound indicated in the title, in the form of light brown crystals.1H-NMR (CDCl3) δ 7,43-7,11 (9H, m)6,91 (1H, s), of 5.50 (1H, Shir. C)of 3.57 (2H, pseudo kV, J=6.9 Hz), 2,98 (2H, t, J=6.9 Hz), and 2.83 (2H, q, J=7,6 Hz)to 2.66 (3H, s), 2,52 (3H, s)of 1.28 (3H, t, J=7,6 Hz).

Stage 2. 3-{4-[2-({[(4-Biphenylmethanol)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a stirred solution of 4-biphenylmethanol (Greenlee, W. J.; Walsh, T. F.; et al. Eur. Pat. Appl., EP 617001 (1994), 56 mg, 0.24 mmol) in DMF (3 ml) was added NaH (60% oil dispersion, 20 mg, 0.5 mmol) at room temperature. After 5 minutes was added phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1, 100 mg, 0.24 mmol) and the mixture was stirred for another 1 hour. The mixture was poured into water (50 ml) and was extracted with diethyl ether (2 x 50 ml). The combined extracts were washed with water (50 ml), saturated brine (50 ml) and dried (MgSO4). Uralenergoles gave a white oily solid. Was purified using preparative TLC (ethyl acetate) to give 66 mg (50%) of the compound indicated in the title, in the form of a colorless oil.

MS (ESI) m/z 554 (M+H)+;1H-NMR (CDCl3) δ of 8.06 (2H, d, J=8.6 Hz), 7,13 (2H, d, J=8.6 Hz), 7,60-7,53 (2H, m), of 7.48 and 7.36 (3H, m), 7,21 (2H, d, J=8,4 Hz), 7,12 (2H, d, J=8,3 Hz), 6,92 (1H, s), 6,11 (1H, shirt, J=5.5 Hz), of 3.54 (2H, dt, J=5,9, 6,0 Hz), 2,89 (2H, d, J=6.0 Hz), of 2.64 (2H, q, J=7.5 Hz), to 2.66 (3H, s), is 2.40 (3H, s)of 1.18 (3H, t, J=7.5 Hz).

Example 19

2-Ethyl-5,7-dimethyl-3-{4-[2-({[(1-naphthylmethyl)amino]carbonyl}amino)ethyl]phenyl}-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for step 2 of example 18, from phenyl-2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 of example 18) and 1-naphthylamide (Arnswald, M.; Neumann, W. P.Chem. Ber., 1991,124, 1997; Khorgami, M. N.Synthesis, 1972, 574).

MS (ESI) m/z 528 (M+H)+;1H-NMR (CDCl3) δ charged 8.52-8,48 (1H, m), at 8.36 (1H, DD, J=1,1, 7,3 Hz), 8,11 (1H, d, 8,3 Hz), 8,00-7,94 (1H, m), 7,63 is 7.50 (3H, m), 7,20 (2H, d, J=8,4 Hz), 7,13 (2H, d, J=8,4 Hz)6,94 (1H, s), 6,32 (1H, shirt, J=5.7 Hz), 3,50 (2H, dt, J=5,9, 6,0 Hz), 2,82 (2H, t, J=6.2 Hz), 2,68 (2H, q, J=7.5 Hz), 2,65 (3H, s)to 2.41 (3H, s)to 1.21 (3H, t, J=7.5 Hz).

Example 20

2-Ethyl-5,7-dimethyl-3-{4-[2-({[(2-naphthylmethyl)amino]carbonyl}amino)ethyl]phenyl}-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for step 2 of example 18, from phenyl 2-[4-(2-ethyl-,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 of example 18) and 2-naphthylamide.

MS (ESI) m/z 528 (M+N)+;1H-NMR (CDCl3) δ at 8.60 (1H, s), 8,01-to 7.84 (5H, m), of 7.64-7,52 (2H, m), 7,20-was 7.08 (4H, m), 6,92 (1H, s), of 6.20 (1H, t, J=5.6 Hz), 3,52 is-3.45 (2H, q, J=6,1 Hz), 2,84 is 2.80 (2H, t, J=6.3 Hz), 2.71 to 2,62 (2H, q, J=6.6 Hz), of 2.66 (3H, s), 2,43 (3H, s), 1,22-of 1.16 (3H, t, J=6.6 Hz).

Example 21

2-Ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for step 2 of example 18, from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 of example 18) and 2-thiophenesulfonyl (Huang, NS; Reinhard, E.J.; Reitz, D.B.Tetrahedron Lett., 1994, 35, 7201.; Graham, S. L.; Scholz, T.N.Synthesis, 1986, 1031).

1H-NMR (CDCl3) δ 8,01 (1H, s), 7,78 (1H, DD, J=1,3, a 4.9 Hz), 7,63 (1H, DD, J=1,3,4,9 Hz), 7,22 (2H, d, J=8,3 Hz), 7,14 (2H, d, J=8,3 Hz), to 7.09 (1H, DD, J=3,8, 5.0 Hz), 6,92 (1H, s), equal to 6.05 (1H, t, J=5.3 Hz), 3,53 (2H, kV, J=6.2 Hz), 2,96 (3H, s), is 2.88 (3H, s), 2,87 (2H, t, J=6.2 Hz), to 2.67 (2H, q, J=7.5 Hz), 2,65 (3H, s), 2,43 (3H, s)of 1.20 (3H, t, J=7.5 Hz).

Example 22

3-(4-{2-[({[(5-Chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for step 2 of example 18, from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 of example 18) and 5-chloro-2-thiophenesulfonyl.

MS (ESI) m/z 518(M+H)+;1H-NMR (CDCl3) δto 7.99 (1H, C)7,58-7,56 (1H, m), 7.23 percent-to 7.15 (4H, m), 6,94-6,92 (1H, m), 6,04 (1H, W), 3,53-3,51 (2H, m), 2,87 (2H, m), 2,73-to 2.65 (2H, q, J=7,6 Hz), 2,65 (3H, s), is 2.44 (3H, s)to 1.21 (3H, t, J=7,6 Hz).

Example 23

3-(4-{2-[({[(4,5-Dichloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for step 2 of example 18, from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 of example 18) and 5,6-dichloro-2-thiophenesulfonyl.

MS (ESI) m/z 552 (M+H)+;1H-NMR (CDCl3) δ 7,49 (1H, s), 7,27-7,14 (4H, m), at 6.84 (1H, s), 3,47 (2H, W), of 2.75 (2H, W), 2,69 (211, kV, J=7,6 Hz)of 2.64 (3H, s), of 2.38 (3H, s)to 1.22 (3H, t, J=7,6 Hz).

Example 24

3-{4-[2-({[(1-Benzothieno-2-ylsulphonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for step 2 of example 18, from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 of example 18) and 1-benzothiophen-2-sulfonamida (Chern, J.; Leu, Y.; et al.J. Med. Chem., 1997, 40, 2276.; Graham, S. L.; Shepard, K. L.; et al.J. Med. Chem., 1989, 32, 2548). TPL USD 128.0-130,0°C; MS (ESI) m/z 534 (M+H)+;1H-NMR (DMSO-d6) δ 8,05-of 8.00 (3H, m), 7,50-7,42 (2H, m), of 7.36 (2H, d, J=7,4 Hz), 7,32 (2H, d, J=7,4 Hz), of 6.96 (1H, s), 6,61-6,56 (1H, m), 3,34 of 3.28 (2H, m), 2,80 (2H, t, J=6.6 Hz), 2,68 (2H, q, J=7.5 Hz), of 2.54 (3H, C)to 2.40 (3H, s)to 1.19 (3H, t, J=7.5 Hz).

<> Example 25

3-(4-{2-[({[(2-Chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 9 of example 1) and 2-chlorobenzenesulfonyl isocyanate.

MS (ESI) m/z 512 (M+H)+;1H-NMR (CDCl3) δ 8,21-8,17 (1H, d, 7.7 Hz), EUR 7.57-the 7.43 (3H, m), 7,32-7,22 (4H, m), 6,93 (s, 1H), 6,34 (1H, t, J=5.6 Hz), 3,56-to 3.49 (2H, q, J=6.3 Hz), 2,89-to 2.85 (2H, t, J=6.4 Hz), 2,80-a 2.71 (q, 2H, J=7,6 Hz)to 2.67 (3H, C)2,49 (3H, s), 1,28-1,22 (3H, t, J=7,6 Hz).

Example 26

2-Ethyl-5-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 2-{4-[(6-Methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2-chloro-6-methyl-3-nitropyridine (Takayama, K.; Iwata, M.; Kono, N.; et al. Jpn.Kokai Tokkyo Koho, JP 11292877 (1999).; Ding, C.Z.; Hunt, J.T.; Kim, S.; et al.PCT Int. Appl.WO 9730992 (1997)) and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 8,24 (1H, d, J=9.1 Hz), 7,28-7,33 (4H, m), of 6.65 (1H, d, J=9,2 Hz), with 3.89 (2H, d, J=6.4 Hz), 2,89 (2H, d, J=6.4 Hz), of 2.81 (3H, s).

Stage 2. 2-{4-[(3-Amino-6-methyl-2-pyridinyl)amino]phenyl}ethanol

To a solution of 2-{4-[(6-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1, 4.6 g, to 16.9 mmol) in methanol is (100 ml) was added 10% Pd-C (300 mg). The resulting mixture was stirred for 2 hours in hydrogen atmosphere. The mixture was filtered through a thick layer of celite and the filtrate was concentrated. The residue was purified column flash chromatography, elwira hexane/ethyl acetate (gradient elution from 1:2 to 1:5), to obtain 3.8 g (92%) of the compound indicated in the title, in the form of a yellow solid.1H-NMR (CDCl3) δ 7,10-7,16 (4H, m)6,91 (1H, d, J=8,4 Hz), 6,70 (1H, d, J=8,4 Hz), to 6.19 (1H, s), 3,83 (2H, t, J=6.4 Hz), of 2.81 (2H, t, J=6.4 Hz), to 2.35 (3H, s).

Stage 3. 2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-6-methyl-2-pyridinyl)amino]phenyl}ethanol (step 2) and propionitrile.

MS (EI) m/z 337 (M+).

Stage 4. 2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ of 7.90 (1H, d, J=8,3 Hz), the 7.43 (2H, d, J=8,2 Hz), 7,34 (2H, d, J=8,2 Hz), 7,07 (1H, d, J=8,3 Hz), 3,93 (2H, t, J=6.6 Hz), of 2.97 (2H, t, J=6.6 Hz), 2,80 (2H, q, J=7.5 Hz), of 2.56 (3H, s)of 1.35 (3H, t, J=7.5 Hz).

Stage 5. 2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

A mixture of 2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyrid the n-3-yl)phenyl]ethanol (step 4, 217 mg, 0.77 mmol) in THF (20 ml) was added diethylazodicarboxylate (DEAD) (0.3 ml, 1.5 mmol), triphenylphosphine (380 mg, 1.5 mmol) and diphenylphosphoryl (DPPA) (0.4 ml, 1.5 mmol). The mixture was stirred at room temperature for 4.5 hours. After removal of solvent the residue was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (gradient elution from 1:1 to 1:2), to obtain 70 mg (30%) of the compound indicated in the title, in the form of a brown oil.

1H-NMR (CDCl3) δ of 7.90 (1H, d, J=8.1 Hz), 7,34-7,44 (4H, m), was 7.08 (1H, d, J=8.1 Hz), of 3.60 (2H, t, J=7,1 Hz)of 3.00 (2H, t, J=7,1 Hz), 2,80 (2H, q, J=7.5 Hz), to 2.57 (3H, s)of 1.35 (3H, t, J=7.5 Hz).

Stage 6. 2-[4-(2-Ethyl-5-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ to $ 7.91 (1H, d, J=8.1 Hz), 7,42 (2H, d, J=8,3 Hz), 7,32 (2H, d, J=8,3 Hz), 7,06 (1H, d, J=8.1 Hz), of 3.13 (2H, t, J=6.8 Hz), 2,95 (2H, t, J=6.8 Hz), of 2.81 (2H, q, J=7,6 Hz)to 2.55 (3H, s)of 1.34 (3H, t, J=7,6 Hz).

Stage 7. 2-Ethyl-5-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine-3-yl)who enyl]ethylamine (step 6).

MS (ESI) m/z 476 (M+H)+;1H-NMR (CDCl3) δ to 7.95 (1H, d, J=8.0 Hz), to 7.84 (2H, d, J=8,2 Hz), 7,32 (2H, d, J=8,2 Hz), 7,25 (2H, d, J=8,2 Hz), 7,17 (2H, d, J=8,2 Hz), 7,10 (1H, d, J=8.0 Hz), 6,17 (1H, Shir. C)to 3.52 (2H, t, J=6.6 Hz), of 2.86 (2H, t, J=6.6 Hz), 2,69 (2H, q, J=7.5 Hz), 2.49 USD (3H, s)to 2.41 (3H, s)of 1.27 (3H, t, J=7.5 Hz).

Example 27

Sodium salt of 2-ethyl-5-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-5-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (example 26).

1H-NMR (DMSO-d6) δ to $ 7.91 (1H, d, J=7.9 Hz), to 7.61 (2H, d, J=6.8 Hz), was 7.36 (4H, s), 7,11-to 7.15 (3H, m), 2,67 is 2.75 (4H, m)of 2.50 (2H, Shir. C)of 2.45 (3H, s), of 2.28 (3H, s), 1,21-1,24 (3H, m).

Example 28

2-Ethyl-5-methoxy-3-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 2-{4-[(6-methoxy-3-nitro-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2-chloro-6-methoxy-3-nitropyridine and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 10,59 (1H, Sirs), scored 8.38 (1H, d, J=9,2 Hz), to 7.59 (2H, d, J=8,3 Hz), 7.23 percent (2H, d, J=8,3 Hz), of 6.20 (1H, d, J=9,2 Hz), of 3.94 (3H, s), a 3.87 (2H, t, J=6.6 Hz), 2,87 (2H, t, J=6.6 Hz).

Stage 2. 2-{4-[(3-Amino-6-methoxy-2-pyridinyl)amino]phenyl}ethanol

<> A mixture of 2-{4-[(6-methoxy-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1, to 3.52 g, 12,17 mmol), iron powder (3.4 g, 60,84 mmol) and ammonium chloride (325 mg, between 6.08 mmol) in ethanol/water (vol./about., 2:1, 90 ml) was boiled under reflux for 1 hour. After cooling, the catalyst was removed and the filtrate was concentrated. The residue was extracted with ethyl acetate (100 ml) and washed with water. The organic layer was dried (MgSO4) and concentrated to obtain 3,41 g (colwid) the connection specified in the header, in the form of a black oil.1H-NMR (CDCl3) δ of 7.48 (2H, d, J=8,4 Hz), 7,14 (2H, d, J=8,4 Hz),? 7.04 baby mortality (1H, d, J=8,2 Hz), to 6.75 (1H, Shir. C), 6,13 (1H, d, J=8,2 Hz), a 3.87 (3H, s), 3,83 (2H, t, J=6.6 Hz), of 2.81 (2H, t, J=6.6 Hz).

Stage 3. 2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-6-methoxy-2-pyridinyl)amino]phenyl}ethanol (step 2) and propionitrile.

TLC Rf = 0.50 in (hexane/ethyl acetate = 2:1).

Stage 4. 2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-5-methoxy-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ to $ 7.91 (1H, d, J=8.6 Hz), the 7.43 (2H, d, J=8,4 Hz), 7,35 (2H, d, J=8,4 G is), to 6.67 (1H, d, J=8.6 Hz), 3,98-3,88 (2H, m), 3,82 (3H, s)to 2.99 (2H, t, J=6.4 Hz), of 2.81 (2H, q, J=7,4 Hz)of 1.34 (3H, t, J=7,4 Hz).

Stage 5. 2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-(4-2-ethyl-5-methoxy-3H-imidazo[4,5-b]pyridine-3-yl)phenyl)ethanol (stage 4).

TLC Rf = 0,78 (hexane/ethyl acetate = 1/1).

Stage 6. 2-[4-(2-Ethyl-5-methoxy-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-5-methoxy-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ a 7.92 (1H, d, J=8.6 Hz), 7,40-7,31 (4H, m), to 6.67 (1H, d, J=8.6 Hz), 3,82 (3H, s), 3,13-3,10 (2H, m), 3.00 and-of 2.97 (2H, m), 2,80 (2H, q, J=7,6 Hz)of 1.33 (3H, t, J=7,6 Hz).

Stage 7. 2-Ethyl-5-methoxy-3-(4-(2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-5-methoxy-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ to 7.95 (1H, d, J=8.7 Hz), 7,74 (2H, d, J=8,4 Hz), 7,34-7,27 (6H, m), 6,69 (1H, d, J=8.7 Hz), 6,55 (1H, m), with 3.79 (3H, s), 3,60-of 3.53 (2H, m), 2,90 (2H, t, J=6.8 Hz), 2,77 (2H, q, J=7.4 Hz), of 1.30 (3H, t, J=7,4 Hz).

Example 29. Sodium salt of 2-ethyl-5-methoxy-3-(4-{2-[({[(4-methylp the Nile)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-5-methoxy-3-(4-[2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (example 28).

1H-NMR (DMSO-d6) δ 7,94 (1H, d, J=8,4 Hz), to 7.59 (2H, d, J=8.1 Hz), 7,41-7,34 (4H, m), 7,12 (2H, d, J=8.1 Hz), of 6.68 (1H, d, J=8,4 Hz), 3,71 (3H, s), 3,14 (2H, m), 2,75 of 2.68 (4H, m), and 2.27 (3H, s)of 1.20 (3H, t, J=7.5 Hz); IR (KBr) Vmax1597, 1518, 1489, 1425, 1389, 1261, 1130, 1086 cm-1.

Example 30

6-Chloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-3H-imidazo[4,5-b]pyridine

Stage 1. 2-{4-[(5-Methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2-chloro-5-methyl-3-nitropyridine and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 9,96 (1H, Sirs), 8,32-8,31 (2H, m), 7,55 (2H, d, J=8,3 Hz), 7,24 (2H, d, J=8,3 Hz), 3,85 (2H, m), of 2.86 (2H, t, J=6.6 Hz), 2,32 (3H, s).

Stage 2. 2-{4-[(3-Amino-5-methyl-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-{4-[(5-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1).

1H-NMR (CDCl3) δ to 7.59 (1H, m), 7,08-to 7.00 (4H, m), to 6.80 (1H, m), 3,74 (2H, t, J=6.6 Hz), is 2.74 (2H, t, J=6.6 Hz), 2,19 (3H, s).

Stage 3. 2-[4-(2-Ethyl-6-methyl-3H-imidazo[4,5-b]PI is one-3-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-5-methyl-2-pyridinyl)amino]phenyl}ethanol (step 2) and propionitrile.

TLC Rf= 0,74 (dichloromethane/methanol = 10:1).

Stage 4. 2-[4-(2-Ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ to 8.12 (1H, s), to 7.84 (1H, s), 7,44 (2H, d, J=8.1 Hz), 7,33 (2H, d, J=8.1 Hz), 3,91-of 3.85 (2H, m), 2,96 (2H, t, J=6,7 Hz), 2,82 (2H, q, J=7.5 Hz), the 2.46 (3H, s)of 1.36 (3H, t, J=7.5 Hz).

Stage 5. 2-[4-(2-Ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ 8,13 (1H, s), to 7.84 (1H, s), 7,44 (2H, d, J=8,4 Hz), was 7.36 (2H, d, J=8,4 Hz)and 3.59 (2H, t, J=7,3 Hz)of 3.00 (2H, t, J=7,3 Hz), and 2.83 (2H, q, J=7,6 Hz), the 2.46 (3H, s)of 1.36 (3H, t, J=7,6 Hz).

Stage 4. 2-[4-(2-Ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (one hundred the Oia 5).

1H-NMR (CDCl3) δ to 8.12 (1H, s), to 7.84 (1H, s), 7,42 (2H, d, J=8,4 Hz), 7,33 (2H, d, J=8,4 Hz), of 3.07 (2H, t, J=6.8 Hz), 2.91 in-2,78 (4H, m), the 2.46 (3H, s)of 1.36 (3H, t, J=7.5 Hz).

Stage 5. 2-Ethyl-6-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The interaction was carried out according to the method described for stage 10 of example 1 from 2-[4-(2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ of 8.04 (1H, d, J=1,8 Hz), 7,86-of 7.82 (3H, m), 7,33-7,21 (6H, m), 6,27 (1H, m), 3,52-to 3.49 (2H, m), 2,87 (2H, t, J=6.8 Hz), was 2.76 (2H, q, J=7,6 Hz), a 2.45 (3H, s)to 2.41 (3H, s)of 1.30 (3H, t, J=7,6 Hz).

Example 31. Sodium salt of 6-chloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-6-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (example 30).

1H-NMR (DMSO-d6) δ 8,04 (1H, m), to 7.84 (1H, m), 7,60 (2H, d, J=8,l Hz), was 7.36 (4H, s), 7,12 (2H, d, J=8.1 Hz), of 3.13 (2H, m), 2,78-a 2.71 (4H, m), 2,39 (3H, s), and 2.27 (3H, s)to 1.22 (3H, t, J=7.5 Hz); IR (KBr) Vmax1601, 1518, 1423, 1375, 1283, 1250, 1128, 1084 cm-1.

Example 32

6-chloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 2-{4-[(5-chloro-3-nitro-2-pyridinyl)amino]phenyl}ethanol

Connection, indicated the data in the header, received in accordance with the method described for stage 3 of example 1, from 2,5-dichloro-3-nitropyridine (Marfat, A.; Robinson, R. P.US pat. Appl., US 5811432 (1998); Haessig, R.; Siegrist, U.Eur. Pat. Appl., EP 483061 (1992)) and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 10,00 (1H, Shir. C)8,51-and 8.50 (1H, m), to 8.41 (1H, d, J=2.4 Hz), 7,53 (2H, d, J=8,4 Hz), 7,27 (2H, d, J=8,4 Hz), 3,88-a 3.87 (2H, m), is 2.88 (2H, t, J=6.6 Hz).

Stage 2. 2-{4-[(3-Amino-5-chloro-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-{4-[(5-chloro-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1).

1H-NMR (CDCl3) δ 7,73 (1H, d, J=2.2 Hz), 7,19-7,01 (4H, m), 6,97 (1H, d, J=2.2 Hz), 6,12 (1H, Sirs), 3,81 (2H, t, J=6.4 Hz), 2,80 (2H, t, J=6.4 Hz).

Stage 3. 2-[4-(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-5-chloro-2-pyridinyl)amino]phenyl}ethanol (step 2).

TLC Rf = 0,43(hexane/ethyl acetate = 2:1).

Stage 4. 2-[4-(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(6-chloro-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 8,23 (1H, d, J=2.1 Hz), 8,01 (1H,d, J=2.1 Hz), was 7.45 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,4 Hz), to 7.09 (1H, s)to 3.92 (2H, t, J=6.4 Hz), 2,95 (2H, t, J=6.4 Hz), and 2.83 (2H, q, J=7.4 Hz), of 1.36 (3H, t, J=7,4 Hz).

Stage 5. 2-[4(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(6-chloro-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ of 8.25 (1H, d, J=2.2 Hz), 8,02 (1H, d, J=2.2 Hz), 7,46 (2H, d, J=8,3 Hz), 7,35 (2H, d, J=8,3 Hz), of 3.60 (2H, t, J=7,2 Hz)of 3.00 (2H, t, J=7.2 Hz), 2,84 (2H, q, J=7.5 Hz), of 1.37 (3H, t, J=7.5 Hz).

Stage 6. 2-[4-(6-Chloro-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(6-chloro-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ by 8.22 (1H, d, J=2.1 Hz), 8,01 (1H, d, J=2.1 Hz), was 7.45 (2H, d, J=8,2 Hz), 7,32 (2H, d, J=8,2 Hz), 3,13-is 3.08 (2H, m), 2.95 and-2,78 (4H, m)of 1.36 (3H, t, J=7,6 Hz).

Stage 7. 6-Chloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(6-chloro-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ to 8.20 (1H, d, J=2.2 Hz), 8,03 (1H, d, J=2.2 Hz), to 7.77 (2H, d, J=8.1 Hz), 7,38-7,27 (6H, m), 6,51-6,48 (1H, m), 3,57-3,50 (2, m), 2,90 (2H, t, J=6.8 Hz), of 2.81 (2H, t, J=7.5 Hz), of 1.34 (3H, t, J=7.5 Hz).

Example 33

Sodium salt of 6-chloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino]carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described in example 2 from 6-chloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (example 32).

1H-NMR (DMSO-d6) δ 8,24-8,21 (2H, m), 7,60 (2H, d, J=8.1 Hz), 7,42-7,34 (4H, m), 7,12 (2H, d, J=8.1 Hz), of 3.13 (2H, m), 2,81-2,69 (4H, m), and 2.27 (3H, s)of 1.24 (3H, t, J=7.4 Hz); IR (KBr) Vmax1597, 1516, 1421, 1375, 1246, 1128, 1084 cm-1.

Example 34

2-Ethyl-5,6-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 2-{4-[(5,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

A mixture of 2-chloro-5,6-dimethyl-3-nitropyridine (Godard, A.; Rocca, P.; Pomel, V.;et al.J.Were obtained. Chem., 1996, 517, 25.; Rocca, P.; Marsais, F.; Godard, A.; et al.Tetrahedron Lett., 1993, 34, 2937, 3,3 g, 17.5 mmol), 4-aminophenylacetamido alcohol (3.6 g, to 26.3 mmol) and 2,6-lutidine (3,7 ml) in toluene (80 ml) was stirred at the boiling point under reflux for 19 hours. The mixture was diluted with ethyl acetate (100 ml) and washed with 1 N. aqueous solution of NaOH (50 ml) and saturated saline (50 ml). The organic layer was dried (Na2SO4) and concentrated. Was purified using flash chromatography and on a column of silica gel, elwira hexane/ethyl acetate (1:1), to obtain 1.8 g (37%) of the compound indicated in the title, in the form of an orange solid.1H-NMR (CDCl3) δ 8,24 (1H, Shir. C)to 7.68 (2H, d, J=8.6 Hz), 7,24 (2H, d, J=8.6 Hz), 3,88 (2H, dt, J=6,1, 7,6 Hz), is 2.88 (2H, t, J=7,6 Hz), 2.49 USD (3H, s), and 2.26 (3H, s), 1,43 (1H, t, J=6,1 Hz).

Stage 2. 2-{4-[(3-Amino-5,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-{4-[(5,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1).

1H-NMR (CDCl3) δ 6,97 (2H, d, J=8,4 Hz), 6,92 (2H, d, J=8,4 Hz), of 6.71 (1H, s), from 6.22 (1H, Shir. C)to 3.67 (2H, t, J=6.8 Hz), 2,68 (2H, t, J=6,8 Hz)to 2.29 (3H, s)a 2.12 (3H, s).

Stage 3. 2-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-5,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 2) and propionitrile.

1H-NMR (CDCl3) δ of 7.75 (1H, Shir. C), 7,42 (2H, d, J=8.6 Hz), 7,34 (2H, d, J=8.6 Hz), 4,37 (2H, t, J=6.6 Hz), 3,05 (2H, t, J=6.6 Hz), 2,80 (2H, q, J=7,6 Hz), 2.49 USD (3H, s), of 2.38 (3H, s), 2,37-of 2.28 (2H, m)of 1.34 (3H, t, J=7,6 Hz), 1,18 (3H, t, J=7.5 Hz).

Stage 4. 2-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-e is Il-5,6-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropylamine (stage 3).

MS (ESI) m/z 296 (M+H)+;1H-NMR (CDCl3) δ of 7.75 (1H, Shir. C)the 7.43 (2H, d, J=8.6 Hz), 7,33 (2H, d, J=8.6 Hz), 3,92 (2H, shirt, J=6.6 Hz), of 2.97 (2H, t, J=6.6 Hz), 2,80 (2H, q, J=7,6 Hz), 2.49 USD (3H, s), of 2.38 (3H, s)of 1.34 (3H, t, J=7,6 Hz).

Stage 5. 3-[4-(2-Chloroethyl)phenyl]-2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ of 7.75 (1H, Shir. C)the 7.43 (2H, d, J=8.6 Hz), was 7.36 (2H, d, J=8.6 Hz), 3,80 (2H, t, J=7,3 Hz), 3,18 (2H, t, J=7,3 Hz), of 2.81 (2H, q, J=7,6 Hz)of 2.50 (3H, s), of 2.38 (3H, s)of 1.34 (3H, t, J=7,6 Hz).

Stage 6. 2-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine (stage 5).

1H-NMR (CDCl3) δ of 7.75 (1H, Shir. C), 7,42 (2H, d, J=8,4 Hz), was 7.36 (2H, d, J=8,4 Hz), of 3.60 (2H, t, J=7,3 Hz)of 3.00 (2H, t, J=7,3 Hz), 2,80 (2H, q, J=7,6 Hz), 2.49 USD (3H, s), of 2.38 (3H, s)of 1.34 (3H, t, J=7,6 Hz).

Stage 7. 2-[4-(2-Ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 6).

1H-NMR (CDCl3) ; 7,76 (1H, Shir. C)7,41 (2H, d, J=7.9 Hz), 7,33 (2H, d, J=7.9 Hz), of 3.12 (2H, t, J=6.9 Hz), 2,95 (2H, t, J=6.9 Hz), and 2.79 (2H, q, J=6.9 Hz), 2,47 (3H, s), is 2.37 (3H, s)of 1.33 (3H, t, J=6.9 Hz).

Stage 8. 2-Ethyl-5,6-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 7).

MS (ESI) m/z 492 (M+H)+;1H-NMR (CDCl3) δ 7,87 (2H, d, J=8,2 Hz), 7,79 (1H, s), 7,31 (2H, d, J=8,2 Hz), 7.23 percent (2H, d, J=8.1 Hz), to 7.15 (2H, d, J=8.1 Hz), 6,24 (1H, m), 3,51 (2H, m), 2,85 (2H, t, J=6,1 Hz)to 2.66 (2H, q, J=7.4 Hz), 2,39 (3H, s), of 2.38 (3H, s), a 2.36 (3H, s), 1,25 (3H, t, J=7,4 Hz).

Example 35

Sodium salt of 2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]aminocarbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (example 34). TPL 156,0-158,5°C;1H-NMR (DMSO-d6) δ 7,58 (1H, s)of 7.48 (2H, d, J=8.1 Hz), 7,19-7,13 (4H, m), 6,98 (2H, q, j 1=8,1 Hz), 6,01 (1H, Sirs), 3,15 are 2.98 (2H, m), 2,59 is 2.55 (2H, m)of 2.50 (2H, q, J=7,6 Hz), 2,19 (3H, s)to 2.13 (3H, s), is 2.09 (3H, C)a 1.01 (3H, t, J=7,6 Hz).

Example 36

2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl(4-were)sulfonylureas

Soy is inania, specified in the header received in accordance with the method described in example 3 from 2-[4-(2-ethyl-5,6-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 4 of example 34).

MS (ESI) m/z 493 (M+H)+;1H-NMR (DMSO-d6) δ 7,94 (2H, d, J=8,4 Hz), 7,78 (1H, s), 7,33 (2H, d, J=8.1 Hz), 7,25-7,16 (4H, m), 4,35 (2H, t, J=6.6 Hz), with 2.93 (2H, t, J=6.6 Hz), 2,73 (2H, q, J=7.4 Hz), the 2.46 (3H, s), 2,43 (3H, s), 2,39 (3H, ), of 1.28 (3H, t, J=7,4 Hz).

Example 37

5,6-dichloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 2-{4-[(5,6-Dichloro-3-nitro-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 34, from 3-nitro-2,5,6-trichloropyridine (Horn, U.; It, F.; Weis, C. D.Helv. Chim. Acta., 1976, 59, 190) and 4-aminophenylacetamido alcohol.

MS (EI) m/z 327 (M+);1H-NMR (CDCl3) δ 10,11 (1H, Shir. C)8,58 (1H, s), EUR 7.57 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), 3,93-3,86 (2H, m), 2,89 (2H, t, J=6.6 Hz).

Stage 2. 2-{4-[(3-Amino-5,6-dichloro-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-{4-[(5,6-dichloro-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1).

MS (EI) m/z 297 (M+).

Stage 3. 2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropane

The connection specified in the header received with the availa able scientific C of the way, described for stage 5 of example 1 from 2-{4-[(3-amino-5,6-dichloro-2-pyridinyl)amino]phenyl}ethanol (step 2) and propionitrile.

TLC Rf= 0,63 (ethyl acetate/hexane = 1:1).

Stage 4. 2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropylamine (stage 3).

MS (EI) m/z 335 (M+);1H-NMR (CDCl3) δ 8,11 (1H, s), 7,46 (2H, d, J=8.1 Hz), 7,32 (2H, d, J=8.1 Hz), of 3.97 (2H, t, J=6.2 Hz), 2,99 (2H, t, J=6.2 Hz), 2,82 (2H, q, J=7.5 Hz), of 1.36 (3H, t, J=7.5 Hz).

Stage 5. 3-[4-(2-Chloroethyl)phenyl]-2-ethyl-5,6-dichloro-3-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ 8,13 (1H, s), was 7.45 (2H, d, J=8.1 Hz), 7,33 (2H, d, J=8.1 Hz), 3,80 (2H, t, J=7.2 Hz), 3,19 (2H, t, J=7.2 Hz), 2,82 (2H, q, J=7.5 Hz), of 1.36 (3H, t, J=7.5 Hz).

Stage 6. 2-4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridine (stage 5).

MS (EI) m/z 360 (M+);1H-NMR (CDCl3) δ 8,11 (1H, s), 7,44 (2H, d, J=8,4 Hz) 7,33 (2H, d, J=8,4 Hz), 3,61 (2H, t, J=7,2 Hz)of 3.00 (2H, t, J=7.2 Hz), of 2.81 (2H, q, J=7.5 Hz), of 1.35 (3H, t, J=7.5 Hz).

Stage 7. 2-[4-(2-Ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine

To a solution of 2-[4-(2-ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 6,69 mg, 0.2 mmol) in methanol (10 ml) was added Lindlar catalyst (Lindlar) (5 mg). The resulting mixture was stirred for 6 hours in an atmosphere of hydrogen. The mixture was filtered through a thick layer of celite and the filtrate was concentrated. Was purified using preparative TLC (dichloromethane/methanol = 10:1) to give 60 mg (94%) of the compound indicated in the title, in the form of a colorless solid. MS (EI) m/z 334 (M+);1H-NMR (CDCl3) δ 8,11 (1H, s), the 7.43 (2H, d, J=8,3 Hz), 7,30 (2H, d, J=8,3 Hz), 3,11 (2H, t, J=6.6 Hz), of 2.92 (2H, t, J=6.6 Hz), of 2.81 (2H, q, J=7.5 Hz), of 1.35 (3H, t, J=7.5 Hz).

Stage 8. 5,6-Dichloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-5,6-dichloro-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 7). TPL 188,0-189,0°C; MS (ESI) m/z 532 (M+H)+;1H-NMR (CDCl3) δ to 8.12 (1H, s), to 7.77 (2H, d, J=8,4 Hz), of 7.36-of 7.25 (6H, m), of 6.49 (1H, shirt, J=5,9 Hz), of 3.54 (2H, dt, J=5,9, 7,0 Hz), 2,90 (2H, t, J=7.0 Hz), 2,78 (2H, q, J=7.5 Hz), is 2.41 (3H, s)of 1.33 (3H, t, J=7.5 Hz,).

Example 38

5-chloro-2-ethyl-6-methyl-3-(4-{2-[({[(4-methylp the Nile)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b] pyridine

Stage 1. 2-{4-[(6-Chloro-5-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 34, from 2,6-dichloro-5-methyl-3-nitropyridine (Horn, U.; It, F.; Weis, C. D.Helv. Chim. Acta., 1976, 59, 190) and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ of 10.05 (1H, Shir. C)to 8.34 (1H, s), EUR 7.57 (2H, d, J=7,7 Hz), 7,24 (2H, d, J=7,7 Hz), 3,86 (2H, t, J=5,9 Hz), 2,87 (2H, t, J=5,9 Hz), of 2.33 (3H, s).

Stage 2. 2-{4-[(3-Amino-6-chloro-5-methyl-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-{4-[(6-chloro-5-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1).

1H-NMR (CDCl3) δ 7,14-was 7.08 (4H, m)6,86 (1H, s), 6,21 (1H, Shir. C), with 3.79 (2H, t, J=6.4 Hz), 2,78 (2H, t, J=6.4 Hz), of 2.33 (3H, s).

Stage 3. 2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-6-chloro-5-methyl-2-pyridinyl)amino]phenyl}ethanol (step 2) and propionitrile.

MS (EI) m/z 371 (M).

Stage 4. 2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(5-chloro-2-ethyl-6-methyl-Ninidze[4,5-b]pyridine-3-yl)phenyl]ethylpropylamine (stage 3).

MS (EI) m/z 315 (M+);1H-NMR (CDCl3) δ 7,87 (1H, s), 7,42 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz)to 3.92 (2H, t, J=6.6 Hz), 2,96 (2H, t, J=6.6 Hz), and 2.79 (2H, q, J=7,7 Hz), 2,47 (3H, s)of 1.34 (3H, t, J=7,7 Hz).

Stage 5. 3-[4-(2-Chloroethyl)phenyl]-5-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(5-chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 4).

MS (EI) m/z 333 (M+);1H-NMR (CDCl3) δ 7,88 (1H, s), 7,42 (2H, d, J=8,3 Hz), 7,33 (2H, d, J=8,3 Hz), with 3.79 (2H, t, J=7,3 Hz), 3,17 (2H, t, J=7,3 Hz), 2,80 (2H, q, J=7.0 Hz), 2,48 (3H, s)of 1.35 (3H, t, J=7,0 Hz).

Stage 6. 2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 3-[4-(2-chloroethyl)phenyl]-5-chloro-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine (stage 5).

1H-NMR (CDCl3) δ 7,87 (1H, s), 7,42 (2H, d, J=8,4 Hz), 7,34 (2H, d, J=8,4 Hz)and 3.59 (2H, t, J=7,1 Hz), 2,98 (2H, t, J=7,1 Hz), of 2.81 (2H, q, J=7,6 Hz), 2,48 (3H, s)of 1.35 (3H, t, J=7,6 Hz).

Stage 7. 2-[4-(5-Chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]-b]pyridine-3-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 2-[4-(5-chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 6).

1H-NMR (CDCl3) δ 7,88(1H, C), 7,40 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,3 Hz), of 3.07 (2H, t, J=6.8 Hz), 2,87 (2H, t, J=6.8 Hz), 2,80 (2H, q, J=7,3 Hz), 2,48 (3H, s)of 1.34 (3H, t, J=7,3 Hz).

Stage 8. 5-Chloro-2-ethyl-6-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(5-chloro-2-ethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 7). TPL 205-206°C; MS (ESI) m/z 512 (M+H)+;1H-NMR (CDCl3) δ of 7.90 (1H, s), 7,79 (2H, d, J=8,3 Hz), 7,33-of 7.23 (6H, m), 6,46 (1H, Sirs), 3,55-to 3.49 (2H, m), is 2.88 (2H, t, J=6.8 Hz), was 2.76 (2H, q, J=7,6 Hz), 2,48 (3H, s)to 2.41 (3H, s)is 1.31 (3H, t, J=7,6 Hz).

Example 39

5-Chloro-2-ethyl-7-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 2-[(6-Chloro-4-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 34, from 2,6-dichloro-4-methyl-3-nitropyridine (Inubushi, A.; Kawano,E.; Shimada,Ke.; et al.PCT Int. Appl., WO 9802442 (1998)) and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ of 9.56 (1H, s), 7,49 (2H, d, J=8,4 Hz), 7,22 (2H, d, J=8,4 Hz), only 6.64 (1H, s), a-3.84 (2H, t, J=6.4 Hz), 2,84 (2H, t, J=6.4 Hz), to 2.55 (3H, s).

Stage 2. 2-{4-[(3-Amino-6-chloro-4-methyl-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described on the I stage 2 of example 28, on the basis of 2-{4-[(6-chloro-4-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1).

MS (EI) m/z 277 (M+).

Stage 3. 2-[4-(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-6-chloro-4-methyl-2-pyridinyl)amino]phenyl}ethanol (step 2).

TLC Rf = 0,46 (ethyl acetate/hexane = 1:1).

Stage 4. 2-[4-(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]-pyridine-3-yl)phenylethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropylamine (stage 3).

MS (EI) m/z 315 (M+);1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,4 Hz), 7,07 (1H, s), 4,00-of 3.85 (2H, m), of 2.97 (2H, t, J=6.6 Hz), and 2.83 (2H, q, J=7.5 Hz), 2,68 (3H, s)of 1.30 (3H, t, J=7.5 Hz).

Stage 5. 3-[4-(2-Chloroethyl)phenyl]-5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8.1 Hz), 7,33 (2H, d, J=8.1 Hz), 7,07 (1H, s), with 3.79 (2H, t, J=7,3 Hz), 3,17 (2H, t, J=7,3 Hz), and 2.83 (2H, q, J=7.5 Hz), 2,68 (3H, s)of 1.30 (3H, t, J=7.5 Hz).

Stage 6. 2-[4-(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]tilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 3-[4-(2-chloroethyl)phenyl]-5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine (stage 5).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8.6 Hz), 7,33 (2H, d, J=8.6 Hz), 7,07 (1H, s), of 3.56 (2H, t, J=7.2 Hz), 2,99 (2H, t, J=7,2 Hz), and 2.83 (2H, q, J=7.5 Hz), 2,68 (3H, s)of 1.29 (3H, t, J=7.5 Hz).

Stage 7. 2-[(5-Chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-3-ylphenyl]ethylamine

To a stirred solution of 2-[4-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 6, 57 mg, 0.2 mmol) in THF (5 ml) was added triphenylphosphine (47 mg, 0.2 mmol) at room temperature. After complete addition, stirring was continued for further 3 hours at the same temperature. To the mixture was added water (0.1 ml) at room temperature, and the reaction mixture was stirred at room temperature for 20 hours. The mixture was concentrated to obtain a colorless solid. Was purified using preparative TLC (dichloromethane/methanol/triethylamine = 10:1:1) to give 13 mg (25%) of the compound indicated in the title, in the form of a colorless solid: MS (EI) m/z 313 (M+).

Stage 8. 5-Chloro-2-ethyl-7-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for study is 10 of example 1, on the basis of 2-[4-(5-chloro-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 7).

MS (ESI) m/z 512 (M+H)+;1H-NMR (CDCl3) δ 7,80 (2H, d, J=8,4 Hz), 7,34-of 7.23 (6H, m), to 7.09 (1H, s), 6,37 (1H, Sirs), 3,56-to 3.52 (2H, m), is 2.88 (2H, t, J=6.8 Hz), 2,77 (2H, q, J=7.5 Hz), 2,69 (3H, s), 2,42 (3H, s)of 1.26 (3H, t, J=7.5 Hz).

Example 40

2-Ethyl-7-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-6-[(methylsulphonyl)amino]-3H-imidazo[4,5-b]pyridine

Stage 1. 2-{4-[(4-Methyl-3,5-dinitro-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2-chloro-4-methyl-3,5-dinitropyridine (Czuba,Rocz. Chem., 1967, 41, 479) and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3)) δ of 8.90 (1H, s), and 8.50 (1H, Sirs), 7,40 (2H, d, J=8,4 Hz), 7.23 percent (2H, d, J=8,4 Hz), 3,82 (2H, t, J=6.6 Hz), 2,84 (2H, t, J=6.6 Hz), 2,62 (3H, s).

Stage 2. 2-{4-[(3-Amino-4-methyl-5-nitro-2-pyridinyl)amino]phenyl}ethanol

To a stirred solution of 2-{4-[(4-methyl-3,5-dinitro-2-pyridinyl)amino]phenyl}ethanol (step 1, 4,2 g of 13.1 mmol), triethylamine (9.6 ml, for 68.9 mmol), 10% Pd-C (624 mg, 0.59 mmol) in acetonitrile (14 ml) was added dropwise formic acid (2.3 ml, 61,0 mmol) in acetonitrile (6.2 ml) at 0°C for 30 minutes. After stirring at room temperature for 5 hours the mixture was filtered through a thick layer of celite and the filtrate was concentrated, the Residue was dissolved in dichloromethane (100 ml). The solution was washed 1 N. aqueous NaOH (50 ml), saturated brine (50 ml), dried (MgSO4) and concentrated. Was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to give 2.2 g (60%) of the compound indicated in the title, in the form of red crystals:

1H-NMR (CDCl3) δ 8,42 (1H, s), 7,42 (2H, d, J=8,4 Hz), 7,21 (2H, d, J=8,4 Hz), 6,7 (1H, Sirs), 3,85 (2H, t, J=6.4 Hz), of 2.86 (2H, t, J=6.6 Hz), 2,47 (3H, s).

Stage 3. 2-[4-(2-Ethyl-7-methyl-6-nitro-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-4-methyl-5-nitro-2-pyridinyl)amino]phenyl}ethanol (step 2) and propionitrile.

1H-NMR (CDCl3) δ 9,03 (1H, s)of 7.48 (2H, d, J=8.6 Hz), 7,33 (2H, d, J=8,4 Hz), to 4.38 (2H, t, 3=6.9 Hz), of 3.07 (2H, t, J=6.9 Hz), 3,03 (3H, s), 2,87 (2H, q, J=7,6 Hz), 2,35 (2H, q, J=7,6 Hz)of 1.35 (3H, t, J=7,4 Hz)of 1.13 (3H, t, J=7,4 Hz).

Stage 4. 2-[4-(6-Amino-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropane

A suspension of 2-[4-(2-ethyl-7-methyl-6-nitro-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropylamine (stage 3, 2.5 g, 6.6 mmol), 10% Pd-C (250 mg, 0.23 mmol) in methanol (100 ml) was stirred in hydrogen atmosphere for 2 hours. The suspension was filtered through a thick layer of celite, and the filtrate was concentrated to obtain 2.4 g (99%) of the compounds indicated the data in the header, in the form of a brown oil.1H-NMR (CDCl3) δ of 7.82 (1H, s), 7,41 (2H, d, J=8,2 Hz), 7,32 (2H, d, J=8,4 Hz), 4,35 (2H, t, J=7.0 Hz), 3,51 (2H, Sirs), 3,03 (2H, t, J=7.0 Hz), 2,82 (2H, q, J=7.5 Hz), 2,53 (3H, s)to 2.35 (2H, q, J=7.5 Hz), 1,29 (3H, t, J=7.5 Hz), the 1.44 (3H, t, J=7.5 Hz).

Stage 5. 2-(4-{2-Ethyl-7-methyl-6-[(methylsulphonyl)amino]-3H-imidazo[4,5-b]pyridine-3-yl}phenyl)ethylpropane

To a stirred solution of 2-[4-(6-amino-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropylamine (stage 4, 1.0 g, 3.0 mmol) and pyridine (280 mg, 3.5 mmol) in dichloromethane (18 ml) was added methanesulfonyl chloride (372 mg, 3.3 mmol) at 0°C and the mixture was stirred at room temperature for 16 hours. The reaction extinguished with water (10 ml)and the mixture was extracted with dichloromethane (50 ml). The organic layer was washed with saturated saline (50 ml), dried (MgSO4) and concentrated. Was purified using flash chromatography on a column of silica gel, elwira with ethyl acetate (gradient elution from 1:1 to 1:2) to give 890 mg (70%) of the compound indicated in the title, in the form of an amber oil.1H-NMR (CDCl3) δ compared to 8.26 (1H, s), the 7.43 (2H, d, J=8,4 Hz), 7,32 (2H, d, J=8,2 Hz), 7,00 (1H, Sirs), 4,35 (2H, t, J=7.0 Hz), 3,03-a 3.01 (5H, m), 2,85 (2H, q, J=7.5 Hz), a 2.75 (3H, s)to 2.35 (2H, q, J=7.5 Hz), of 1.30 (3H, t, J=7.5 Hz), to 1.14 (3H, t, J=7.5 Hz).

Stage 6. N-{2-Ethyl-3-[4-(2-hydroxyethyl)phenyl]-7-methyl-3H-imidazo[4,5-6]methanesulfonamide

The connection specified in the header received in accordance with the by procedure, described for stage 6 of example 1 from 2-(4-{2-ethyl-7-methyl-6-[(methylsulphonyl)amino]-3H-imidazo[4,5-b]pyridine-3-yl}phenyl)ethylpropylamine (stage 5).

1H-NMR (CDCl3) δ by 8.22 (1H, s), 7,46 (2H, d, J=8,2 Hz), 7,31 (2H, d, J=8,4 Hz), of 6.52 (1H, Sirs), 3,93 (2H, t, J=6.6 Hz), 3,03 (3H, s), of 2.97 (2H, t, J=6.6 Hz), 2,85 (2H, q, J=7,6 Hz), was 2.76 (3H, s)of 1.32 (3H, t, J=7,4 Hz).

Stage 7. N-{3-[4-(2-Chloroethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-6-yl}methanesulfonamide

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from N- {2-ethyl-3-[4-(2-hydroxyethyl)phenyl]-7-methyl-3H-imidazo[4,5-b]pyridine-6-yl}methanesulfonamide (stage 6).

TLC Rf = 0.40 in (ethyl acetate).

Stage 8 N-{3-[4-(2-Azidoethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-6-yl}methanesulfonamide

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from N-3-[4-(2-chloroethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-6-yl}methanesulfonamide (stage 7).

1H-NMR (CDCl3) δ compared to 8.26 (1H, s), 7,44 (2H, d, J=8.1 Hz), 7,34 (2H, d, J=8.1 Hz), of 6.65 (1H, Sirs)and 3.59 (2H, t, J=7.0 Hz), 3,03 (3H, s)to 2.99 (2H, t, J=7,1 Hz), of 2.86 (2H, q, J=7.4 Hz), a 2.75 (3H, s)is 1.31 (3H, t, J=7.5 Hz).

Stage 9. N-{3-[4-(2-amino-ethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-6-yl}methanesulfonamide

The connection specified in the header received in accordance with the method described for stage 9 of example 1, recognize the I N-3-[4-(2-azidoethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-6-yl}methanesulfonamide (stage 8).

TLC Rf = 0,05 (ethyl acetate).

Stage 10. 2-Ethyl-7-methyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-6-[(methylsulphonyl)amino]-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from N-{3-[4-(2-amino-ethyl)phenyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-6-yl}methanesulfonamide (stage 9).

TPL 166°C; MS (ESI) m/z 571,25 (M+H)+;1H-NMR (CDCl3) δ is 8.16 (1H, s), 7,81 (2H, d, J=8.1 Hz), 7,31-to 7.18 (6H, m), to 6.39 (1H, Sirs), 3,48-of 3.46 (2H, m)of 3.00 (3H, s), 2,82-2,71 (7H, m), 2,39 (3H, s)of 1.26 (3H, t, J=7.2 Hz).

Example 41

6-Cyano-2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 6-Hydroxy-2,4-dimethylpentanenitrile

To a stirred solution of 6-amino-2,4-dimethylpentanenitrile (Sato, K.; et al.Bull. Chem. Soc. Jpn., 1969,42, 2319, 22,4 g, 152 mmol) in 5% aqueous solution of sulfuric acid (600 ml) was added dropwise a solution of sodium nitrite (25,2 g, 365 mmol) in water (100 ml) at 0°C and the mixture was stirred at room temperature for 16 hours. The precipitate was collected by filtration to obtain 10.2 g (45%) of the connection specified in the header.1H-NMR (DMSO-d6) δ 12,27 (1H, Sirs), 6,17 (1H, s), of 2.38 (3H, s), measuring 2.20 (3H, s).

Stage 2. 6-Hydroxy-2,4-dimethyl-5-nitronicotinic

To a stirred mixture of nitric sour is s (Smokey, 36 ml) and sulfuric acid (18 ml) in one portion was added 6-hydroxy-2,4-dimethylpentanenitrile (stage 1, 9.0 g, of 60.8 mmol) and the mixture was stirred at room temperature. After 1 hour the mixture was poured into water (100 ml) and neutralized 2 N. aqueous solution of NaOH. The precipitate was collected by filtration to obtain 3.2 g (27%) of the connection specified in the header.1H-NMR (DMSO-d6) δ of 2.28 (3H, s), 2,11 (3H, s).

Stage 3. 6-Chloro-2,4-dimethyl-5-nitronicotinic

A mixture of 6-hydroxy-2,4-dimethyl-5-nitronicotinic (stage 2, 3.2 g, of 16.6 mmol) and phosphorus oxychloride (20 ml) was stirred at 100 C for 16 hours. After cooling, the mixture was poured into water (100 ml). The resulting mixture was extracted with dichloromethane (3 x 100 ml). The organic layer was washed with saturated saline (50 ml), dried (MgSO4) and concentrated to obtain 2.3 g (66%) of the compound indicated in the title, in the form of a brown solid.1H-NMR (DMSO-d6) δ 2,82 (3H, s), 2,52 (3H, s).

Stage 4. 6-[4-(2-Hydroxyethyl)aniline]-2,4-dimethyl-5-nitronicotinic

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 6-chloro-2,4-dimethyl-5-nitronicotinic (stage 3) and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 9,37 (1H, Sirs), 7,51 (2H, d, J=8,4 Hz), 7,26 (2H, d, J=8,4 Hz), 3,89-a 3.87 (2H, m), 2,89 (2H, t, J=6.4 Hz), 2,72 (H, C)to 2.65 (3H, s)of 1.46 (1H, t, J=5.8 Hz).

Stage 5. 5-Amino-6-[4-(2-hydroxyethyl)aniline]-2,4-diethylnicotinamide

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 6-[4-(2-hydroxyethyl)aniline]-2,4-dimethyl-5-nitronicotinic (stage 4).

1H-NMR (CDCl3) δ 7,49 (2H, d, J=8.6 Hz), 7,19 (2H, d, J=8,4 Hz), 6,98 (1H, Sirs), 3,89-3,82 (2H, m), 3,11 (2H, Sirs), 2,85 (2H, t, J=6.6 Hz), 2,58 (3H, s), of 2.38 (3H, s)of 1.44 (1H, t, J=5.6 Hz).

Stage 6. 2-[4-(6-cyano-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1, starting from 5-amino-6-[4-(2-hydroxyethyl)aniline]-2,4-dimethylpentanenitrile (stage 5) and propionitrile.

TLC Rf = 0.4 (of hexane/ethyl acetate = 1:1).

Stage 7. 2-Ethyl-3-[4-(2-hydroxyethyl)phenyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(6-cyano-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenylethylamine (stage 6).

1H-NMR (CDCl3) δ 7,46 (2H, d, J=8,2 Hz), 7,31 (2H, d, J=8,2 Hz), 4,01-of 3.94 (2H, m), 3,49-3,47 (1H, m)of 3.00 (2H, t, J=6.3 Hz), of 2.86 (3H, s), and 2.83 (2H, q, J=7.4 Hz), is 2.74 (3H, s)of 1.32 (3H, t, J=7,6 Hz).

Stage 8. 3-[4-(2-Chloraniline]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile

With the unity, specified in the header received in accordance with the method described for stage 7 of example 1 from 2-ethyl-3-[4-(2-hydroxyethyl)phenyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile (stage 7).

TLC Rf= 0.8 in (hexane/ethyl acetate = 1:1).

Stage 9. 3-[4-(2-Azidoethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile (stage 8).

1H-NMR (CDCl3) δ 7,46 (2H, d, J=8.1 Hz), 7,33 (2H, d, J=8,2 Hz), 3,62 (2H, t, J=7,1 Hz), to 3.02 (2H, t, J=7,1 Hz), of 2.86 (3H, s), 2,82 (2H, q, J=7,6 Hz), 2,73 (3H, s)is 1.31 (3H, t, J=7,6 Hz).

Stage 10. 3-[4-(2-amino-ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 3-[4-(2-azidoethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile (stage 9).

TLC Rf = 0,05 (hexane/ethyl acetate = 1:1).

Stage 11. 6-Cyano-2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 3-[4-(2-amino-ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile (one hundred the Oia 10).

TPL 133°C; MS (ESI) m/z 517,12 (M+H)+;1H-NMR (CDCl3) δ for 7.78 (2H, d, J=8.1 Hz), 7,37-of 7.25 (6H, m), 6,46 (1H, Sirs), 3,56-of 3.54 (2H, m), of 2.92 (2H, t, J=7.0 Hz), 2,85 (3H, s), was 2.76 (2H, q, J=6.0 Hz), 2,68 (3H, s)to 2.41 (3H, s)of 1.29 (3H, t, J=6.2 Hz).

Example 42

2-Ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine

Stage 1. 2-{4-[(2,6-Dimethyl-3-nitro-4-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 4-chloro-2,6-dimethyl-3-nitropyridine (Tanaka, A.; et al. J. Med. Chem., 1999,41, 4408) and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ a total of 8.74 (1H, Sirs), 7,31 (2H, d, J=8,2 Hz), 7,18 (2H, d, J=8,2 Hz), of 6.68 (1H, s), 3.95 to the 3.89 (2H, m), only 2.91 (2H, t, J=6.6 Hz), of 2.72 (3H, s), a 2.36 (3H, s).

Stage 2. 2-{4-[(3-Amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 2-{4-[(2,6-dimethyl-3-nitro-4-pyridinyl)amino]phenyl}ethanol (step 1).

1H-NMR (CDCl3) δ 7,19 (2H, d, J=8,4 Hz), 7,01 (2H, d, J=8.6 Hz), 6,76 (1H, s), of 5.82 (1H, Sirs), a 3.87 (2H, t, J=6.4 Hz), 3,18 (2H, Sirs), 2,85 (2H, t, J=6.4 Hz), 2,44 (3H, s)to 2.35 (3H, s).

Stage 3. 2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo-[4,5-c]pyridin-1-yl)phenyl]ethylpropane

A mixture of 2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2, 2.4 g, 9.3 mmol), propionic dioxide is IDA (13 ml,101 mmol) and propionic acid (13 ml, 174 mmol) was stirred at 120°C for 16 hours. After cooling, the mixture was diluted 2 N. aqueous solution of NaOH (150 ml) and was extracted with dichloromethane (3 x 150 ml). The combined organic extracts were washed with saturated brine (50 ml), dried (MgSO4) and concentrated. Was purified using flash chromatography on a column of silica gel, elwira dichloromethane/methanol (gradient elution from 20:1 to 10:1) to give 2.3 g (69%) of the compound indicated in the title, in the form of a brown oil.1H-NMR (CDCl3) δ 7,44 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8,2 Hz), 6,72 (1H, s), to 4.38 (2H, t, J=6.9 Hz), of 3.07 (2H, t, J=7,1 Hz), is 2.88 (3H, s), 2,82 (2H, q, J=7,6 Hz), of 2.56 (3H, s), a 2.36 (2H, q, J=7,6 Hz), 1,29 (3H, t, J=7,6 Hz)and 1.15 (3H, t, J=7,7 Hz).

Stage 4. 2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 7,46 (2H, d, J=8.1 Hz), 7,26 (2H, d, J=8.1 Hz), 6.73 x (1H, s), of 4.00 (2H, t, J=6.6 Hz), a 3.01 (2H, t, J=6.4 Hz), is 2.88 (3H, s), of 2.81 (2H, q, J=7.5 Hz), of 2.54 (3H, s)of 1.29 (3H, t, J=7.5 Hz).

Stage 5. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-4,6-d is methyl-1 H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol (step 4).

TLC Rf = 0.1 (ethyl acetate).

Stage 6. 1-[4-(2-Azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine (stage 5).

1H-NMR (CDCl3) δ 7,46 (2H, d, J=8.0 Hz), 7,29 (2H, d, J=7,7 Hz), 6,72 (1H, s), 3,62 (2H, t, J=6.9 Hz), to 3.02 (2H, t, J=6.9 Hz), is 2.88 (3H, s), of 2.81 (2H, q, J=7.4 Hz), of 2.56 (3H, s)of 1.29 (3H, t, J=7,6 Hz).

Stage 7. 2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 1-[4-(2-azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-imidazo[4,5-C]pyridine (stage 6).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,2 Hz), 7,26 (2H, d, J=8,4 Hz), was 6.73 (1H, s), is 3.08 (2H, t, J=6.9 Hz), 2,90-2,78 (4H, m), is 2.88 (3H, s), of 2.56 (3H, s)of 1.30 (3H, t, J=7,3 Hz).

Stage 8. 2-Ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylamine (step 7).

TPL 143°C; MS (ESI) m/z 492,12 (M+H)+;1H-NMR (CDCl3) δ to 7.77 (2H, d, J=8,3 Hz), 7,38 (2H, d, J=8,4 Hz) to 7.25 (2H, d, J=8,4 Hz), 7,20 (2H, d, J=8,4 Hz), 6,77 (1H, s), to 3.58-3,51 (2H, m), of 2.92 (2H, t, J=7.0 Hz), 2,89 (3H, s), and 2.79 (2H, q, J=7.5 Hz), 2,53 (3H, s), of 2.38 (3H, s)of 1.28 (3H, t, J=7.5 Hz).

Example 43. 2-Ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[4-(2-Nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2-chloronitrobenzene and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ for 9.47 (1H, s), 8,21 (1H, DD, J=1,5, 8,8 Hz), 7,40-7,16 (6H, m), for 6.81-6,70 (1H, m), 3,91 (2H, t, J=6.5 Hz), 2,90 (2H, t, J=6.5 Hz).

Stage 2. 2-[4-(2-Aminoaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 2-[4-(2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,15-of 6.96 (4H, m), 6,82 of 6.66 (4H, m), 5,14 (1H, s), 3,80 (2H, t, J=6,6 Hz in), 3.75 (2H, Sirs), and 2.79 (2H, t, J=6.6 Hz).

Stage 3. 2-[4-(2-Ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-aminoaniline)phenyl]ethanol (step 2) and propionitrile.

MS (EI) m/z 322 (M+);1H-NMR (CDCl3) δ 7,79 (1H, d, J=7,7 Hz), the 7.43 (2H, d, J=8.6 Hz), 7,34-7,06 (5H, m), to 4.38 (2H, t, J=7.0 Hz), of 3.07 (2H, t, 3=1.0 Hz), 2,80 (2H, q, J=7.5 Hz), a 2.36 (2H, q, J=7,6 Hz)of 1.35 (3H, t, J=7.5 Hz), 1,15 (3H, t, J=7,6 Hz).

Stage . 2-[4-(2-Ethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 7,81 to 7.75 (1H, m), 7,45 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,3 Hz), 7,25-was 7.08 (3H, m), 3,98 (2H, t, J=6.5 Hz), of 3.00 (2H, t, J=6.5 Hz), 2,80 (2H, q, J=7.5 Hz), of 1.26 (3H, t, J=7.5 Hz).

Stage 5. 2-[4-(2-Ethyl-1-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

MS (EI) m/z 291(M+);1H-NMR (CDCl3) δ 7,81-7,76 (1H, m), the 7.43 (2H, d, J=8,3 Hz), 7,40-7,06 (5H, m), 3,62 (2H, t, J=6.5 Hz), totaling 3.04 (2H, t, J=6.5 Hz), 2,80 (2H, q, J=7.5 Hz), of 1.27 (3H, t, J=7.5 Hz).

Stage 6. 2-[4-(2-Ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ 7,80-7,74 (1H, m), 7,45-7,06 (7H, m), 3,06 (2H, t, J=6.5 Hz), 2,89 (2H, t, J=6.5 Hz), was 2.76 (2H, q, J=7.5 Hz), of 1.26 (3H, t, J=7.5 Hz).

Stage 7. 2-Ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described is for stage 10 of example 1, on the basis of 2-[4-(2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ of 7.75 (1H, d, J=8,8 Hz), 7,71 (2H, d, J=8,3 Hz), 7,39-7,14 (8H, m), 7,07 (1H, d, J=8,8 Hz), of 6.68 (1H, Sirs), 3,62-of 3.54 (2H, m)to 2.94 (2H, t, J=6.3 Hz), and 2.79 (2H, q, J=7.0 Hz), is 2.41 (3H, s)of 1.33 (3H, t, J=7,0 Hz).

Example 44

2-[4-(2-Ethyl-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4 of example 43).

1H-NMR (CDCl3) δ to 7.93 (2H, d, J=8,3 Hz), 7,85 to 7.75 (2H, m), 7,40-to 7.15 (7H, m), was 7.08 (1H, d, J=8,8 Hz), of 4.77 (1H, Sirs) 4,36 (2H, t, J=6,4 Hz)of 3.00 (2H, t, J=6.4 Hz), 2,78 (2H, q, J=7.0 Hz), 2,44 (3H, s)of 1.32 (3H, t, J=7,0 Hz).

Example 45

4-Methyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-1H-benzimidazole

Stage 1. 2-[4-(3-Methyl-2-nitroaniline)phenyl]ethanol

A mixture of 2-nitro-3-methylaniline (Newman, M.S.; R. KannanJ. Org. Chem., 1976, 41, 3356., 1,9 g, 12.4 mmol), 4-bromophenylacetate alcohol (2.5 g, 12.4 mmol), K2CO3(1.7 g, 12.4 mmol) and CuI (230 mg, 1,24 mmol) were placed in a sealed tube and heated at 200°C for 2 hours. After cooling, the mixture was poured into water (100 ml) and was extracted with ethyl acetate (300 ml). The organic layer was washed 2 N. aqueous NaOH (100 ml) and saturated saline (100 ml), then dried (Na2SO4and concentrated. Was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (1:1), to obtain 700 mg (21%) of the compound indicated in the title, in the form of an orange oil.1H-NMR (CDCl3) δ to 7.77 (1H, Sirs), 7,09 was 7.45 (6H, m), 6,69 (1H, d, J=6.3 Hz), 3,83 (2H, t, J=6.6 Hz), 2,82 (2H, t, J=6.6 Hz), at 2.59 (3H, s).

Stage 2. 2-[4-(2-Amino-3-methylaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 26, from 2-[4-(3-methyl-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,02 (2H, d, J=8,2 Hz), to 6.95 (1H, d, J=7,7 Hz)6,91 (1H, d, J=7,0 Hz), of 6.65 (1H, DD, J=7,0 Hz, 7.7 Hz), 6,62 (2H, d, J=8,2 Hz), 5,15 (1H, Sirs in), 3.75 (2H, t, J=6.6 Hz), 2,73 (2H, t, J=6.6 Hz), 2,19 (3H, s).

Stage 3. 2-[4-(2-Ethyl-4-methyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-amino-3-methylaniline)phenyl]ethanol (step 2) and propionitrile.

TLC Rf = 0,6 (hexane:ethyl acetate = 1:1).

Stage 4. 2-[4-Ethyl-2-methyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-4-methyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 7,41-the 7.43 (2H, m), 7,29 (2H, d, J=6.4 Hz), 7,07 (2H, d, J=6.4 G is), 6,91-6,94 (1H, m), of 3.97 (2H, t, J=6.6 Hz), 2,99 (2H, t, J=6.6 Hz), 2,84 (2H, q, J=7.5 Hz), 2,71 (3H, s)of 1.27 (3H, t, J=7.5 Hz).

Stage 5. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-4-methyl-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-4-methyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), 7,07-to 7.09 (2H, m), 6.90 to-6,95 (1H, m), 3,81 (2H, t, J=7.2 Hz), 3,19 (2H, t, J=7.2 Hz), 2,84 (2H, q, J=7.5 Hz), of 2.72 (3H, s)of 1.27 (3H, t, J=7.5 Hz,).

Stage 6. 2-[4-(2-Ethyl-4-methyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4-methyl-1H-benzimidazole (step 5).

1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8.0 Hz), 7,31 (2H, d, J=8.0 Hz), 7,05-to 7.09 (2H, m), 6.90 to-6,94 (1H, m), 3,61 (2H, t, J=7.0 Hz), a 3.01 (2H, t, J=7.0 Hz), 2,84 (2H, q, J=7.5 Hz), of 2.72 (3H, s)of 1.27 (3H, t, J=7.5 Hz,).

Stage 7. 2-[4-(2-Ethyl-4-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-4-methyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 6).

1H-NMR (CDCl3) δ 7,40 (2H, d, J=8,3 Hz), 7,28 (2H, d, 8,3 Hz),? 7.04 baby mortality-7,11 (2H, m), 6,86-to 6.95 (1H, m), of 3.07 (2H, t, J=6.6 Hz), 2,87 (2H, t, J=6.6 Hz), 2,84 (2H, q, J=7.5 Hz), 2,71 (3H, s)of 1.27 (3H, t, J=7.5 Hz)

Stage 8. 2-Ethyl-4-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-4-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 7).

MS (ESI) m/z 477 (M+N)+;1H-NMR (DMSO-d6) δ the 7.65 (2H, d, J=7,7 Hz), 7,33-7,41 (4H, m), to 7.15 (2H, d, J=7,7 Hz), 7,01-7,07 (2H, m)6,86 (1H, d, J=6.8 Hz), 3,19 (2H, Sirs), 2,68-to 2.74 (4H, m), of 2.56 (3H, s), of 2.28 (3H, s)to 1.21 (3H, t, J=7,1 Hz); IR (KBr) Vmax3390, 1602, 1519, 1429, 1230, 1130, 1085 cm-1.

Example 46

Sodium salt of 4-methyl-2-ethyl-3-(4-{2-[{[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-4-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 45).

1H-NMR (DMSO-d6) δ the 7.65 (2H, d, J=7,7 Hz), 7,33-7,41 (4H, m), to 7.15 (2H, d, J=7,7 Hz), 7,01-7,07 (2H, m)6,86 (1H, d, J=6.8 Hz), 3,19 (2H, Sirs), 2,68-to 2.74 (4H, m), of 2.56 (3H, s), of 2.28 (3H, s)to 1.21 (3H, t, J=7,1 Hz); IR (KBr) Vmax3390, 1602,1519, 1429, 1230,1130, 1085 cm-1.

Example 47

2-Ethyl-5-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[(4-Methyl-2-nitroaniline)phenyl]ethanol

The connection specified in the header, the floor is made in accordance with the method, described for stage 1 of example 45, from 4-methyl-2-nitroaniline and 4-iodinization alcohol.

1H-NMR (CDCl3) δ a 9.35 (1H, Sirs), of 8.00 (1H, s), 7,33-to 7.09 (6H, m), 3,91-to 3.89 (2H, m), 2,89 (2H, t, J=6.4 Hz), is 2.30 (3H, s).

Stage 2. 2-[(2-amino-4-methylaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[(4-methyl-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,05 (2H, d, J=8,3 Hz), 6,98 (1H, d, J=7,7 Hz), 6,67-only 6.64 (3H, m), 6,58-6,55 (1H, m), is 5.06 (1H, Sirs), 3,80-of 3.78 (4H, m), 2,77 (2H, t, J=6.4 Hz), 2,28 (3H, s).

Stage 3. 2-[4-(2-Ethyl-5-methyl-1H-benzimidazole-1-yl]phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[(2-amino-4-methylaniline)phenyl]ethanol (step 2) and propionitrile.

TLC Rf = 0,33 (hexane/ethyl acetate = 2:1).

Stage 4. 2-[4-(2-Ethyl-5-methyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-Ethyl-5-methyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ at 7.55 (1H, s), the 7.43 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), 6,99-to 6.95 (2H, m)to 3.99 (2H, t, J=6,6 Hz)of 3.00 (2H, t, J=6.6 Hz), 2,77 (2H, q, J=7,7 Hz), 2,47 (3H, s)of 1.32 (3H, t, J=7,7 Hz).

Stage 5. 2-[4-(2-Ethyl-5-methyl-1Hbenzimida the ol-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(2-ethyl-5-methyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

TLC Rf = 0,74 (hexane/ethyl acetate = 1:1).

Stage 6. 2-[4-(2-Ethyl-5-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-5-methyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ at 7.55 (1H, s), the 7.43 (2H, d, J=8,2 Hz), 7,29 (2H, d, J=8,2 Hz), 7,01-to 6.95 (2H, m), is 4.85 (2H, Sirs), 3,30-of 3.25 (2H, m), 3,16-3,11 (2H, m), was 2.76 (2H, q, J=7,6 Hz), a 2.45 (3H, s)is 1.31 (3H, t, J=7,6 Hz).

Stage 7. 2-Ethyl-5-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-5-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (DMSO-d6) δ 7,76 (2H, d, J=8,4 Hz), 7,42 and 7.36 (6H, m), 7,00-6,91 (2H, m), 6,53-of 6.49 (1H, m), 3,29-3,24 (2H, m), 2,79-to 2.65 (4H, m), is 2.40 (3H, s), of 2.33 (3H, s)of 1.20 (3H, t, J=7,4 Hz).

Example 48

Sodium salt of 2-ethyl-5-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2, Ref the Dublin core from 2-ethyl-5-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1 H-benzimidazole (example 47).

1H-NMR (DMSO-d6) δ of 7.60 (2H, d, J=7,7 Hz), 7,42-7,33 (5H, m), 7,13 (2H, d, J=7,7 Hz), of 6.96 (2H, m), and 3.16 (2H, m), 2.71 to to 2.66 (4H, m), 2,39 (3H, s), and 2.27 (3H, s)of 1.20 (3H, t, J=7.5 Hz); IR (KBr) Vmax1599, 1514, 1285, 1232, 1130, 1086 cm-1.

Example 49

2-Butyl-5-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]butyl}phenyl)-1H-benzimidazole

Stage 1. 2-[4-(2-Butyl-5-methyl-1H-benzimidazole-1-yl)phenyl]ethylpentane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[(2-amino-4-methylaniline)phenyl]ethanol (step 2 of example 47) and pentanolide.

1H-NMR (CDCl3) δ 7,56-of 7.55 (1H, m), 7,43-7,40 (2H, m), 7,29-7,26 (2H, m), 7,02-6,94 (2H, m), to 4.38 (2H, t, J=6.9 Hz), 3,06 (2H, t, J=6.9 Hz), a 2.75 (2H, t, J=7.4 Hz), 2,47 (3H, s), of 2.33 (2H, t, J=7.4 Hz), 1,80-1.55V (4H, m), 1.41 to to 1.23 (4H, m), 0,94-of 0.83 (6H, m).

Stage 2. 2-[4-(2-Butyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-butyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethylpentane(stage 1).

1H-NMR (CDCl3) δ at 7.55 (1H, s), 7,44 (2H, d, J=8,2 Hz), 7,27 (2H, d, J=8,2 Hz), 7,02-to 6.95 (2H, m)to 3.99 (2H, t, J=6.6 Hz), a 3.01 (2H, t, J=6.6 Hz), a 2.75 (2H, t, J=7,3 Hz), 2,47 (3H, s), 1,79 by 1.68 (2H, m), 1,36-1,23 (2H, m)of 0.85 (3H, t, J=7,3 Hz).

Stage 3. 2-[4-(2-Butyl-6-methyl-1H-benzimidazole-1-yl)phenyl]utilised

Soy is inania, specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(2-butyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 2).

1H-NMR (CDCl3) δ 7,56 (1H, s), 7,42 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 7.03 is-to 6.95 (2H, m), 3,61 (2H, t, J=6.9 Hz), a 3.01 (2H, t, J=6.9 Hz), a 2.75 (2H, t, J=7,3 Hz), 2,47 (3H, s), 1,80 by 1.68 (2H, m), 1,37-1,26 (2H, m)of 0.85 (3H, t, J=7,3 Hz).

Stage 3. 2-[4-(2-Butyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-butyl-6-methyl-1H-benzimidazol-1-yl)phenyl]utilised (stage 2).

1H-NMR (CDCl3) δ at 7.55 (1H, s), 7,40 (2H, d, J=8,3 Hz), 7,26 (2H, d, J=8,3 Hz), 7,01-6,94 (2H, m)and 3.15 (2H, t, J=7,3 Hz), 2,98 (2H, t, J=7,3 Hz), is 2.74 (2H, t, J=7,7 Hz), the 2.46 (3H, s), 1.77 in-1,67 (2H, m), 1,35 of 1.28 (2H, m), is 0.84 (3H, t, J=7,7 Hz).

Stage 4. 2-Butyl-5-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-butyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 3).

1H-NMR (CDCl3) δ 7,76 (2H, d, J=8,2 Hz), 7,54 (1H, m), 7,31-7,21 (6H, m), 7.03 is-to 6.95 (2H, m), 6,67-6,63 (1H, m), 3,61-of 3.54 (2H, m), only 2.91 (2H, t, J=7,1 Hz), 2,73 (2H, t, J=7,3 Hz), 2,47 (3H, s), is 2.40 (3H, s), 1,76-of 1.65 (2H, m), 1,36 of 1.28 (2H, m), or 0.83 (3H, t, J=7,3 Hz).

Example 50

Sodium salt of 2-butyl-5-methyl-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]butyl}phenyl)-1 H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 2-butyl-5-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 49).

TPL 130-140°C;1H-NMR (DMSO-d6) δ to 7.59 (2H, d, J=7.8 Hz), 7,40-7,31 (5H, m), 7,11 (2H, d, J=7.8 Hz), 6,98-6,92 (2H, m)and 3.15 (2H, m), 2.71 to to 2.66 (4H, m), 2,39 (3H, s), and 2.26 (3H, s), 1,67-of 1.57 (2H, m), 1,31-to 1.21 (2H, m)of 0.79 (3H, t, J=7.5 Hz); IR (KBr) Vmax1599, 1514, 1400, 1130, 1086 cm-1.

Example 51

6-Methyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[4-(5-Methyl-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2-fluoro-4-methylnitrobenzene and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 9,51 (1H, Sirs), 8,10 (1H, d, J=8,8 Hz), 7,20-7,31 (4H, m), 6,98 (1H, s), to 6.58 (1H, d, J=8,4 Hz), 3,91 (2H, t, J=6.4 Hz), 2,89 (t, J=6.4 Hz), and 2.27 (3H, s).

Stage 2. 2-[4-(2-Amino-5-methylaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 26, from 2-[4-(5-methyl-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,07 (2H, d, J=8,3 Hz), 6,93 (1H, s), for 6.81 (1H, d, J=8.1 Hz), 6,70-6,72 (3H, m), 3,81 (2H, t, J=6.4 Hz), 3,61 (2H, Sirs), 2,78 (2H, t, J=6.4 Hz), 2,22 (3H, s).

Stage 3. 2-[4-2-Ethyl-6-methyl-1 H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-Amino-5-methylaniline)phenyl]ethanol (step 2) and propionitrile.

1H-NMR (CDCl3) δ to 7.64 (1H, d, J=8,3 Hz), 7,42 (2H, d, J=8.0 Hz), 7,28 (2H, d, J=8.0 Hz), was 7.08 (1H, d, J=8,3 Hz), 6.87 in (1H, s), to 4.38 (2H, t, J=6.9 Hz), 3,06 (2H, t, J=6.9 Hz), was 2.76 2H, q, J=7.5 Hz), is 2.41 (3H, ), a 2.36 (2H, q, J=7,7 Hz)of 1.35 (3H, t, J=7.5 Hz)and 1.15 (3H, t, J=7,7 Hz).

Stage 4. 2-[4-(2-Ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ to 7.64 (1H, d, J=8.1 Hz), was 7.45 (2H, d, J=8.1 Hz), 7,19-7,30 (2H, m), was 7.08 (1H, d, J=8.1 Hz), to 6.88 (1H, s)to 3.99 (2H, t, J=6,6 Hz)of 3.00 (2H, t, J=6.6 Hz), 2,77 (2H, q, J=7,6 Hz), is 2.40 (3H, s), of 1.33 (3H, t, J=7,6 Hz).

Stage 5. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ the 7.65 (1H, d, J=8,2 Hz), the 7.43 (2H, d, J=8,2 Hz), 7,31 (2H, d, J=8,2 Hz), 7,07 (1H, d, J=8,2 Hz), to 6.88 (1H, s), 3,82 (2H, t, J=7.0 Hz), 3,19 (2H, t, 7.0 Hz), 2,77 (2H, q, J=7,6 Hz)to 2.41 (3H, s), of 1.33 (3H, t, J=7,6 Hz).

Stage 6. 2-[4-(2-Ethyl-6-meth is l-1 H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazole (step 5).

1H-NMR (CDCl3) δ to 7.64 (1H, d, J=8,2 Hz), the 7.43 (2H, d, J=8,2 Hz), 7,31 (2H, d, J=8,2 Hz), was 7.08 (1H, d, J=8,2 Hz), 6.87 in (1H, s), 3,62 (2H, t, J=7.0 Hz), a 3.01 (2H, t, J=7.0 Hz), 2,77 (2H, q, J=7,6 Hz), is 2.37 (3H, C)to 1.33 (3H, t, J=7,6 Hz).

Stage 7. 2-[4-(2-Ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 6).

1H-NMR (CDCl3) δ to 7.64 (1H, d, J=8,3 Hz), 7,40 (2H, d, J=8,2 Hz), 7,28 (2H, d, J=8,2 Hz), 7,07 (1H, d, J=8,3 Hz), to 6.88 (1H, s), of 3.07 (2H, Sirs), 2,87 (2H, t, J=6.8 Hz), was 2.76 (2H, q, J=7,6 Hz), is 2.40 (3H, s), 1,33 (3H, t, J=7,6 Hz).

Stage 8. 6-Methyl-2-Ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 7).

1H-NMR (CDCl3) δ 7,73 (2H, d, J=8,3 Hz), 7,66 (1H, d, J=8.0 Hz), 7,27-7,38 (6H, m), to 7.09 (1H, d, J=8.0 Hz), to 6.88 (1H, s), 3,59-3,63 (2H, m), 2,95 (2H, t, J=6.6 Hz), 2,77 (2H, q, J=7.5 Hz), is 2.41 (3H, s), 2,39 (3H, C)of 1.33 (3H, t, J=7.5 Hz).

Example 52

Sodium salt of 6-methyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 6-methyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 51).

TPL 151-165°C;1H-NMR (DMSO-d6) δ to 7.64 (2H, d, J=8.0 Hz), 7,51 (1H, d, J=8,2 Hz), 7,33-7,42 (4H, m), to 7.15 (2H, d, J=8.0 Hz), 7,02 (1H, DD, J=1.4 Hz and 8.2 Hz), 6.87 in (1H, s)3,18 (2H, Sirs), 2,65-2,78 (4H, m), of 2.34 (3H, s), 2,78 (3H, ), to 1.21 (3H, t, J=7,6 Hz).

Example 53

7-Methyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-4-(2-Methyl-6-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 45, from 6-methyl-2-nitroaniline and 4-bromophenylacetate alcohol.

1H-NMR (CDCl3) δ of 8.28 (1H, Sirs), of 7.96 (1H, d, J=8,4 Hz), 7,39-7,44 (1H, m), 7,02 for 7.12 (3H, m), 6,72 (2H, d, J=8,4 Hz), 3,82 (2H, t, J=6.5 Hz), of 2.81 (2H, t, J=6.5 Hz), of 2.08 (3H, s).

Stage 2. 2-[4-(2-Amino-6-methylaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 26, from 2-[4-(2-methyl-6-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 6,97-7,03 (3H, m), of 6.66 (2H, d, J=7,6 Hz), of 6.52 (2H, d, J=7,6 Hz), equal to 4.97 1H, Sirs), 3,86 (2H, Sirs), with 3.79 (2H, t, J=6.4 Hz), was 2.76 (2H, t, J=6,4 Hz)of 2.16 (3H, s).

Stage 3. 2-[4-(2-Ethyl-7-methyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-amino-6-methylaniline)phenyl]ethanol (step 2) and propionitrile.

TLC Rf= 0,6 (hexane:ethyl acetate = 1:1).

Stage 4. 2-[4-(2-Ethyl-7-methyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-7-methyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 7,63 (1H, d, J=8.0 Hz), 7,38-7,41 (2H, m), 7,26-7,31 (2H, m), 7,14 (1H, DD, J=7,4 Hz, 8.0 Hz), 6,91 (1H, d, J=7,4 Hz), 3,98 (2H, t, J=6.6 Hz), a 3.01 (2H, t, J=6.6 Hz), 2,63 (2H, q, J=7.5 Hz), 1,89 (3H, s)is 1.31 (3H, t, J=7.5 Hz).

Stage 5. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-7-methyl-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-7-methyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ to 7.64 (1H, d, J=8.1 Hz), 7,26-7,39 (4H, m), 7,14 (1H, DD, J=7,4 Hz, 8.1 Hz), 6,91 (1H, d, J=7,4 Hz), 3,81 (2H, t, J=7.2 Hz), 3,19 (2H, d, J=7.2 Hz), 2.63 in (2H, q, J=7,6 Hz), a 1.88 (3H, s)of 1.32 (3H, t, J=7,6 Hz).

Stage 6. 2-[4-(2-Ethyl-7-methyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection of the decree is Noah in the header, received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-7-methyl-1H-benzimidazole (step 5).

1H-NMR (CDCl3) δ to 7.64 (1H, d, J=7,4 Hz), 7,39 (2H, d, J=8.0 Hz), 7,31 (2H, d, J=8.0 Hz), 7,14 (1H, DD, J=7,4 Hz, 8.1 Hz), 6,91 (1H, d, J=8.1 Hz), 3,61 (2H, t, J=6.8 Hz), to 3.02 (2H, t, J=6.8 Hz), 2,63 (2H, q, J=a 7.6 Hz), 1,89 (3H, s)is 1.31 (3H, t, J=7.5 Hz).

Stage 7. 2-[4-(2-Ethyl-7-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-7-methyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 6).

1H-NMR (CDCl3) δ to 7.64 (1H, d, J=7.9 Hz), was 7.36 (2H, d, J=8,2 Hz), 7,28 (2H, d, J=8,2 Hz), 7,14 (1H, DD, J=7.5 Hz, 7.9 Hz), 6,91 (1H, d, J=7.5 Hz), 3,06 (2H, t, J=6.8 Hz), 2,87 (2H, t, J=6.8 Hz), 2,63 (2H, q, J=7.5 Hz), 1,89 (3H, s)of 1.32 (3H, t, J=7.5 Hz).

Stage 8. 2-Ethyl-7-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-7-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 7).

MS (ESI) m/z 477 (M+N)+;1H-NMR (CDCl3) δ of 7.75 (2H, d, J=8,3 Hz), a 7.62 (1H, d, J=7.9 Hz), 7,28-7,33 (5H, m), 7,14 (2H, d, J=7,6 Hz)6,91 (1H, d, J=7.9 Hz), 6,72 (1H, Sirs), to 3.58 (2H, d, J=6.8 Hz), with 2.93 (2H, t, J=6.8 Hz), 2,62 (2H, q, J=7,6 Hz)to 2.41 (3H, s)to 1.86 (3H, s)of 1.29 (3H, t, J=7,6 Hz).

Example 54

Natrii what I Sol 7-methyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1 H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-7-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 53).

1H-NMR (DMSO-d6) δ 7,63 (2H, d, J=7,4 Hz), 7,47 (1H, d, J=8.1 Hz), was 7.36 (4H, s), to 7.15 (2H, d, J=7,7 Hz), 7,06 (1H, DD, J=7,2 Hz, 8.1 Hz), 6.87 in (1H, d, J=7,2 Hz), of 5.99 (1H, Sirs), and 3.16 (2H, Sirs), was 2.76 (2H, Sirs), 2,52 (2H, kV, 1=1,6 Hz), 2,28 (3H, s), equal to 1.82 (3H, s)to 1.19 (3H, t, J=7,6 Hz); IR (KBr) Vmax3400, 1610, 1525, 1290, 1132, 1095, 820, 751 cm-1.

Example 55

4-Chloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[(3-Chloro-2-nitroaniline)phenyl]ethanol

A mixture of 2,6-dichloronitrobenzene (Norman, M. H.; Chen, N.; et al.PCT Int. Appl., WO 9940091 (1999)., Spada, A.P.; Fink, C. A.; Myers, M.R.PCT Int. Appl., WO 9205177 (1992)., 6.3 g, is 32.8 mmol), 4-aminophenylacetamido alcohol (4.9 g, 36 mmol) and sodium acetate (3.2 g, or 39.3 mmol) were placed in a sealed tube and heated at 160°C for 3 hours. After cooling, the mixture was poured into water (100 ml) and was extracted with ethyl acetate (300 ml). The organic layer was washed 2 N. aqueous NaOH (100 ml) and saturated saline (100 ml), then dried (Na2SO4) and concentrated. Was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (1:1), obtaining of 4.57 g (72%) connections, specify the CSOs in the header, in the form of a red oil.

1H-NMR (CDCl3) δ 7,09-7,28 (6H, m)6,91 (1H, DD, J=2.0 a, 7,1 Hz), a 3.87 (2H, t, J=6.6 Hz), of 2.86 (2H, t, J=6.6 Hz).

Stage 2. 2-[4-(2-Amino-3-chloroanilino)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[4-(3-chloro-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,06-7,10 (3H, m), 7,00 (1H, DD, J=1.0 Hz, 7.9 Hz), 6,62-of 6.73 (3H, m), 5,16 (1H, Sirs), 4,14 (2H, Sirs), 3,81 (2H, t, J=6,1 Hz), 2,77 (2H, t, J=6,1 Hz).

Stage 3. 2-[4-(4-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-amino-3-chloroanilino)phenyl]ethanol (step 2) and propionitrile.

TLC Rf = 0,5 (hexane:ethyl acetate = 1:1).

Stage 4. 2-[4-(4-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(4-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ was 7.45 (2H, d, J=8.6 Hz), 7,26-7,31 (3H, m), to 7.09 (1H, d, J=7.9 Hz), of 6.96 (1H, DD, J=0.9 Hz, 7.9 Hz), 3,99 (2H, t, J=6,6 Hz)of 3.00 (2H, t, J=6.6 Hz), 2,84 (2H, q, J=7.5 Hz), of 1.30 (3H, t, J=7.5 Hz).

Stage 5. 4-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole

The connection specified in the header received in soo is according to the way described for stage 7 of example 1 from 2-[4-(4-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ was 7.45 (2H, d, J=8.6 Hz), 7,30 (2H, d, J=8.6 Hz), 7,27 (1H, s), 7,10 (1H, d, J=8.1 Hz), 6,98 (1H, d, J=8.1 Hz), 3,81 (2H, t, J=7,1 Hz), 3,19 (2H, t, J=7,1 Hz), 2,84 (2H, q, J=7,6 Hz)is 1.31 (3H, t, J=7,6 Hz).

Stage 6. 2-[4-(4-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 4-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole (step 5).

1H-NMR (CDCl3) δ was 7.45 (2H, d, J=8,2 Hz), 7,29-7,33 (3H, m), 7,10 (1H, DD, J=8,1 Hz, 7.7 Hz), of 6.96 (1H, d, J=7,7 Hz), 3,62 (2H, t, J=7,1 Hz), to 3.02 (2H, t, J=7,1 Hz), 2,84 (2H, q, J=7,6 Hz)of 1.30 (3H, t, J=7,6 Hz).

Stage 7. 2-[4-(4-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 2-[4-(4-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 6).

1H-NMR (CDCl3)) δ 7,42 (2H, d, J=8.1 Hz), 7,29-7,33 (3H, m), to 7.09 (1H, DD, J=7,7 Hz, 7.9 Hz), to 7.99 (1H, d, J=7.9 Hz), of 3.07 (2H, t, J=6.8 Hz), 2,87 (2H, t, J=6.8 Hz), 2,85 (2H, q, J=7,6 Hz)of 1.30 (3H, t, J=7,6 Hz).

Stage 8. 4-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of the example is 1, on the basis of 2-[4-(4-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 7).

MS (ESI) m/z 498 (M+N)+;1H-NMR (CDCl3) δ 7,73 (2H, d, J=8.5 Hz), 7,28-7,38 (7H, m), to 7.09 (1H, d, J=7.9 Hz), 6,97 (1H, d, J=7.9 Hz), 6,69 (1H, Sirs), to 3.58 (2H, t, J=6.9 Hz), to 2.94 (2H, t, J=6.9 Hz), and 2.83 (2H, q, J=7.5 Hz), 2.40 a (3H, s), of 1.31 (3H, t, J=7.5 Hz).

Example 56

Sodium salt of 4-chloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 4-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 54).

1H-NMR (DMSO-d6) δ a 7.62 (2H, d, J=8.0 Hz), 7,41 (4H, s), 7,29 (1H, d, J=6.6 Hz), 7,12-to 7.18 (3H, m), 7,02? 7.04 baby mortality (1H, m), 3,18 (2H, Sirs), 2,70-and 2.79 (4H, m), and 2.27 (3H, s)of 1.23 (3H, t, J=7.4 Hz); IR (KBr) Vmax3385, 1602, 1519, 1433, 1174, 1130, 1085, 813 cm-1.

Example 57

5-Chloro-2-ethyl-1-(4-(2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[4-(4-Chloro-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 2,5-dichloronitrobenzene and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 9,42 (1H, s), to 8.20 (1H, d, J=2.0 Hz), 7,35-7,10 (6H, m), 3.96 points-of 3.85 (2H, m), only 2.91 (2H, t, J=7,0 Hz).

Stage 2. 2-[4-(2-Amino-4-chloroanilino)phenyl]etano the

The connection specified in the header received in accordance with the method described for stage 3 of example 6, from 2-[4-(4-chloro-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,30-7,05 (4H, m), 6,83-6,62 (3H, m), 5,15 (1H, Sirs), 3,86 of 3.75 (2H, m in), 3.75 (2H, Sirs), 2,77 (2H, t, J=7,0 Hz).

Stage 3. 2-[4-(5-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-amino-4-chloroanilino)phenyl]ethanol (step 2) and propionitrile.

1H-NMR (CDCl3) δ of 7.75 (1H, d, J=2.0 Hz), the 7.43 (2H, d, J=8.0 Hz), 7,28 (2H, d, J=8.0 Hz), to 7.15 (1H, DD, J=2,0, 8.6 Hz), of 6.99 (1H, d, J=8.6 Hz), to 4.38 (2H, t, J=7.0 Hz), of 3.07 (2H, t, J=7.0 Hz), 2,78 (2H, q, J=7,5 Hz), a 2.36 (2H, q, J=7.5 Hz), 1,24 (3H, t, J=7.5 Hz)and 1.15 (3H, t, J=7.5 Hz).

Stage 4. 2-[4-(5-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(5-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ of 7.75 (1H, d, J=2.0 Hz), 7,46 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), to 7.15 (1H, DD, J=2,0, 8.6 Hz), 7,00 (1H, d, J=8.6 Hz), 3,99 (2H, t, J=6.5 Hz), of 3.00 (2H, t, J=6.5 Hz), 2,78 (2H, q, J=7,5 Hz), of 1.26 (3H, t, J=7.5 Hz).

Stage 5. 2-[4-(5-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the JV the way described for stage 5 of example 26, from 2-[4-(5-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

MS (EI) m/z 325(M+);1H-NMR (CDCl3) δ of 7.75 (1H, d, J=2.0 Hz), was 7.45 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), to 7.15 (1H, DD, J=2,0, 8.6 Hz), of 6.99 (1H, d, J=8.6 Hz), 3,62 (211, t, J=7.0 Hz), to 3.02 (2H, t, J=7.0 Hz), 2,78 (2H, q, J=7,5 Hz), of 1.26 (3H, t, J=7.5 Hz).

Stage 6. 2-[4-(5-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 2-[4-(5-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ of 7.75 (1H, d, J=2.0 Hz), 7,41 (2H, d, J=8,3 Hz), 7,27 (2H, d, J=8,3 Hz), 7,14 (1H, DD, J=2,0, 8.6 Hz), of 6.99 (1H, d, J=8.6 Hz), is 3.08 (2H, t, J=7.0 Hz), of 2.86 (2H, t, J=7.0 Hz), 2,77 (2H, q, J=7,5 Hz)of 1.34 (3H, t, J=7.5 Hz).

Stage 7. 5-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(5-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ 7,76 (1H, d, J=1,8 Hz), 7,72 (2H, d, J=8,4 Hz), 7,39 (2H, d, J=8,3 Hz), 7,30 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,3 Hz), 7,17 (1H, DD, J=8,6,1,8 Hz), 7,00 (1H, d, J=8.6 Hz), was 6.73 (1H, Sirs), 3,59-3,53 (2H, m)to 2.94 (2H, t, J=7.0 Hz), of 2.81 (2H, q, J=7.5 Hz), of 1.34 (3H, t, J=7.5 Hz).

Example 58

2-[4-(5-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl (methylphenyl)sulfonylurea

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(5-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4 of example 57).

1H-NMR (CDCl3) δ a 7.92 (2H, d, J=8,4 Hz), 7,74 (1H, d, J=2.0 Hz), 7,34 (2H, d, J=8,4 Hz), 7,33 (2H, d, J=8,4 Hz), 7.23 percent (2H, d, J=8,4 Hz), 7,16 (1H, DD, J=8,5, 2.0 Hz), of 6.99 (1H, d, 1=8.5 Hz), 4,74 (1H, Sirs), 4,37 (2H, t, J=6.8 Hz), a 3.01 (2H, t, J=6.8 Hz), a 2.75 (2H, q, J=7,6 Hz)of 1.33 (3H, t, J=7,6 Hz).

Example 59

6-Chloro-2-ethyl-1-(4-{2-[({[4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[(5-Chloro-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 2,4-dichloronitrobenzene and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 9,52 (1H, Sirs), 8,16 (1H, d, J=9,2 Hz), 7,33 (2H, d, J=8,2 Hz), 7,25 (2H, d, J=8,2 Hz), 7,13 (1H, d, J=2.2 Hz), of 6.71 (1H, DD, J=9,2, 2.2 Hz), 3,92 (q, 2H, J=6.4 Hz), of 2.92 (t, 2H, J=6.4 Hz).

Stage 2. 2-[(2-Amino-5-chloroanilino)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[(5-chloro-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,12-to 7.09 (3H, m), 6,92 (1H, DD, J=8,4, 2.4 Hz), 6,78-6,70 (3H, m), 5,16 (1H, Sirs), 3,83 (2H, t, J=6.6 Hz), of 2.81 (2H, t, J=6.6 Hz).

Stage 3. 2-[4-(6-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane/u>

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[(2-amino-5-chloroanilino)phenyl]ethanol (step 2) and propionitrile.

1H-NMR (CDCl3) δ to 7.67 (1H, d, J=8.6 Hz), 7,44 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), 7,22 (1H, DD, J=8,4, 2.0 Hz), 7,07 (1H, d, J=2.0 Hz), to 4.38 (2H, t, J=7.0 Hz), of 3.07 (2H, t, J=7.0 Hz), 2,77 (2H, q, J=7,5 Hz), a 2.36 (2H, q, J=7.5 Hz), of 1.35 (3H, t, J=7.5 Hz)and 1.15 (3H, t, J=7.5 Hz).

Stage 4. 2-[4-(6-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(6-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ to 7.67 (1H, d, J=8.6 Hz), 7,46 (2H, d, J=8.6 Hz), 7,30-7,26 (3H, m), 7,22 (1H, DD, J=8,6 and 2.2 Hz), was 7.08 (1H, d, J=2.0 Hz), 3,99 (2H, q, J=6.4 Hz), a 3.01 (2H, t, J=6.4 Hz), 2,78 (2H, q, J=7,6 Hz), 1,72 (1H, t, J=5.6 Hz), of 1.35 (3H, t, J=7,6 Hz).

Stage 5. 2-[4-(6-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(6-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

MS (EI) m/z 325 (M+).

Stage 6. 2 [4-(6-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(6-chloro-2-ethyl- H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ to 7.67 (1H, d, J=8.6 Hz), 7,41 (2H, d, J=8,4 Hz), 7,31-7,19 (3H, m), 7,12 (1H, d, J=2.0 Hz), of 4.66 (2H, Sirs), 3,23-3,17 (2H, m), is 3.08 totaling 3.04 (2H, m)of 2.75 (2H, q, J=7.5 Hz), of 1.33 (3H, t, J=7.5 Hz).

Stage 7. 6-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(6-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ 7,74 (2H, d, J=8,4 Hz), to 7.67 (1H, d, J=8,4 Hz), 7,37 (2H, d, J=8,4 Hz), 7,30-7,20 (6H, m), 7,05 (1H, d, J=2.0 Hz), 6.73 x (1H, m), 3,62-3,55 (2H, m), with 2.93 (2H, t, J=7.2 Hz), 2,77 (2H, t, J=7.5 Hz,), to 1.32 (3H, t, J=7.5 Hz).

Example 60

Sodium salt of 6-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 6-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 59).

1H-NMR (DMSO-d6) δ to 7.64 (1H, d, J=8.6 Hz), to 7.59 (2H, d, J=8.1 Hz), 7,38 (4H, m), 7,22 (1H, DD, J=8,6, 2.0 Hz), 7,11 (2H, d, J=8.1 Hz), 7,05 (1H, d, J=2.0 Hz)and 3.15 (2H, m), 2,74-of 2.66 (4H, m), of 2.25 (3H, s)to 1.21 (3H, t, J=7.4 Hz); IR (KBr) Vmax1601, 1516, 1398, 1178, 1130, 1084 cm-1.

Example 61

4-(6-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenethyl-(4-Mei is phenyl)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(6-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4 of example 59).

TPL 183-187°C;1H-NMR (DMSO-d6) δ of 7.75 (2H, d, J=8.1 Hz), 7,66 (1H, d, J=8.6 Hz), the 7.43 (4H, s), 7,40 (2H, d, J=8.1 Hz), 7,24 (1H, DD, J=8,6, 2.0 Hz), 7,03 (1H, d, J=2.0 Hz), 4,27 (2H, t, J=6.6 Hz), 2,95 (2H, t, J=6.6 Hz), 2,70 (2H, q, J=7.5 Hz), was 2.34 (3H, s)to 1.22 (3H, t, J=7.5 Hz); IR (KBr) Vmax1744, 1516, 1352, 1225, 1165 cm-1.

Example 62

2-Butyl-6-chloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]butyl}phenyl)-1H-benzimidazole

Stage 1. 2-[4-(2-Butyl-6-chloro-1H-benzimidazole-1-yl)phenyl]ethylpentane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[(2-amino-5-chloroanilino)phenyl]ethanol (step 2 of example 59) and pentanolide.

1H-NMR (CDCl3) δ 7,66 (1H, d, J=8,4 Hz), 7,44 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8.1 Hz), 7,22 (1H, DD, J=8,4, 2.0 Hz), 7,06 (1H, d, J=2.0 Hz), to 4.38 (2H, t, J=6.8 Hz), of 3.07 (2H, t, J=6.8 Hz), is 2.74 (2H, t, J=7,7 Hz), 2,33 (2H, t, J=7.5 Hz), 1,81 is 1.70 (2H, m), 1,66-of 1.56 (2H, m), 1,40 of 1.28 (4H, m), 0,94 is 0.84 (6H, m).

Stage 2. 2-[4-(2-Butyl-6-chloro-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-butyl-6-chloro-1H-benzimidazole-1-yl)phenyl]ethylpentane (stage 1).

1H-NMR (CDCl3) δ 7,66 (1H, d, J=8.6 Hz), 7,46 (2H, d, J=8.1 Hz), 7,29-7,26 (2H, m), 7,22 (1H, DD, J=8,6, 2.0 Hz), 7,07 (1H, d, J=2.0 Hz), of 4.00 (2H, q, J=6.4 Hz), a 3.01 (2H, t, J=6.4 Hz), a 2.75 (2H, t, J=7.5 Hz), 2,24-2,19 (1H, m), 1,81-1,71 (2H, m), 1,37-of 1.26 (2H, m)of 0.87 (3H, t, J=7,3 Hz).

Stage 3. 2-4-(2-Butyl-6-chloro-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 4 of example on the basis of 2-[4-(2-butyl-6-chloro-1H-benzimidazole-1-yl)phenyl]ethanol (step 2).

1H-NMR (CDCl3) δ 7,66 (1H, d, J=8.6 Hz), was 7.45 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), 7,22 (1H, DD, J=8,6, 2.0 Hz), 7,07 (1H, d, J=2.0 Hz), 3,62 (2H, t, J=7.0 Hz), to 3.02 (2H, t, J=7.0 Hz), is 2.74 (2H, t, J=7,5 Hz), 1,80 is 1.70 (2H, m), 1,40-of 1.26 (2H, m)0,86 (2H, t, J=7,3 Hz).

Stage 3. 2-[2-Butyl-6-chloro-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-butyl-6-chloro-1H-benzimidazole-1-yl)phenyl]utilised (stage 2).

1H-NMR (CDCl3) δ 7,66 (1H, d, J=8.6 Hz), the 7.43 (2H, d, J=8,2 Hz), 7,27 (2H, d, J=8,2 Hz), 7,21 (1H, DD, J=8,6, 2.0 Hz), was 7.08 (1H, d, J=2.0 Hz), 3,11 (2H, t, J=7,1 Hz), only 2.91 (2H, t, J=7,1 Hz), is 2.74 (2H, t, J=7,4 Hz), 1,81 is 1.70 (2H, m), 1.41 to 1.27mm (2H, m)0,86 (3H, t, J=7,4 Hz).

Stage 4. 2-Butyl-6-chloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl]-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 note the RA 1, on the basis of 2-[4-(2-butyl-6-chloro-1H-benzimidazole-1-yl)phenyl]ethylamine (step 3).

1H-NMR (CDCl3) δ of 7.75 (2H, d, J=8,4 Hz), 7,66 (1H, d, J=8,2 Hz), 7,38 (2H, d, J=8,4 Hz), 7,30-7,20 (6H, m), 7,05 (1H, d, J=2.0 Hz), 6,77-6,72 (1H, m), 3,61-3,55 (2H, m), 2,96 of 2.92 (2H, m), is 2.74 (2H, t, J=7.5 Hz), 2,39 (3H, s), 1,78-to 1.67 (2H, m), 1,35-of 1.26 (2H, m), is 0.84 (3H, t, J=7,3 Hz).

Example 63

Sodium salt of 2-butyl-6-chloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]butyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 2-butyl-6-chloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 62).

TPL 137-145°C;1H-NMR (DMSO-d6) δ the 7.65 7,63 (1H, m), to 7.59 (2H, d, J=7.8 Hz), 7,38 (4H, s), 7.23 percent-7,20 (1H, m), 7,12 (2H, d, J=7.8 Hz),? 7.04 baby mortality (1H, s)and 3.15 (2H, m), 2,72-to 2.67 (4H, m), and 2.26 (3H, s), 1,66-to 1.61 (2H, m), 1,29-1,22 (2H, m,), of 0.79 (3H, t, J=7.5 Hz); IR (KBr) Vmax1603, 1520, 1458, 1396, 1130, 1086 cm-1.

Example 64

7-Chloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[4-(2-Chloro-6-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2,3-dichloronitrobenzene and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 8,11 (1H, Sirs), of 8.00 (1H, DD, J=1.5 Hz, 8.5 Hz), to 7.61 (1H, DD, J=1.5 Hz, 7.9 Hz), 7,12 (2H, d, J=8,4 Hz), 7,03 (1H, DD, J=7.9 Hz, 8.5 Hz), to 6.80 (2H, d, J=8,4 Hz), 3,82 (2H, t, J=6.6 Hz), of 2.81 (2H, d, J=6,6 Hz).

Stage 2. 2-[4-(2-Amino-6-chloroanilino)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[4-(2-chloro-6-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ? 7.04 baby mortality (2H, d, J=7.8 Hz), 6,97 (1H, DD, J=7.9 Hz, 8.0 Hz), PC 6.82 (1H, DD, J=1.5 Hz, 7.9 Hz), of 6.66 (1H, DD, J=1.5 Hz, 8.0 Hz), 6,59 (2H, d, J=7.8 Hz), are 5.36 (1H, Sirs), of 3.94 (2H, Sirs), of 3.78 (2H, t, J=6.6 Hz), of 2.75 (2H, d, J=6,6 Hz).

Stage 3. 2-[4-(7-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-amino-6-chloroanilino)phenyl]ethanol (step 2) and propionitrile.

TLC Rf = 0,6 (hexane:ethyl acetate = 1:1).

Stage 4. 2-[4-(7-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-amino-6-chloroanilino)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ to 7.68 (1H, DD, J=1.9 Hz, 7.0 Hz), 7,39 (2H, d, J=8,2 Hz), 7,28 (2H, d, J=8,2 Hz), 7,11-7,20 (2H, m), of 3.97 (2H, t, J=6.6 Hz), a 3.01 (2H, t, J=6.6 Hz), 2,65 (2H, q, J=7,6 Hz)of 1.32 (3H, t, J=7,6 Hz).

Stage 5. 7-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole

The connection specified in the header received in accordance with the by procedure, described for stage 7 of example 1 from 2-[4-(7-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ of 7.69 (1H, DD, J=2.2 Hz and 7.1 Hz), 7,37 (2H, d, J=8,2 Hz), 7,31 (2H, d, J=8,2 Hz), 7,11-7,17 (2H, m), 3,81 (2H, t, J=7,3 Hz), 3,19 (2H, t, J=7,3 Hz), 2,65 (2H, q, J=7.5 Hz), of 1.33 (3H, t, J=7.5 Hz).

Stage 6. 2-[4-(7-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 7-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole (step 5).

1H-NMR (CDCl3) δ of 7.69 (1H, DD, J=1,8 Hz, 7.4 Hz), 7,38 (2H, d, J=8,2 Hz), 7,34 (2H, d, J=8,2 Hz), 7,11-7,28 (2H, m), of 3.60 (2H, t, J=7.0 Hz), to 3.02 (2H, t, J=7,0 Hz)of 2.64 (2H, q, J=7,6 Hz)of 1.32 (3H, t, J=7,6 Hz).

Stage 7. 2-[4-(7-Chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 2-[4-(7-chloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 6).

1H-NMR (CDCl3) δ of 7.69 (1H, d, J=7.9 Hz), 7,35 (2H, d, J=8,3 Hz), 7,28 (1H, d, J=8,3 Hz), 7,11-7,19 (2H, m), 3,06 (2H, t, J=6.8 Hz), is 2.88 (2H, t, J=6 Hz), 2,65 (2H, q, J=7.5 Hz), of 1.33 (3H, t, J=7.5 Hz).

Stage 8. 7-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1, based on the C 2-[4-(7-chloro-2-ethyl-1 H-benzimidazole-1-yl)phenyl]ethylamine (step 7).

MS (ESI) m/z 498 (M+H)+;1H-NMR (CDCl3) δ 7,74 (2H, d, J=8,4 Hz), 7,69 (1H, DD, J=1.9 Hz, 7.4 Hz), 7,29-to 7.32 (6H, m), 7,11-7,20 (2H, m), 6,72 (1H, Sirs)and 3.59 (2H, t, J=6.9 Hz), with 2.93 (2H, t, J=6.9 Hz), of 2.64 (2H, q, J=7,6 Hz), 2,42 (3H, s), of 1.31 (3H, t, J=7,6 Hz).

Example 65

Sodium salt of 7-chloro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2, from 7-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 64).

1H-NMR (CDCl3) δ a 7.62 to 7.64 (3H, m), 7,31-7,39 (4H, m), 7,14-7,20 (4H, m)6,00 (1H, Sirs), 3,17 (2H, Sirs), a 2.75 (2H, Sirs), to 2.55 (2H, q, J=7,8 Hz)to 2.29 (3H, s)to 1.21 (3H, t, J=7.8 Hz); IR (KBr) Vmax3380, 2891, 1605, 1520, 1425, 1285, 1126, 1075, 798 cm-1.

Example 66

5-fluoro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl]-1H-benzimidazole

Stage 1. 2-[4-(4-Fluoro-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 2,5-deformirovannoe and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ to 9.32 (1H, s), 7,88-to 7.93 (1H, m), 7,11-7,30 (5H, m), 3,90 (2H, t, J=6.2 Hz), 2,90 (2H, t, J=6.2 Hz).

Stage 2. 2-[4-(2-Amino-4-foronline)phenyl]ethanol

The connection pointed to by the e in the title, received in accordance with the method described for step 2 of example 26, from 2-[4-(4-fluoro-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 6,98-7,06 (3H, m), 6,60 (2H, d, J=8,2 Hz), of 6.49 (1H, DD, J=2,8 Hz to 12.8 Hz), 6,41 (1H, DD, J=2,8 Hz and 8.4 Hz), 4,99 (1H, Sirs), of 3.94 (2H, Sirs), with 3.79 (2H, Sirs), was 2.76 (2H, t, J=6.4 Hz).

Stage 3. 2-[4-(2-Ethyl-5-fluoro-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-amino-4-foronline)phenyl]ethanol (step 2) and propionitrile.

MS (EI) m/z 340 (M+).

Stage 4. 2-[4-(2-Ethyl-5-fluoro-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-amino-4-foronline)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 7,40-7,47 (3H, m), 7,28 (2H, d, J=8.0 Hz), 6,88-7,02 (2H, m), 3,98 (2H, t, J=6.3 Hz), a 3.01 (2H, t, J=6.3 Hz), 2,78 (2H, q, J=7.5 Hz), of 1.34 (3H, t, J=7.5 Hz).

Stage 5. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-5-fluoro-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-5-fluoro-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ 7,42-7,46 (3H, m), 7,31 (2H, d, J=8.1 Hz), 6.89 in-7,02 (2H, m), 3,81 (2H, t, J=7,1 Hz), 3,19 (2H, t, J=7,1 Hz), 2,78 (2H, q, J=7,6 Hz), 1,35 (H, t, J=7,6 Hz).

Stage 6. 2-[4-(2-Ethyl-5-fluoro-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-fluoro-1H-benzimidazole (step 5).

1H-NMR (CDCl3) δ 7,43 was 7.45 (3H, m), 7,31 (2H, d, J=8,2 Hz), 6.89 in-7,02 (2H, m), 3,62 (2H, t, J=7.0 Hz), a 3.01 (2H, t, J=7.0 Hz), 2,77 (2H, q, J=7.5 Hz), of 1.34 (3H, t, J=7.5 Hz).

Stage 7. 2-4-(2-Ethyl-5-fluoro-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-5-fluoro-1H-benzimidazole-1-yl)phenyl]utilised (stage 6).

1H-NMR (CDCl3) δ 7,40-7,46 (3H, m), 7,27-7,29 (2H, m), 6.87 in-6,99 (2H, m), 3,06 (2H, t, J=7,1 Hz), 2,87 (2H, t, J=7,1 Hz), 2,78 (2H, q, J=7.5 Hz), of 1.35 (3H, t, J=7.5 Hz).

Stage 8. 5-fluoro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-5-fluoro-1H-benzimidazole-1-yl)phenyl]ethylamine (step 7).

MS (ESI) m/z 481 (M+H)+;1H-NMR (CDCl3) δ 7,73 (2H, d, J=8,2 Hz), 7,35-7,45 (3H, m), 7.24 to 7,29 (4H, m), 6.87 in-7,00 (2H, m), of 6.73 (1H, Sirs), of 3.57 (2H, t, J=7.0 Hz), with 2.93 (2H, t, J=7.0 Hz), 2,77 (2H, q, J=7,6 Hz), 2,39 (3H, s)is 1.31 (3H, t, J=7,6 Hz).

Example 67

Sodium salt of 5-fluoro-2-ethyl-3-(4-{2-[([(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1 H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2, starting from 5-fluoro-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 66).

TPL 135-146°C; MS (ESI) m/z 481 (M+N)+;1H-NMR (DMSO-d6) δ a 7.62 (2H, d, J=8.1 Hz), 7,39-of 7.48 (5H, m), 6,97-to 7.15 (4H, m), of 5.92 (1H, Sirs), 2,67 was 2.76 (4H, m), of 2.51 (2H, Sirs), and 2.27 (3H, s)of 1.23 (3H, t, J=7,6 Hz).

Example 68

2-Butyl-6-fluoro-1-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}-1H-benzimidazole

Stage 1. 2-[4-(5-fluoro-2-nitroaniline)phenyl]ethanol]

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 2,4-deformirovannoe and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ being 9.61 (1H, Sirs), compared to 8.26 (1H, DD, J=6,1, 9.5 Hz), 7,32 (2H, d, J=8,2 Hz), 7,22 (2H, d, J=8,3 Hz), 6,78 (1H, DD, J=2,6,11,3 Hz), 6,47 (1H, DDD, J=2,2, 7,2, 9.7 Hz), 3,91 (2H, dt, J=6,2, 6.2 Hz), only 2.91 (2H, t, J=6,4 Hz), of 1.52 (1H, t, J=5.7 Hz).

Stage 2. 2-[4-(2-Amino-5-foronline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[4-(5-fluoro-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ for 7.12 (2H, d, JN8,4 Hz), 6.87 in (1H, DD, J=2,7,10,1 Hz), 6,83 (2H, d, J=8,4 Hz), 6,72 (1H, DD, J=5,7, 8.6 Hz), 6,63 (1H, DDD, J=2,7, 8,4, 8,4 Hz), and 5.30 (1H, s), 3,83 (2H, t, J=6.4 Hz), 2,80 (2H, t, J6,4 Hz).

Stage 3. 2-[4-(2-Butyl-6-fluoro-1H-benzimidazole-1-yl)phenyl]ethylpentane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-amino-5-foronline)phenyl]ethanol (step 2) and pentanolide.

1H-NMR (CDCl3) δ to 7.67 (1H, DD, J=4,8, 8,8 Hz), 7,44 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8.1 Hz),? 7.04 baby mortality-to 6.95 (1H, m), 6,76 (1H, DD, J=2,6, 8,8 Hz), to 4.38 (2H, t, J=6.8 Hz), of 3.07 (2H, t, J=6.8 Hz), is 2.74 (2H, t, J=7.5 Hz,), of 2.33 (2H, t, J=7,7 Hz), 1,81-of 1.55 (4H, m), 1,42-1,25 (4H, m)6,91 (3H, t, J=7,3 Hz)of 0.87 (3H, t, J=7,3 Hz).

Stage 4. 2-[4-(2-Butyl-6-fluoro-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-butyl-6-fluoro-1H-benzimidazole-1-yl)phenyl]ethylpentane (stage 3).

1H-NMR (CDCl3) δ to 7.67 (1H, DD, J=4,8, 8,8 Hz), 7,46 (2H, d, J=8,2 Hz), 7,28 (2H, d, J=8,3 Hz), 6,99 (1H, DDD, J=2,4, 9,0, 9.5 Hz), 4,10-of 3.85 (2H, m), a 3.01 (2H, t, J=6.4 Hz), is 2.74 (2H, t, J=7,7 Hz), 1,84 was 1.69 (2H, m), 1,41-of 1.27 (2H, m)of 0.87 (3H, t, J=7,3 Hz).

Stage 5. 2-[4-(2-Butyl-6-fluoro-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(2-butyl-6-fluoro-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

MS (EI) m/z 337 (M+);1H-NMR (CDCl3) δ to 7.68 (1H, DD, J=4,8, 8,8 Hz), was 7.45 (2H, d, J=8,1 Hz), 7,30 (2H, d, J=8.1 Hz),? 7.04 baby mortality-6,94 (1H, m), 6,77 (1H, DD, J=2,4, 8.6 Hz), 3,2 (2H, t, J=7.0 Hz), to 3.02 (2H, t, J=6.8 Hz), is 2.74 (2H, t, J=7,7 Hz), 1,86 was 1.69 (2H, m), 1.41 to 1,2 (2H, m)0,86 (3H, t, J=7,3 Hz).

Stage 6. 2-[4-(2-Butyl-6-fluoro-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 2-[4-(2-butyl-6-fluoro-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ to 7.67 (1H, DD, J=4,8, 8,8 Hz), 7,42 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8,2 Hz), 7,05-to 6.95 (1H, m), is 6.78 (1H, DD, J=2,6, 8.6 Hz), is 3.08 (2H, t, J=7,1 Hz), is 2.88 (2H, t, J=6.8 Hz), a 2.75 (2H, t, J=7.5 Hz,), 1,82 was 1.69 (2H, m), 1.41 to 1,24 (2H, m)of 0.87 (3H, t, J=7,3 Hz).

Stage 7. 2-Butyl-6-fluoro-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-butyl-6-fluoro-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ 7,73 (2H, d, J=8,4 Hz), to 7.68 (1H, DD, J=4,6, 8,8 Hz), 7,38 (2H, d, J=8,4 Hz), 7,32-7,24 (4H, m), 7,00 (1H, DDD, J=2,4, 8,8, 11.2 Hz), to 6.75 (1H, DD, J=2,4, 8.6 Hz), 3,64-of 3.54 (2H, m)to 2.94 (2H, t, J=7,0 Hz), is 2.74 (2H, d, J=7.5 Hz), 1,80-of 1.65 (2H, m), 1,40-1,20 (2H, m), is 0.84 (3H, t, J=7,3 Hz).

Example 69

Sodium salt of 2-butyl-6-fluoro-1-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}-1-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 2-butyl-6-fluoro-3-(4-{2-[({[(4-were)Sul is of IMT]amino}carbonyl)amino]ethyl}phenyl)-benzimidazole (example 69).

1H-NMR (DMSO-d6) δ 7,70-EUR 7.57 (3H, m), 7,39 (4H, W), 7,14 (2H, d, J=8.0 Hz), 7,11-7,02 (1H, m), cent to 8.85 (1H, DD, J=2,4, 9,2 Hz), 3,48-to 3.34 (2H, m), 3,17 (2H, W), 2,80-to 2.65 (4H, m), of 2.28 (3H, s), 1,72-of 1.55 (2H, m), 1,35-1,20 (2H, m)to 0.80 (3H, t, J=7,1 Hz); IR (KBr) Vmax3387, 2872, 1601, 1516, 1479, 1400, 1130, 1086 cm-1.

Example 70

2-Ethyl-6-fluoro-1-(4-2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[4-(6-fluoro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-amino-5-foronline)phenyl]ethanol (step 2 of example 68) and propionitrile.

MS (EI) m/z 340 (M+);1H-NMR (CDCl3) δ to 7.67 (1H, DD, J=4,8, 8,8 Hz), the 7.43 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), 6,99 (1H, DDD, J=2.5 a, 8,8, 9.5 Hz), 6,77 (1H, DD, J=2.5 a, 8,8 Hz), to 4.38 (2H, t, J=6.6 Hz), of 3.07 (2H, t, J=6.6 Hz), and 2.79 (2H,, kV, J=7,4 Hz), 2,35 (2H, q, J=7.4 Hz), of 1.35 (3H, t, J=7.4 Hz), to 1.14 (3H, t, J=7,4 Hz).

Stage 2. 2-[4-(6-fluoro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(6-fluoro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 1).

1H-NMR (CDCl3) δ to 7.67 (1H, DD, J=4,8, 8,8 Hz), was 7.45 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 6,99 (1H, DDD, J=2.5 a, 8,8, 9.5 Hz), 6,78 (1H, DD, J=2.5 a, 8,8 Hz)to 3.99 (2H, t, J=6,6 Hz)of 3.00 (2H, t, J=6.6 Hz), 2,77 (2H,, kV, J=7.5 Hz), of 1.35 (3H, t, J=7.5 Hz).

Stud is I 3. 6-Fluoro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(6-fluoro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 2).

MS (EI) m/z 302 (M+).

Stage 4. 2-[4-(6-fluoro-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-fluoro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole (stage 3).

MS (EI) m/z 309 (M+);1H-NMR (CDCl3) δ to 7.68 (1H, DD, J=4,8, 8,8 Hz), 7,44 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,3 Hz), 6,99 (1H, DDD, J=2.5 a, 8,8, 9.6 Hz), 6,77 (1H, DD, J=2.5 a, 8,8 Hz), 3,62 (2H, t, J=6.9 Hz), to 3.02 (2H, t, J=6.9 Hz), 2,77 (2H,, kV, J=7,4 Hz)of 1.34 (3H, t, J=7,4 Hz).

Stage 5. 2-[4-(6-fluoro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 2-[4-(6-fluoro-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 4).

1H-NMR (CDCl3) δ to 7.68 (1H, DD, J=4,8, 8,8 Hz), the 7.43 (2H, d, J=8,2 Hz), 7,28 (2H, d, J=8,2 Hz), 6,98 (1H, DDD, J=2,4, 8,8, 8,8 Hz), PC 6.82 (1H, DD, J=2,4, 8,8 Hz), 3,37 (2H, Sirs), 3,18 (2H, t, J=7,1 Hz), a 3.01 (2H, t, J=7,1 Hz), was 2.76 (2H, q, J=7.5 Hz), of 1.33 (3H, t, J=7.5 Hz).

Stage 6. 2-Ethyl-6-fluoro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header, p. what was given in accordance with the method, described for stage 10 of example 1 from 2-[4-(6-fluoro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 5).

1H-NMR (CDCl3) δ 7,73 (2H, d, J=8,4 Hz), to 7.68 (1H, DD, J=8,7, a 4.9 Hz), 7,37 (2H, d, J=8,4 Hz), 7,32-of 7.23 (4H, m), 7,00 (1H, DDD, J=9,5, 8,7,2,5 Hz), 6,79-6,69 (2H, m), 3,63-of 3.53 (2H, m)to 2.94 (2H, t, J=7.5 Hz), was 2.76 (2H, kV, J=7.5 Hz), 2.40 a (3H, s)of 1.32 (3H, t, J=7.5 Hz).

Example 71

5-Methoxy-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[4-(4-Methoxy-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2-chloro-5-methoxyethanol and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ was 9.33 (1H, Sirs), 7,63 (1H, d, J=3.0 Hz), 7,17-7,27 (5H, m),? 7.04 baby mortality-was 7.08 (1H, m), 3,88 (2H, Sirs), 3,82 (3H, s), is 2.88 (2H, t, J=6.6 Hz).

Stage 2. 2-[4-(2-Amino-4-methoxyaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 26, from 2-[4-(4-methoxy-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,03 (2H, d, J=8.6 Hz), 6,98 (1H, d, J=8,4 Hz), 6,59 (2H, d, J=8.6 Hz), 6,28-6,36 (2H, m), of 3.77-of 3.85 (5H, m), was 2.76 (2H, t, J=6.6 Hz).

Stage 3. 2-[4-(2-Ethyl-5-methoxy-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 the example is 1, on the basis of 2-[4-(2-amino-4-methoxyaniline)phenyl]ethanol (step 2).

1H-NMR (CDCl3) δ 7,40 (2H, d, J=8.0 Hz), 7,12-7,29 (3H, m), 6,97 (1H, d, J=8,8 Hz), PC 6.82 (1H, DD, J=2,4 Hz and 8.8 Hz), 4,37 (2H, t, J=6,7 Hz), 3,86 (3H, s), 3,05 (2H, t, J=6,7 Hz), 2,77 (2H, q, J=7.5 Hz), a 2.36 (2H, kV, J=7.5 Hz), of 1.36 (3H, t, J=7.5 Hz), to 1.14 (3H, t, J=7.5 Hz).

Stage 4. 2-[4-(2-Ethyl-5-methoxy-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-5-methoxy-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8,2 Hz), 7,27-7,30 (3H, m), 6,98 (1H, d, J=8,8 Hz), PC 6.82 (1H, DD, J=2.3 Hz, 8,8 Hz), 3,98 (2H, t, J=6.5 Hz), 3,86 (3H, s)to 2.99 (2H, t, J=6.5 Hz), 2,77 (2H, q, J=7,6 Hz)of 1.33 (3H, t, J=7,6 Hz).

Stage 5. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-5-methoxy-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-5-methoxy-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,2 Hz), 7,26-7,33 (3H, m), of 6.99 (1H, d, J=8,8 Hz), PC 6.82 (1H, DD, J=2,5 Hz and 8.8 Hz), 3,86 (3H, s), 3,81 (2H, t, J=7.2 Hz), 3,18 (2H, t, J=7.2 Hz), 2,78 (2H, q, J=7,6 Hz)of 1.34 (3H, t, J=7,6 Hz).

Stage 6. 1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl methyl ether

The connection specified in the header received in accordance with the method described for stage 8 of example 1, the outcome is 1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-methoxy-1 H-benzimidazole (step 5).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,4 Hz), 7,27-to 7.32 (3H, m), 6,98 (1H, d, J=8,8 Hz), PC 6.82 (1H, DD, J=2.3 Hz, 8,8 Hz), a 3.87 (3H, s), 3,61 (2H, t, J=6.9 Hz), a 3.01 (2H, t, J=6.9 Hz), was 2.76 (2H, q, J=7,7 Hz)of 1.34 (3H, t, J=7,7 Hz).

Stage 7. 2-[4-(2-Ethyl-5-methoxy-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl-methyl ester (stage 6).

1H-NMR (CDCl3) δ 7,39 (2H, d, J=8,2 Hz), 7,26-7,30 (3H, m), of 6.99 (1H, d, J=8.7 Hz), PC 6.82 (1H, DD, J=2.3 Hz, 8.7 Hz), 3,86 (3H, s), of 3.07 (2H, t, J=6.9 Hz), 2,84 (2H, t, J=6.9 Hz), 2,77 (2H, q, J=7,6 Hz)of 1.34 (3H, t, J=7,6 Hz).

Stage 8. 5-Methoxy-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-5-methoxy-1H-benzimidazole-1-yl)phenyl]ethylamine (step 7).

1H-NMR (CDCl3) δ 7,74 (2H, d, J=8,2 Hz), 7.23 percent-7,34 (7H, m), 6,97 (1H, d, J=8.7 Hz), PC 6.82 (1H, DD, J=1,8 Hz, 8.7 Hz), to 6.67 (1H, Sirs), 3,86 (3H, s), of 3.57 (2H, t, J=6.4 Hz), of 2.92 (2H, t, 6.4 Hz), a 2.75 (2H, q, J=7,6 Hz)that is 2.40 (3H, s)is 1.31 (3H, t, J=7,6 Hz).

Example 72

Sodium salt of 5-methoxy-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method, described in example 2, starting from 5-methoxy-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 72).

TPL 163-175°C;1H-NMR (DMSO-d6) δ of 7.60 (2H, d, J=7.5 Hz), 7,34-7,41 (4H, m), 7,12-to 7.18 (3H, m), 6,97 (1H, d, J=8.7 Hz), 6,78 (1H, d, J=8.7 Hz), of 3.78 (3H, s), 2,66 was 2.76 (4H, m)of 2.50 (2H, Sirs), 2,78 (3H, s)to 1.22 (3H, t, J=7,6 Hz); IR (KBr) Vmax3363, 2833, 1596, 1404, 1128, 1085, 1026, 950 cm-1.

Example 73

2-[4-(2-Ethyl-5-methoxy-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(2-ethyl-5-methoxy-1H-benzimidazole-1-yl)phenyl]ethanol (step 4 of example 71).

TPL 95-98 C; MS (ESI) m/z 494 (M +H)+;1H-NMR (CDCl3) δ to 7.93 (2H, d, J=8,2 Hz), 7.23 percent-7,30 (3H, m), 7,16 (2H, d, J=8,2 Hz), 7,06 (2H, d, J=8,3 Hz), 6,92 (1H, d, J=8,8 Hz), for 6.81 (1H, DD, J=2.2 Hz, 8.6 Hz), to 4.33 (2H, t, J=6.3 Hz), of 3.84 (3H, s), with 2.93 (2H, t, J=6.3 Hz), 2,68 (2H, q, J=7.5 Hz), is 2.37 (3H, s)to 1.22 (3H, t, J=7.5 Hz); IR (KBr) Vmax 1743, 1596, 1517, 1487, 1444, 1278, 1159, 1074, 813 cm-1.

Example 74

2-Ethyl-6-methoxy-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[(5-Methoxy-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2-chloro-4-mitoxantrone and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl 3) δ 9,74 (1H, Sirs), 8,18 (1H, d, J=9.5 Hz), 7,30 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), 6,55 (1H, d, J=2,8 Hz), 6,34 (1H, DD, J=9,5,2,8 Hz), 3,90 (2H, m), 3,74 (3H, s), 2,90 (3H, t, J=6.6 Hz).

Stage 2. 2-[(2-Amino-5-methoxyaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[(5-methoxy-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ to 7.09 (2H, d, J=8,4 Hz), to 6.80 (2H, d, J=8,4 Hz), 6,76-of 6.73 (2H, m), is 6.54 (1H, DD, J=8,6, 2,8 Hz), 3,81 (2H, t, J=6.6 Hz), 3,71 (3H, s), and 2.79 (2H, t, J=6.6 Hz).

Stage 3. 2-[(2-Ethyl-6-methoxy-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[(2-amino-5-methoxyaniline)phenyl]ethanol (step 2) and propionitrile.

MS (EI) m/z 352 (M+).

Stage 4. 2-[4-(2-Ethyl-6-methoxy-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-6-methoxy-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 7,63 (1H, d, J=8,8 Hz), was 7.45 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), 6.89 in (1H, DD, J=8,8, and 2.6 Hz), 6,56 (1H, d, J=2.6 Hz), of 4.00 (2H, t, J=6,6 Hz in), 3.75 (3H, s), a 3.01 (2H, t, J=6.6 Hz), 2,74 (2H, q, J=7.5 Hz), 1,32 (3H, t, J=7.5 Hz).

Stage 5. 2-[4-(2-Ethyl-6-methoxy-1H-benzimidazole-1-phenyl]utilised

The is a group of specified in the header received in accordance with the method described for stage 4 of example 26, from 2-(4-(2-ethyl-6-methoxy-1H-benzimidazole-1-yl)phenyl)ethanol (stage 4).

TLC Rf = 0.50 in (hexane/ethyl acetate = 1:1).

Stage 6. 2-[4-(2-Ethyl-6-methoxy-1H-benzimidazole-1-yl)phenyl)ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-6-methoxy-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ the 7.65 (1H, d, J=8,8 Hz), 7,41 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), 6.89 in (1H, DD, J=8,8,2,4 Hz), 6,56 (1H, d, J=2.4 Hz), 3,76 (3H, s)to 3.09 (2H, t, J=7.0 Hz), 2,89 (2H, t, J=7.0 Hz), a 2.75 (2H, kV, J=7.5 Hz), 1,32 (3H, t, J=7.5 Hz).

Stage 7. 2-Ethyl-6-methoxy-1-(4-{2-[({[(4-were)l}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-6-methoxy-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ of 7.75 (2H, d, J=8,2 Hz), a 7.62 (1H, d, J=8.7 Hz), 7,35-of 7.23 (6H, m), 6.89 in (1H, DD, J=8,7,2,5 Hz), 6,66 (1H, m), 6,55 (1H, d, J=2.5 Hz), and 3.72 (3H, s), 3,59 is 3.57 (2H, m), with 2.93 (2H, t, J=7.0 Hz), 2,73 (2H,, kV, J=7,6 Hz)of 1.29 (3H, t, J=7,6 Hz).

Example 75

Sodium salt of 2-ethyl-6-methoxy-1-(4-{2-[({[(4-were)sulfonyl)amino]carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header is, received in accordance with the method described in example 2 from 2-ethyl-6-methoxy-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 74).

1H-NMR (DMSO-d6) δ to 7.59 (2H, d, J=8,3 Hz)to 7.50 (1H, d, J=8,8 Hz), 7,41-to 7.35 (4H, m), 7,12 (2H, d, J=8,3 Hz), to 6.80 (1H, DD, J=8,8, 2.4 Hz), 6,53 (1H, d, J=2.4 Hz), to 3.67 (3H, s)and 3.15 (2H, m), 2,73-2,62 (4H, m), 1,19 (3H, t, J=7,7 Hz); IR (KBr) vmax1595, 1516, 1485, 1454, 1400, 1157, 1128, 1086 cm-1.

Example 76

5-Trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-1H-benzimidazole

Stage 1. 2-[2-Nitro-4-(trifluoromethyl)aniline]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2-chloro-5-triftormetilfosfinov and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 9,68 (1H, Sirs), and 8.50 (1H, s), 7,51 (1H, DD, J=2.2 Hz, 9,2 Hz), 7,33 (2H, d, J=8,2 Hz), 7,19-7,26 (3H, m)to 3.92 (2H, t, J=6.3 Hz), of 2.92 (2H, t, J=6.3 Hz).

Stage 2. 2-[2-Amino-4-(trifluoromethyl)aniline]phenyl}ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 26, from 2-[2-nitro-4-(trifluoromethyl)aniline]phenyl}ethanol (step 1).

1H-NMR (CDCl3) δ 7,10-7,16 (3H, m), 6,97 (2H, d, J=8,2 Hz), PC 6.82 (2H, d, J=8,2 Hz), 3,82 (2H, t, J=6.6 Hz), and 2.79 (2H, t, J=6.6 Hz).

Stage 3. 2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-the l]phenyl}ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[2-amino-4-(trifluoromethyl)aniline]phenyl}ethanol (step 2) and propionitrile.

1H-NMR (CDCl3) δ with 8.05 (1H, s), 7,42-7,47 (2H, m), 7,27-7,31 (2H, m), 7,13 (2H, d, J=8,4 Hz), 4,39 (2H, t, J=7.0 Hz), is 3.08 (2H, t, J=7.0 Hz), 2,80 (2H, q, J=7,6 Hz), a 2.36 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz), to 1.14 (3H, t, J=7,6 Hz).

Stage 4. 2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-{4-[2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ with 8.05 (1H, s), 7,49 (1H, d, J=8,4 Hz), 7,44 (2H, d, J=8.6 Hz), 7,30 (2H, d, J=8.6 Hz), 7,16 (1H, d, J=8,4 Hz)to 4.01 (2H, t, J=6.4 Hz), 3,03 (2H, t, J=6.4 Hz), 2,80 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

Stage 5. 2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-{4-[2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 4).

1H-NMR (CDCl3) δ with 8.05 (1H, s), 7,22-of 7.48 (5H, m), to 7.15 (1H, d, J=8,4 Hz), 3,62 (2H, t, J=6.8 Hz), to 3.02 (2H, t, J=6.8 Hz), 2,80 (2H, q, J=7.5 Hz), of 1.36 (3H, t, J=7.5 Hz).

Stage 6. 2-{4-[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethylamine

The connection of the criminal code is mentioned in the header, received in accordance with the method described for stage 9 of example 1 from 2-{4-[2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}Adelaida (stage 5).

1H-NMR (CDCl3) δ with 8.05 (1H, s), 7,44 (3H, d, J=8,8 Hz), 7,29 (2H, d, J=8,8 Hz), 7,16 (1H, d, J=8.6 Hz), to 3.09 (2H, t, J=6.8 Hz), 2,89 (2H, t, J=6.8 Hz), of 2.81 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

Stage 7. 5-Trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)l}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-{4-[2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethylamine (step 6).

MS (ESI) m/z 533 (M+H)+;1H-NMR (CDCl3) δ 8,03 (1H, s), 7,80 (2H, d, J=8,2 Hz), 7,73 (2H, d, J=8,2 Hz), 7,38-the 7.43 (3H, m), 7,26-7,29 (2H, m), 7,13 (1H, d, J=8,4 Hz), 6,70 (1H, Sirs), of 3.57 (2H, t, 6,7 Hz)to 2.94 (2H, t, J=6,7 Hz), 2,80 (2H, kV, J=7,6 Hz), 2,43 (3H, s)of 1.34 (3H, t, J=7,6 Hz).

Example 77

Sodium salt of 5-trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2, starting from 5-trifluoromethyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 76).

1H-NMR (DMSO-d6) δ 8,02 (1H, s), to 7.61-7,66 (4H, m), of 7.48-7,51 (1H, m), 7.24 to 7,28 (3H, m), 7,14 (2H, d, 7.9 Hz), to 3.09 (2H, Sirs), 2,60-and 2.83 (4H, m), 2,22 (3H, s), 113 (3H, t, J=7.5 Hz).

Example 78

5-Acetyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-1H-benzimidazole

Stage 1. 1-{4-[4-(2-hydroxyethyl)aniline]-3-nitrophenyl}alanon

A mixture of 2-chloro-5-acetylnitrate (Oelschlaeger,H.; Schreiber,O.Liebigs Ann.Chem., 1961, 641, 81., 2 g, 10 mmol), 4-aminophenylacetamido alcohol (1.64 g, 12 mmol) and NaHCO3(1 g, 12 mmol) in DMF (60 ml) was heated at 150°C for 3 hours. After cooling, the mixture was poured into water (100 ml) and was extracted with ethyl acetate (300 ml). The organic layer was washed 2 N. aqueous NaOH (100 ml) and saturated saline (100 ml), then dried (Na2SO4) and concentrated. Was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (1:1), obtaining of 1.36 g (45%) of the compound indicated in the title, in the form of an orange oil.

1H-NMR (CDCl3) δ 9,83 (1H, Sirs), to 8.20 (1H, d, J=2.1 Hz), 7,94 (1H, DD, J=2.1 Hz, 9.3 Hz), 7,34 (2H, d, J=8,2 Hz), 7,24 (2H, d, J=8,2 Hz), 7,16 (1H, d, J=9.3 Hz), 3,91 (2H, t, J=6.6 Hz), of 2.92 (2H, t, J=6.6 Hz), 2.57 m (3H, s).

Stage 2. 1-3-Amino-4-[4-(2-hydroxyethyl)aniline]phenyl}alanon

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 1-{4-[4-(2-hydroxyethyl)aniline]-3-nitrophenyl}of ethanone (stage 1).

1H-NMR (CDCl3) δ 7,41 (1H, d, J=2.0 Hz), 7,37 (1H, DD, J=2.0 Hz and 8.2 Hz), 7,11-7,17 (3H, m)6,94 (2H, d, J=8,2 G is), 5,72 (1H, Sirs), 3,85 (2H, t, J=6.6 Hz), the 3.65 (2H, Sirs), and 2.83 (2H, t, J=6.6 Hz), 2,52 (3H, s).

Stage 3. 2-4-(5-Acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl)ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 1-{3-amino-4-[4-(2-hydroxyethyl)aniline]phenyl}of ethanone (stage 2) and propionitrile.

TLC Rf = 0.4 (of hexane/ethyl acetate = 1:1).

Stage 4. 1-{2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}ethylpropane

The connection specified in the header received in accordance with the method described for stage 6 of example 1, from 2-4-(5-acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl)ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 8,39 (1H, d, J=1.2 Hz), 7,89 (1H, DD, J=1.2 Hz, 8.6 Hz), of 7.48 (2H, d, J=7,4 Hz), 7,30 (2H, d, J=7,4 Hz), 7,13 (1H, d, J=8.6 Hz), of 4.00 (2H, t, J=6.4 Hz), to 3.02 (2H, t, J=6.4 Hz), 2,80 (2H, q, J=a 7.6 Hz), 2,68 (3H, s)to 1.38 (2H, t, J=7,6 Hz).

Stage 5. 1-{1-[4-(2-Chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}alanon

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}ethanone (stage 4).

1H-NMR (CDCl3) δ to 8.40 (1H, d, 3=12 Hz), of 7.90 (1H, DD, 3=12 Hz and 8.4 Hz), 7,47 (2H, d, J=8,4 Hz), 7,32 (2H, d, J=8,4 Hz), 7,13 (1H, d, J=8,4 Hz), 3,83 (2H, t, J=7,3 Hz), 3,21 (2H, t, J=7,3 Hz), 2,82 (2H, q, J=a 7.6 Hz), 2,68 (3H, s)to 1.38 (3H, t, J=7,6 Hz).

Stage 6. 1-{1-[4-(2-Azi is oethyl)phenyl]-2-ethyl-1 H-benzimidazole-5-yl}alanon

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-{1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}ethanone (stage 5).

1H-NMR (CDCl3) δ to 8.40 (1H, d, J=1.5 Hz), of 7.90 (1H, DD, J=1.5 Hz, 8.6 Hz), 7,46 (2H, d, J=8,3 Hz), 7,12 (2H, d, J=8,3 Hz), 7,02 (1H, d, J=8.6 Hz), 3,63 (2H, t, J=6.9 Hz), 3,03 (2H, t, J=6.9 Hz), 2,80 (2H, q, J=7,4 Hz)to 2.67 (3H, s)to 1.37 (3H, t, J=7,4 Hz).

Stage 7. 1-{1-[4-(2-amino-ethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}alanon

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-{1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}ethanone (stage 6).

1H-NMR (CDCl3) δ to 8.40 (1H, d, J=1.7 Hz), of 7.90 (1H, DD, J=1.7 Hz, 8.6 Hz), the 7.43 (2H, d, J=8,2 Hz), 7,30 (2H, d, J=8,2 Hz), 7,13 (1H, d, J=8.6 Hz), is 3.08 (2H, t, J=6,7 Hz), is 2.88 (2H, t, J=6,7 Hz), 2,80 (2H, q, J=a 7.6 Hz), 2,68 (3H, s)to 1.38 (3H, t, J=7,6 Hz).

Stage 8. 5-Acetyl-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-{1-[4-(2-amino-ethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}ethanone (stage 7).

MS (ESI) m/z 505 (M+N)+;1H-NMR (CDCl3) δ to 8.40 (1H, d, J=1.1 Hz), 7,88 (1H, DD, J=1.1 Hz, 8.6 Hz), 7,73 (2H, d, J=8,4 Hz), 7,40 (2H, d, J=8,4 Hz), 7,27-7,31 (4H, m), 7,10 (1H, d, J=8.6 Hz), 6,74 (1 is, Sirs)and 3.59 (2H, t, J=6.9 Hz), 2,95 (2H, t, J=6.9 Hz), 2,80 (2H, q, J=7,6 Hz)to 2.67 (3H, s), is 2.40 (3H, s)of 1.36 (3H, t, J=7,6 Hz).

Example 79

Sodium salt of 5-acetyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2, starting from 5-acetyl-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 78).

TPL 155-160°C;1H-NMR (DMSO-d6) δ 8,32 (1H, d, J=1.6 Hz), 7,81 (1H, DD, J=1.6 Hz, 8.6 Hz), a 7.62 (2H, d, J=8.1 Hz), 7,42 (4H, s), 7,12-7,17, (3H, m), 3,18 (2H, Sirs), 2,71-and 2.79 (4H, m), 2.63 in (3H, s), and 2.27 (3H, s), 1,25 (3H, t, J=7,4 Hz); IR (KBr) Vmax3373, 1676, 1604, 1519, 1294, 1130, 1085, 885, 813 cm-1.

Example 80

2-Ethyl-5-methylsulphonyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-{-[4-(Methylsulphonyl)-2-nitroaniline]phenyl}ethanol

A mixture of 2-chloro-5-methylsulfonylbenzoyl (Kavalek, J.; et al.Collect. Czech. Chem. Commun, 1971, 36, 209., 2 g, 8.5 mmol), 4-aminophenylacetamido alcohol (1.4 g, 10.2 mmol) and Na2CO3(1.4 g, 12.7 mmol) in ethanol was stirred at 100°C for 16 hours. The insoluble substance was removed by filtration and washed with ethanol (100 ml). The filtrate was concentrated, and the residue was purified using flash chromatography on a column of silica gel, elwira hexane/ethylacetate the (1:4), to obtain 960 mg (34%) of the compound indicated in the title, in the form of a yellow solid.

1H-NMR (CDCl3) δ 9,84 (1H, Sirs), 8,82 (1H, d, J=2.1 Hz), 7,79 (1H, DD, J=2.1 Hz, 9.1 Hz), was 7.36 (2H, d, J=8,4 Hz), 7,22-7,38 (3H, m), of 3.94 (2H, Sirs), of 3.07 (3H, s), with 2.93 (2H, t, J=6.6 Hz).

Stage 2. 2-{4-[2-Amino-4-(methylsulphonyl)aniline]phenyl}ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-{4-[4-(methylsulphonyl)-2-nitroaniline]phenyl}ethanol (step 1).

1H-NMR (CDCl3) δ 7,31 (1H, s), 7,28 (1H, s), 7,16-7,21 (3H, m), of 6.96 (2H, d, J=8.5 Hz), to 5.56 (1H, Sirs), 3,86 (2H, t, J=6.4 Hz), 3,76 (2H, Sirs), 3,03 (3H, s)2,84 (2H, t, J=6.4 Hz).

Stage 3. 2-{4-[2-Ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[2-amino-4-(methylsulphonyl)aniline]phenyl}ethanol (step 2) and propionitrile.

TLC Rf= 0.8 in (dichloromethane/methanol = 10:1).

Stage 4. 2-{4-[2-Ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-{4-[2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ scored 8.38 (1H, d, J=1.4 Hz), to 7.77 (1H, DD, J=1.4 Hz, 8.6 Hz), to 7.50 (2H, d, J=8,4 Hz), from 7.24 to 7.32 (2H, m), 7,22 (1H, d, J=8.6 Hz), 4,01 (t, J=6.6 Hz), is 3.08 (3H, s), to 3.02 (2H, t, J=6.6 Hz), 2,82 (2H, q, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz).

Stage 5. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-5-(methylsulphonyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-{4-[2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 4).

1H-NMR (CDCl3) δ scored 8.38 (1H, d, J=1.6 Hz), 7,78 (1H, d, J=1.6 Hz, 8.6 Hz), 7,49 (2H, d, J=8.1 Hz), 7,32 (2H, d, J=8.1 Hz), 7.23 percent (1H, d, J=8.6 Hz), a-3.84 (2H, t, J=6.9 Hz), up 3.22 (2H, t, J=6.9 Hz), is 3.08 (3H, s), 2,82 (2H, q, J=7.5 Hz), to 1.38 (3H, t, J=7.5 Hz).

Stage 6. 1-[4-(2-Azidoethyl]-2-ethyl-1H-benzimidazole-5-yl methyl sulfon

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-(methylsulphonyl)-1H-benzimidazole (step 5).

1H-NMR (CDCl3) δ scored 8.38 (1H, d, J=1.5 Hz), 7,78 (1H, DD, JM,5 Hz, 8.6 Hz), 7,49 (2H, d, J=8,4 Hz), 7,32 (2H, d, J=8,4 Hz), 7,21 (1H, d, J=8.6 Hz), to 3.64 (2H, t, J=6.9 Hz), is 3.08 (3H, s), 3,03 (2H, t, J=6.9 Hz), 2,83 (2H, q, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz).

Stage 7. 2-{4-[2-Ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl methyl sulfone (stage 6).

1H-NMR (CDC 3) δ scored 8.38 (1H, d, J=1.7 Hz), to 7.77 (1H, DD, J=1.7 Hz, 8.6 Hz), 7,46 (2H, d, J=8,4 Hz), 7,21-7,30 (3H, m), 3,03-is 3.08 (5H, m), 2,89 (2H, t, J=6,7 Hz), 2,82 (2H, q, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz).

Stage 8. 2-Ethyl-5-(methylsulphonyl)-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-{4-[2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethylamine (step 7).

1H-NMR (CDCl3) δ of 8.37 (1H3 d, J=1.6 Hz), of 7.75 (1H, DD, J=1.6 Hz, 8.6 Hz), 7,74 (2H, d, J=8,4 Hz), the 7.43 (2H, d, J=8,2 Hz), 121-132 (4H, m), 7,18 (1H, d, J=8.6 Hz), 6,70 (1H, Sirs)and 3.59 (2H, t, J=6.8 Hz), is 3.08 (3H, s), 2,96 (2H, t, J=6.8 Hz), 2,82 (2H, q, J=7,6 Hz)to 2.41 (3H, s)of 1.35 (4H, t, J=7,6 Hz).

Example 81

Sodium salt of 2-ethyl-5-methylsulphonyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-5-(methylsulphonyl)-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 80).

TPL 171-178°C;1H-NMR (DMSO-d6) δ 8,08 (1H, Sirs), 7,51 to 7.62 (3H, m), 7,32 (4H, s), 7,16 (1H, d, J=8.6 Hz), 7,03 (2H, d, J=7,3 Hz), 3,09 is 3.25 (7H, m), 2,63-of 2.66 (2H, m)of 2.16 (3H, s)of 1.13 (3H, t, J=7,3 Hz); IR (KBr) Vmax3386, 1604, 1519, 1396,1299, 1128, 1085, 962, 887 cm-1.

Example 82

5-Cyano-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1 H-benzimidazole

Stage 1. 2-[(4-cyano-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 4-chloro-3-nitrobenzonitrile and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 9,80 (1H, Sirs), 8,54 (1H, d, J=2.0 Hz), to 7.50 (1H, DD, J=9,1,2,0 Hz), was 7.36 (2H, d, J=8,4 Hz), 7.23 percent (2H, d, J=8,4 Hz), 7,16 (1H, d, J=9.1 Hz), 3,94-3,91 (2H, m), with 2.93 (2H, t, J=6.6 Hz), is 1.81 (1H, m).

Stage 2. 2-[(2-Amino-4-cyanoaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[(4-cyano-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,18-7,10 (3H, m), 7,01-to 6.95 (4H, m)6,09 (1H, m), of 3.97 (2H, Sirs), 3,83-3,82 (2H, m), and 2.83 (2H, t, J=6.8 Hz), 2,31 (1H, m).

Stage 3. 2-[4-(5-Cyano-2-ethyl-1H-benzimidazole-1-phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[(2-amino-4-cyanoaniline)phenyl]ethanol (step 2).

MS (EI) m/z 347 (M+).

Stage 4. 2-[4-(5-Cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(5-cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ of 8.09 (1H, is), 7,50-the 7.43 (3H, m), 7,32-7,28 (2H, m), to 7.15 (1H, d, J=8,2 Hz), of 4.00 (2H, q, J=6.4 Hz), a 3.01 (2H, t, J=6.4 Hz), of 2.81 (2H, t, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz).

Stage 5. 2-[4-(5-Cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(5-cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

TLC Rf = 0,83 (dichloromethane/methanol = 10:1).

Stage 6. 2-[4-(5-Cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(5-cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ of 8.09 (1H, s), 7,47-7,42 (3H, m), 7,29-7,26 (2H, m), to 7.15 (1H, d, J=8,4 Hz)to 3.09 (2H, t, J=6.8 Hz), only 2.91 (2H, t, J=6.8 Hz), of 2.81 (2H, q, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz).

Stage 7. 5-Cyano-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(5-cyano-2-ethyl-1H-benzimidazole-1-yl)ethylamine (step 6).

1H-NMR (CDCl3) δ with 8.05 (1H, d, J=0.9 Hz), of 7.75 (2H, d, J=8,4 Hz), 7,43-7,40 (3H, m), 7,30-7,26 (4H, m), 7,12 (1H, d, J=8,4 Hz), 6,74 (1H, m), 3,60-to 3.58 (2H, m), 2,96 (2H, t, J=7.0 Hz), of 2.81 (2H, q, J=7.5 Hz), 2,41 (3H, s)of 1.34 (3H, t, J=7.5 Hz).

Example 83

Sodium salt of 5-cyano-2-ethyl-1-(4-{2[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-1 H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2, starting from 5-cyano-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 82).

1H-NMR (DMSO-d6) δ 8,19 (1H, d, J=1.5 Hz), to 7.59 (2H, d, J=7.9 Hz), 7,54 (1H, DD, J=8,4, 1.5 Hz), 7,41 (4H, s), 7.23 percent (1H, d, J=8,4 Hz), 7,11 (2H, d, J=7.9 Hz), 3,14 (2H, m), 2,78-2,70 (4H, m), and 2.26 (3H, s), 1,24 (3H, t, J=7,4 Hz).

Example 84

2-Ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

Stage 1. 2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide

To a mixture of 2-[4-(5-cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4 of example 82, 200 mg of 0.68 mmol), DMSO (0.06 ml, 0.82 mmol) and methanol (10 ml) was added 30% aqueous hydrogen peroxide solution (of 0.12 ml, 1.0 mmol) and 0.2 M aqueous NaOH solution (0.06 ml). The mixture was stirred at 50°C for 4 hours, then cooled. The mixture was poured into water (50 ml) and was extracted with ethyl acetate (100 ml). The organic layer was washed 2 N. aqueous NaOH (50 ml) and saturated saline (50 ml), then dried (Na2SO4) and concentrated to obtain the connection specified in the header, in the form of a light yellow solid.1H-NMR (CDCl3) δ 8,23 (1H, d, J=1.1 Hz), of 7.96 (1H, Sirs), 7,76 (1H, DD, J=1.1 Hz, 8,4 Hz), 7,42-7,51 (4H, m), 7,25 (1H, Sirs), to 7.09 (1H, d,J=8,4 Hz), 3,70 (2H, t, J=6.6 Hz), 2,85 (2H, t, J=6.9 Hz), was 2.76 (2H, q, J=7.4 Hz), 1,24 (3H, t, J=7,4 Hz).

Stage 2. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (step 1).

1H-NMR (CDCl3) δ 8,17 (1H, d, J=1.7 Hz), 7,79 (1H, DD, J=1.7 Hz, 8.5 Hz), 7,46 (2H, d, J=8,3 Hz), 7,33 (2H, d, J=8,3 Hz), to 7.15 (1H, d, J=8.5 Hz), 3,83 (2H, t, J=7.0 Hz), 3,21 (2H, t, J=7.0 Hz), 2,82 (2H, q, J=a 7.6 Hz), of 1.37 (3H, t, J=7,6 Hz).

Stage 3. 1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide (stage 2).

1H-NMR (CDCl3) δ 8,17 (1H, d, J=1.5 Hz), 7,78 (1H, DD, J=1.5 Hz, 8,4 Hz), 7,46 (2H, d, J=8,2 Hz), 7,32 (2H, d, J=8,2 Hz), 7,13 (1H, d, J=8,4 Hz), 3,62 (2H, t, J=6.8 Hz), 3,03 (2H, t, J=6.8 Hz), of 2.81 (2H, q, J=7.5 Hz), of 1.36 (3H, t, J=7.5 Hz).

Stage 4. 1-[4-(2-amino-ethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide (stage 3).

1H-NMR (CDCl3) δ 8,21 (1H, d, J=1.5 Hz), 7,79 (1H, DD, J=1.5 Hz, 8,4 Hz), the 7.43 (2H, d, J=8,2 Hz), 7,28-of 7.3 (2H, m), 7,13 (1H, d, J=8,4 Hz), 3,05 (2H, t, J=6,7 Hz), is 2.88 (2H, t, J=6,7 Hz), of 2.81 (2H, q, J=7,6 Hz)of 1.35 (3H, t, J=7,6 Hz).

Stage 5. 2-Ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-[4-(2-amino-ethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide (stage 4).

MS (ESI) m/z 506 (M+H)+;1H-NMR (CD3OD) δ 8,13 (1H, s), 7,65-7,73 (3H, m), 7,32 (2H, d, J=8,2 Hz), 7,16-7,21 (4H, m), 7,00 (1H, d, J=8.6 Hz), and 3.31 (2H, t, J=6.9 Hz), a 2.75 (2H, t, J=6.9 Hz), 2,69 (2H, q, J=7,6 Hz), of 2.21 (3H, s), 1,48 (3H, t, J=7,6 Hz).

Example 85

6-Cyano-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 3-[4-(2-Gidroksistil)aniline]-4-nitrobenzonitrile

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 3-chloro-4-nitrobenzonitrile (Tsuji,K. Chem. Pharm. Bull. 1992, 40, 2399) and 4-aminophenylacetamido alcohol.

MS (EI) m/z 383 (M+).

Stage 2. 3-[4-(2-Chloroethyl)aniline]-4-nitrobenzonitrile

The connection specified in the header received in accordance with the method described for stage 7 example 1 from 3-[4-(2-hydroxyethyl)aniline]-4-nitrobenzonitrile (stage 1).

1H-NMR (CDCl3) δ 9,46 (1H, Sirs), 8,29 (1H, d, J=8,8 Hz), 7,42 (1H, d, J=1.7 Hz), 7,35 (2H, d, J=8,3 Hz), 7,22 (2H, the, J=8,3 Hz), 6,97 (1H, DD, J=8,8, 1.7 Hz), of 3.77 (2H, t, J=7.2 Hz), of 3.13 (2H, t, J=7).

Stage 3. 4-Amino-3-[4-(2-chloroethyl)aniline]benzonitrile

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 3-[4-(2-chloroethyl)aniline]-4-nitrobenzonitrile (stage 2).

MS (EI) m/z 383 (M+).

Stage 4. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-6-carbonitrile

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 4-amino-3-[4-(2-chloroethyl)aniline]benzonitrile (stage 3) and propionitrile.

MS (EI) m/z 309 (M+);1H-NMR (CDCl3) δ of 7.82 (1H, d, J=8.6 Hz), 7,53 (1H, DD, J=8,6, 2.0 Hz), of 7.48 (2H, d, J=8,3 Hz), 7,42 (1H, d, J=2.0 Hz), 7,31 (2H, d, J=8,3 Hz), a-3.84 (2H, t, J=7.0 Hz), 3,21 (2H, t, J=7.0 Hz), 2,82 (2H, q, J=7,4 Hz)of 1.39 (3H, t, J=7,4 Hz).

Stage 5. 2-[4-(6-Cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-6-carbonitrile (stage 4).

MS (EI) m/z 316 (M+);1H-NMR (CDCl3) δ 7,83 (1H, d, J=8,4 Hz), 7,54 (1H, DD, J=8,4, 2.0 Hz), to 7.50 (2H, d, J=8,3 Hz), 7,40 (1H, d, J=2.0 Hz), 7,30 (2H, d, J=8,3 Hz)to 3.64 (2H, t, J=6.5 Hz), totaling 3.04 (2H, t, J=6.5 Hz), and 2.83 (2H, q, J=7,3 Hz), of 1.37 (3H, t, J=7,3 Hz).

Stage 6. 2-[4-(6-Cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method, described for stage 9 of example 1 from 2-[4-(6-cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (DMSO-d6) δ 8,11 (2H, Sirs), 7,87 (1H, d, J=8,4 Hz), to 7.64 (1H, DD, J=8,4, 2.0 Hz), 7,60-7,53 (5H, m), 3,20-to 3.02 (4H, m), and 2.79 (2H, q, J=7,4 Hz)of 1.28 (3H, t, J=7,4 Hz).

Stage 7. 6-Cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(6-cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ 7,83 (1H, d, J=8,4 Hz), 7,74 (2H, d, J=8,4 Hz), 7,53 (1H, DD, J=8,4, 1.5 Hz), the 7.43 (2H, d, J=8,4 Hz), 7,39 (1H, d, J=1.5 Hz), 7,33 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), to 6.75 (1H, Sirs), the 3.65-of 3.54 (2H, m), of 2.97 (2H, t, J=7.0 Hz), 2,82 (2H, q, J=7.5 Hz), 2,42 (3H, s)to 1.37 (3H, t, J=7.5 Hz).

Example 86

2-Ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-6-carboxamide

To a solution of 6-cyano-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 85, 162 mg, 0.33 mmol) in 2-methyl-2-propanol (10 ml) was added powdered KOH (66 mg, 1.0 mmol). The resulting mixture was boiled under reflux for 3 hours. After removal of solvent, the reaction mixture was distributed between dichloromethane (50 ml) and phosphate buffer (50 ml). The organic phase was separated, and the waters of the second phase was extracted with dichloromethane (50 ml). The combined organic phases were washed with saturated brine (50 ml), dried (Na2SO4) and concentrated. The residue solids papercraftantonella from ethyl acetate to obtain 105 mg (63%) of the compound indicated in the title, in the form of a white solid.

1H-NMR (CDCl3) δ 7,79 (2H, d, J=8,4 Hz), of 7.75 (1H, d, J=8,8 Hz), 7,71-7,63 (2H, m), 7,35-of 7.25 (4H, m), 7,16 (2H, d, J=8,4 Hz), 6.75 in (2H, Sirs), 6,55 (1H, Sirs), of 3.54 (2H, t, J=6.4 Hz), is 2.88 (2H, t, J=6.4 Hz), and 2.79 (2H,, kV, J=7.5 Hz), 2.40 a (3H, s)of 1.34 (3H, t, J=7.5 Hz).

Example 87

5-[(Tert-butylamino)sulfonyl]-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. N-(tert-butyl)-4-chloro-3-nitrobenzenesulfonamide

To a stirred solution of tert-butylamine (5,1 g, 70 mmol) in dichloromethane (200 ml) was added dropwise a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (17.9 g, 70 mmol) in dichloromethane (100 ml) at room temperature for 30 minutes and then the reaction mixture was stirred for 2 hours. The reaction mixture was poured into water (100 ml), the organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with water (50 ml) and saturated saline (20 ml), dried (Na2SO4) and concentrated to obtain 21,3 g (colwid) the connection specified in the header, in the form of a yellow TV is Gogo substances.

1H-NMR (CDCl3) δ scored 8.38 (1H, d, J=2.0 Hz), 8,02 (1H, DD, J=2,0, 8.6 Hz), of 7.70 (1H, d, J=8.6 Hz), of 4.95 (1H, Sirs), of 1.28 (9H, s).

Stage 2. N-(tert-butyl)-4-[4-(2-hydroxyethyl)aniline]-3-nitrobenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from N-(tert-butyl)-4-chloro-3-nitrobenzenesulfonamide (stage 1) and 4-aminophenylacetamido alcohol.

MS (EI) m/z 393 (M+);1H-NMR (CDCl3) δ 9,76 (1H, Sirs), is 8.75 (1H, d, J=2.0 Hz), 7,74 (1H, DD, J=2,0, 8.5 Hz), 7,35 (2H, d, J=8,3 Hz), 7,24 (2H, d, J=8,3 Hz), 7,17 (1H, d, J=8.5 Hz), 4,42 (1H, Sirs), 3,97-3,88 (2H, m)to 2.94 (2H, t, J=7,0 Hz), of 1.27 (9H, s).

Stage 3. N-(tert-butyl-4-(2-chloroethyl)aniline]-3-nitrobenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from N-(tert-butyl)-4-[4-(2-hydroxyethyl)aniline]-3-nitrobenzenesulfonamide (stage 2).

MS (EI) m/z 411 (M+);1H-NMR (CDCl3) δ 9,77 (1H, Sirs), 8,77 (1H, d, J=2.0 Hz), to 7.77 (1H, DD, J=2.0 a, and 8.4 Hz), 7,34 (2H, d, J=8,3 Hz), 7,25 (2H, d, J=8,3 Hz), 7,18 (1H, d, J=8,4 Hz), 4,46 (1H, Sirs), 3,76 (2H, t, J=6.8 Hz), of 3.13 (2H, t, J=6,8 Hz)of 1.28 (9H, s).

Stage 4. 3-Amino-N-(tert-butyl)-4-[4-(2-chloroethyl)aniline]benzosulfimide

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from N-(tert-butyl)-4-[4-(2-chloroethyl)aniline]-3-nitrobenzenesulfonamide (stage 3).

1 H-NMR (CDCl3) δ 7,31 (1H, d, J=2.0 Hz), 7,26 (1H, DD, 1=2,0, 8,3 Hz), to 7.15 (1H, d, J=8,3 Hz), 7,14 (2H, d, J=8,4 Hz), 6.89 in (2H, d, J=8,4 Hz), 5,49 (1H, Sirs), with 4.64 (1H, Sirs), of 3.77 (2H, Sirs), of 3.69 (2H, t, J=7.4 Hz), to 3.02 (2H, t, J=7.4 Hz), 1,24 (9H, s).

Stage 5. N-(tert-butyl)-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-sulfonamide

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 3-amino-N-(tert-butyl)-4-[4-(2-chloroethyl)aniline]benzosulfimide (stage 4) and propionitrile.

MS (EI) m/z 419 (M+);1H-NMR (CDCl3) δ a 8.34 (1H, d, J=2.0 Hz), 7,74 (1H, DD, J=2.0 a, 8,3 Hz), 7,47 (2H, d, J=8.6 Hz), 7,33 (2H, d, J=8.6 Hz), 7,16 (1H, d, J=8,3 Hz), to 4.62 (1H, Sirs), 3,83 (2H, t, J=7.0 Hz), 3,21 (2H, t, J=7.0 Hz), 2,82 (2H, q, J=7,4 Hz)of 1.39 (3H, t, J=7.4 Hz), 1,24 (9H, s).

Stage 6. 1-[4-(2-Azidoethyl)phenyl]-N-(tert-butyl-2-ethyl-1H-benzimidazole-5-sulfonamide

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from N-(tert-butyl)-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-sulfonamida (stage 5).

MS (EI) m/z 426 (M+);1H-NMR (CDCl3) δ with 8.33 (1H, d, J=2.0 Hz), 7,73 (1H, DD, J=2.0 a, and 8.4 Hz), of 7.48 (2H, d, J=8,4 Hz), 7,33 (2H, d, J=8,4 Hz), 7,14 (1H, d, J=8,4 Hz), 4,47 (1H, Sirs), 3,62 (2H, t, J=7.0 Hz), 3,03 (2H, t, J=7.0 Hz), 2,82 (2H, q, J=7.2 Hz), to 1.38 (3H, t, J=7.2 Hz) of 1.24 (9H, s).

Stage 7. 1-[4-(2-amino-ethyl)phenyl]-N-(tert-butyl)-2-ethyl-1H-benzimidazole-5-sulfonamide

The connection specified in the header, which was lucali in accordance with the method, described for stage 9 of example 1 from 1-[4-(2-azidoethyl)phenyl]-N-(tert-butyl)-2-ethyl-1H-benzimidazole-5-sulfonamida (stage 6).

1H-NMR (CDCl3) δ a 8.34 (1H, d, J=1.9 Hz), 7,74 (1H, DD, J=1,9, 8,3 Hz), 7,44 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), to 7.15 (1H, d, J=8,3 Hz), 4,88 (1H, Sirs), to 3.09 (2H, t, J=7.0 Hz), 2,95 (2H, t, J=7.0 Hz), 2,83 (2H, q, J=7.4 Hz), of 1.37 (3H, t, J=7,4 Hz) of 1.23 (9H, s).

Stage 8. 5-[(Tert-butylamino)sulfonyl]-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-[4-(2-amino-ethyl)phenyl]-N-(tert-butyl)-2-ethyl-1H-benzimidazole-5-sulfonamida (stage 7).

MS (ESI) m/z 598 (M +H)+;1H-NMR (CDCl3) δ 8,32 (1H, d, J=1.3 Hz), to 7.77-of 7.69 (3H, m), 7,41(2H, d, J=8,3 Hz), 7,33-of 7.25 (4H, m), 7,11 (1H, d, J=8.6 Hz), of 6.65 (1H, Sirs), 4,59 (1H, s), 3,63-of 3.53 (2H, m), 2,95 (2H, t, J=7.0 Hz), 2,80 (2H, q, J=7,6 Hz)to 2.41 (3H, s)of 1.36 (3H, t, J=7,6 Hz) of 1.23 (9H, s).

Example 88

5-(Aminosulfonyl)-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

A solution of 5-[(tert-butylamino)sulfonyl]-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 87, 330 mg, 0.55 mmol) in triperoxonane acid (10 ml) was heated at 80°C for 2 hours. The mixture was concentrated, and the residue was purified flash chromatography with silicagel is m, elwira dichloromethane/methanol (10:1), to obtain 215 mg (73%) of the connection specified in the header.

MS (EI) m/z 542(M+N)+.

1H-NMR (CDCl3) δ 8,32 (1H, d, J=1.3 Hz), to 7.77-of 7.69 (3H, m), 7,41(2H, d, J=8,3 Hz), 7,33-of 7.25 (4H, m), 7,11 (1H, d, J=8.6 Hz), of 6.65 (1H, Sirs), 4,59 (1H, s), 3,63-of 3.53 (2H, m), 2,95 (2H, t, J=7.0 Hz), 2,80 (2H, q, J=7,6 Hz)to 2.41 (3H, s)of 1.36 (3H, t, J=7,6 Hz) of 1.23 (9H, s).

Example 89

2-Ethyl-1-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}-5-[(methylsulphonyl)amino]-1H-benzimidazole

Stage 1. 2-4-(2,4-Dinitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2-chloro-1,5-dinitrobenzene and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 9,95 (1H, s), 9,18 (1H, d, J=2.4 Hz), 8,16 (1H, DD, J=2.7, and 9.7 Hz), 7,39 (2H, d, J=8,4 Hz), 7,26 (2H, d, J=8.1 Hz), 7,16 (1H, d, J=9.5 Hz), 3,93 (2H, dt, J=5,7, 6.2 Hz), to 2.94 (2H, t, J=6.8 Hz), 1,50 (1H, t, J=5.7 Hz).

Stage 2. 2-[4-(2-Amino-4-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 40, from 2-[4-(2,4-dinitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,73-to 7.67 (2H, m), 7,22 (2H, d, J=8,3 Hz), 7,11 (1H, d, J=9.3 Hz),? 7.04 baby mortality (2H, d, J=8,3 Hz), 5,80 (1H, s), 3,88 (2H, dt, J=5,7, 6,0 Hz), of 3.69 (2H, Sirs), 2,87 (2H, t, J=6.4 Hz), 1,48 (1H, Shir.).

Stage 3. 2-[4-(2-Ethyl-5-nitro-1H-benzimidazole-1-yl)phenyl]ethylpropane

Connection, asanee in the header, received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-amino-4-nitroaniline)phenyl]ethanol (step 2) and propionitrile.

1H-NMR (CDCl3) δ 8,68 (1H, d, J=2.2 Hz), 8,13 (1H, DD, 3=2,2, 9.0 Hz), of 7.48 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,3 Hz), 7,13 (1H, d, J=8,97 Hz), 4,39 (2H, t, J=6.8 Hz), to 3.09 (2H, t, J=7.0 Hz), of 2.81 (2H, q, J=7,5 Hz), a 2.36 (2H, q, J=7.5 Hz), to 1.38 (3H, t, J=7.5 Hz)and 1.15 (3H, q, J=7.5 Hz).

Stage 4. 2-[4-(5-Amino-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

To a stirred solution of 2-[4-(2-ethyl-5-nitro-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3, 1.12 g, 3.0 mmol) in ethanol/water (vol./about., 2:1, 15 ml) was added ammonium chloride (80 mg, 1.5 mmol) and iron powder (840 mg, 15 mmol) at room temperature. The mixture was boiled under reflux for 4 hours and filtered through a thick layer of celite. The filtrate was concentrated and the residue was dissolved in dichloromethane (200 ml), then dried (MgSO4). Removal of solvent gave 0.84 g (83%) of the compound indicated in the title, in the form of a yellow oil.1H-NMR (CDCl3) δ 7,41 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8.6 Hz), 7,10 (1H, d, J=1,8 Hz), 6.89 in (1H, d, J=8,4 Hz), 6,63 (1H, DD, J=2,2, 8,4 Hz), 4,37 (2H, t, J=7.0 Hz), 3,05 82H, t, J=7,1 Hz), and 2.79 (2H, q, J=7.5 Hz,), to 2.35 (2H, q, J=7.5 Hz), of 1.33 (3H, t, J=7,50 Hz)to 1.14 (3H, t, J=7,7 Hz).

Stage 5. (4-{2-Ethyl-5-[(methylsulphonyl)amino]-1H-benzimidazole-1-yl}phenyl)ethylpropane

To a stirred solution of 2-[4-(5-amino-2-the Teal-1 H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 4, 1.18 g, 3.50 mmol) in dichloromethane (20 ml) was added methanesulfonyl chloride (0,40 ml of 5.25 mmol) and pyridine (0,42 ml of 5.25 mmol) at room temperature. After stirring for 6 hours the mixture was poured into 10% aqueous citric acid solution (100 ml) and was extracted with ethyl acetate (100 ml). The aqueous layer was podslushivaet saturated aqueous sodium bicarbonate (100 ml) and was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with saturated salt solution (100 ml) and dried (MgSO4) and concentrated to obtain 1.28 g (88%) of the compound indicated in the title, in the form of a brown amorphous substance.1H-NMR (CDCl3) δ of 8.47 (1H, s), 7,66 (1H, d, 3=1.1 Hz), to 7.50 (2H, d, J=8,4 Hz), 7,42 (1H, DD, J=2.0 a, 8,8 Hz), 7,41 (2H, d, J=8,4 Hz), to 7.09 (1H, d, J=8,8 Hz), 4,39 (2H, t, J=7,0 Hz)to 3.09 (2H, t, J=6.8 Hz), 3,00 (2H, q, J=7,7 Hz), a 2.36 (2H, q, J=7,7 Hz)of 1.42 (3H, t, J=7,7 Hz)and 1.15 (3H, t, J=7.5 Hz).

Stage 6. 2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}methanesulfonamide

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-(4-{2-ethyl-5-[(methylsulphonyl)amino]-1H-benzimidazole-1-yl}phenyl)ethylpropylamine (stage 5).

1H-NMR (CDCl3) δ 7,63 (1H, d, J=1,8 Hz), 7,46 (2H, d, J=8,2 Hz), 7,29 (2H, d, J=8,4 Hz), 7,18 (1H, DD, J=2,1, 8.6 Hz), 7,07 (1H, d, J=8.6 Hz), of 6.68 (1H, W), to 3.99 (2H, t, J=6.4 Hz), 3,01 (2H, the, J=6.8 Hz), 2,98 (3H, s), and 2.79 (2H, q, J=7.4 Hz), of 1.35 (3H, t, J=7,6 Hz).

Stage 7. N-{1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}methanesulfonamide

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}methanesulfonamide (stage 6).

1H-NMR (CDCl3) δ 7,74-6,85 (7H, m), 3,83 (2H, t, J=7,1 Hz), 3,21 (2H, t, J=7,1 Hz), 2,98 (3H, s), 2,85 (2H, q, J=7.5 Hz), to 1.38 (3H, t, J=7.5 Hz).

Stage 8. N-{1-[4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}methanesulfonamide

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from N- {1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}methanesulfonamide (stage 7).

1H-NMR (CDCl3) δ to 7.64 (1H, W), was 7.45 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8.1 Hz), 7,19 (1H, DD, J=1,8, 8,8 Hz), 7,07 (1H, d, J=8,4 Hz), for 6.81 (1H, s), 3,62 (2H, t, J=6.8 Hz), to 3.02 (2H, t, J=7.0 Hz), 2,98 (3H, s), and 2.79 (2H, q, J=7.5 Hz), of 1.35 (3H, t, J=7.5 Hz).

Stage 9. N-{1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}methanesulfonamide

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from N- {1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}methanesulfonamide (stage 8).

MS (EI) m/z 358 (M+).

Stage 10. N-{1-[4-(2-amino-ethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}methane is sulfonamid

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from N - {1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}methanesulfonamide (stage 9).

MS (ESI) m/z 556 (M+N)+;1H-NMR (CDCl3) δ 9,49 (1H, s), 7,76 (2H, d, J=7,1 Hz), 7,51 (1H, W), 7,42-7,34 (6H, m), 7,07 (1H, d, J=8.6 Hz), 7,01 (1H, d, J=8.6 Hz), 6,53 (1H, W), 3,40-to 3.33 (2H, m), 2,89 (3H, s), 2,81-of 2.66 (4H, m), of 2.33 (3H, s)to 1.21 (3H, t, J=7.5 Hz); IR (KBr) Vmax1697, 1684, 1508, 1458, 1148 cm-1.

Example 90

2-Ethyl-5-hydroxy-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 1-[4-(2-Bromacil)phenyl]-2-ethyl-1H-benzimidazole-5-ol

A mixture of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-methoxy-1H-benzimidazole (step 5 of example 71, 600 mg, 1.9 mmol) in 48% Hydrobromic acid (60 ml) was stirred at 100°C for 6 hours. After cooling, the mixture was neutralized 2 N. aqueous NaOH and was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated saline (50 ml), dried (Na2SO4) and concentrated, to obtain 890 mg (Nr. output) connections specified in the header, in the form of a light yellow solid.

1H-NMR (CDCl3) δ to 7.64 (4H, s), 7,16 (2H, m), 6,97-7,01 (1H, m), 3,86 (2H, t, J=7,1 Hz), 3,30 (2H, t, J=7,1 Hz), of 2.92 (2H, q, J=7,8 Hz)of 1.29 (3H, t, J=7,8 Hz).

Stage 2. Tert-butyl(dimethyl)silloway ester 1-[4-(2-brome who yl)phenyl]-2-ethyl-1 H-benzimidazole-5-Il

A mixture of 1-[4-(2-bromoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-ol (step 1, 200 mg of 0.58 mmol), tert-butyldimethylsilyl chloride (100 mg, 0.7 mmol) and imidazole (47 mg, 1,45 mmol) in DMF (5 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water (50 ml) and was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated saline (50 ml), then dried (Na2SO4). After removal of solvent the crude product was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (1:1), to obtain 119 mg (45%) of the compound indicated in the title, in the form of a white solid.

1H-NMR (CDCl3) δ then 7.20 (2H, d, J=8,4 Hz), 7,10 (2H, d, J=8,4 Hz), 7,01 (1H, d, J=2.3 Hz), 6,72 (1H, d, J=8.6 Hz), of 6.52 (1H, DD, J=2.3 Hz, 8.6 Hz), of 3.45 (2H, t, J=7.4 Hz), of 3.07 (2H, t, J=7.4 Hz), of 2.56 (2H, q, J=7.5 Hz), to 1.14 (3H, t, J=7.5 Hz), of 0.79 (9H, s), of 0.05 (6H, s).

Stage 3. Tert-butyl(dimethyl)silloway ether1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-Il

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from tert-butyl(dimethyl)salelologa ester 1-[4-(2-bromoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl (stage 2).

1H-NMR (CDCl3) δ then 7.20 (2H, d, J=8,3 Hz), 7,02 for 7.12 (3H, m), 6,70 (1H, d, J=8.6 Hz), 6,50-is 6.54 (1H, m), 3,39 (2H, t, J=6.9 Hz), and 2.79 (2H, t, J=6.9 Hz), to 2.55 (2H, q, J=7,6 Hz)of 1.13(3H, t, J=7,6 Hz)of 0.79 (9H, s)0,00 (6H, s).

Stage 4. 2-[4-(5-{[Tert-butyl(dimethyl)silyl]oxy}-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from tert-butyl(dimethyl)salelologa ester 1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl (stage 3).

1H-NMR (CDCl3) δ to 7.18 (2H, d, J=8,2 Hz), 7,02-was 7.08 (3H, m), 6,72 (1H, d, J=8.6 Hz), of 6.52 (1H, DD, J=2.2 Hz, 8.6 Hz), of 2.86 (2H, t, J=6.6 Hz), to 2.66 (2H, t, J=6.6 Hz), to 2.55 (2H, q, J=7.5 Hz), of 1.13 (3H, t, J=7.5 Hz), of 0.79 (9H, s)0,00 (6H, s).

Stage 5. 5-{[Tert-butyl(dimethyl)silyl]oxy}-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(5-{[[tert-butyl(dimethyl)silyl]oxy}-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (stage 4).

1H-NMR (CDCl3) δ 7,53 (2H, d, J=8,3 Hz), 7,02-7,13 (711, m)6,70 (1H; d, J=8.6 Hz), of 6.52 (1H, DD, J=2.2 Hz, 8.6 Hz), 6,46 (1H, Sirs), 3,37 (2H, t, J=6.4 Hz), a 2.71 (2H, t, J=6.4 Hz), 2,53 (2H, q, J=7,6 Hz)to 2.18 (3H, C)a 1.11 (3H, t, J=7,6 Hz)of 0.79 (9H, s)0,00 (6H, s).

Stage 6. 2-Ethyl-5-hydroxy-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

A solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazo the La (stage 5,78 mg, 0.13 mmol) in THF (5 ml) was added tetrabutylammonium fluoride (a 1.0 M solution in THF, 0.16 ml, 0.16 mmol) at 0°C. the Mixture was stirred at 0°C for 2.5 hours, then was concentrated. The residue was dissolved in water (30 ml) and was extracted with dichloromethane (50 ml). The organic layer was dried (Na2SO4) and concentrated. The residue was purified using flash chromatography on a column of silica gel, elwira dichloromethane/methanol (gradient elution from 20:1 to 10:1), with 57 mg (92%) of the compound indicated in the title, in the form of a white amorphous substance.

MS (ESI) m/z 479 (M+N)+;1H-NMR (DMSO-d6) δ 7,76 (2H, d, J=7,6 Hz), 7,35-7,39 (6H, m), of 6.96 (1H, s), 6,85 (1H, d, J=8.6 Hz), of 6.65 (1H, d, J=8.6 Hz), 6,51 (1H, Sirs), 3,17 (2H, Sirs), was 2.76 (2H, t, 6.6 Hz), to 2.67 (2H, q, J=7,6 Hz), was 2.34 (3H, s), of 1.20 (3H, t, J=7,6 Hz).

Example 91

2-Ethyl-4,5-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[(3,4-Dimethyl-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 45, from 3,4-dimethyl-2-nitroaniline and 4-bromperidol ethanol.

1H-NMR (CDCl3) δ 7,16 (2H, d, J=8,4 Hz), to 7.09 (1H, s), 7,03 (2H, d, J=8,4 Hz)6,91 (1H, s), 3,89-3,81 (2H, m), and 2.83 (2H, t, J=6.4 Hz), and 2.27 (3H, in), 2.25 (3H, s).

Stage 2. 2-[(2-Amino-3,4-dimethylaniline)phenyl]ethanol

The connection specified in sagola the ke, received in accordance with the method described for step 2 of example 28, from 2-[(3,4-dimethyl-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,02 (2H, d, J=8.6 Hz), 6,86 (1H, d, J=7.9 Hz), 6,62 return of 6.58 (3H, m), 5,09 (1H, Sirs), of 3.77 (2H, t, J=6.6 Hz), is 2.74 (2H, t, J=6.6 Hz), and 2.27 (3H, s), 2,11 (3H, s).

Stage 3. 2-[4-(2-Ethyl-4,5-dimethyl-1H-benzimidazole-1-yl)phenyl ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[(2-amino-3,4-dimethylaniline)phenyl]ethanol (step 2) and propionitrile.

MS (EI) m/z 350 (M+).

Stage 4. 2-[4-(2-Ethyl-4,5-dimethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-4,5-dimethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,4 Hz), 7,27 (2H, d, J=8,4 Hz), of 6.99 (1H, d, J=8,3 Hz), PC 6.82 (1H, d, J=8,3 Hz), 3,98 (2H, t, J=6.6 Hz), 2,99 (2H, t, J=5.6 Hz), 2,82 (2H, q, J=7.5 Hz), 2.63 in (3H, s), 2,39 (3H, C)of 1.26 (3H, t, J=7.5 Hz).

Stage 5. 2-[4-(2-Ethyl-4,5-dimethyl-1H-benzimidazole-1-phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(2-ethyl-4,5-dimethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8.6 Hz), 7,30 2H, d, J=8.6 Hz), 7,00 (1H, d, J=8,2 Hz), PC 6.82 (1H, d, J=8,2 Hz), 3,61 (2H, t, J=7,1 Hz), a 3.01 (2H, t, J=7,1 Hz), and 2.83 (2H, q, J=7,6 Hz), 2.63 in (3H, s), 2,39 (3H, s)of 1.26 (3H, t, J=7,6 Hz).

Stage 6. 2-[4-(2-Ethyl-4,5-dimethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-4,5-dimethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ 7,39 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), of 6.99 (1H, d, J=8,2 Hz), 6,83 (1H, d, J=8,2 Hz), to 3.09 (2H, t, J=6.6 Hz), 2,92-and 2.79 (4H, m), 2.63 in (3H, s), 2,39 (3H, s)of 1.27 (3H, t, J=7,6 Hz).

Stage 7. 2-Ethyl-4,5-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-4,5-dimethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ 7,76 (2H, d, J=8,2 Hz), 7,30-7,19 (6H, m), 7,00 (1H, d, J=8,2 Hz), for 6.81 (1H, d, J=8,2 Hz), of 6.65 (1H, m), 3,56-of 3.54 (2H, m), 2,89 (2H, t, J=6.9 Hz), 2,80 (2H, q, J=7,6 Hz)at 2.59 (3H, s), of 2.38 (6H with), to 1.22 (3H, t, J=7,6 Hz).

Example 92

Sodium salt of 2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]Amin is}carbonyl)amino]ethyl}phenyl)-1 H-benzimidazole (example 91).

1H-NMR (DMSO-d6) δ to 7.59 (2H, d, J=8,4 Hz), 7,39-7,30 (4H, m), 7,12 (2H, d, J=8,4 Hz)6,94 (1H, d, J=8,3 Hz), 6,77 (1H, d, J=8,3 Hz), of 3.13 (2H, m), 2,74-to 2.67 (4H, m), 2,48 (3H, s), is 2.30 (3H, s), and 2.27 (3H, s), 1,19 (3H, t, J=7.5 Hz); IR (KBr) Vmax1599, 1516, 1425, 1227, 1128, 1086 cm-1.

Example 93

4,6-Dimethyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[4-(3,5-Dimethyl-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 4,6-dimethyl-2-peritrabecular and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 8,08 (1H, Sirs), 7,22 (2H, d, J=8,4 Hz), 7,13 (2H, d, J=8,4 Hz)6,91 (1H, s), 6,51 (1H, s)to 3.89 (2H, t, J=6.4 Hz), 2,87 (2H, t, J=6.4 Hz), 2,47 (3H, s), 2,22 (3H, s).

Stage 2. 2-[4-2-Amino-3,5-dimethylaniline]phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 2-[4-(3,5-dimethyl-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 6,97? 7.04 baby mortality (2H, m), 6,78 (1H, s), 6,74 (1H, s), 6,59 is 6.67 (1H, s), 5,15 (1H, Sirs), 3,76 (2H, t, J=6.6 Hz), is 2.74 (2H, t, J=6.6 Hz), to 2.18 (3H, s), 2,17 (3H, s).

Stage 3. 2-[4-(2-Ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(amino-3,5-dimethylaniline)phenyl]ethanol (step 2) and propionitrile.

TLC Rf = 0,7 (hexane/ethyl acetate= 1:1).

Stage 4. 2-[4-(2-Ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-amino-3,5-dimethylaniline)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8.1 Hz), make 6.90 (1H, s)of 6.71 (1H, s), 3,98 (2H, t, J=6.4 Hz), 2,99 (2H, t, J=6.4 Hz), of 2.81 (2H, q, J=7,3 Hz), 2,65 (3H, s), a 2.36 (3H, s)of 1.24 (3H, t, J=7,3 Hz).

Stage 5. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8.0 Hz), 7,30 (2H, d, J=8.0 Hz), 6.90 to (1H, s)of 6.71 (1H, s), 3,81 (2H, t, J=7.2 Hz), 3,19 (2H, t, J=7.2 Hz), of 2.81 (2H, q, J=7,7 Hz)to 2.67 (3H, s), is 2.37 (3H, s), 1,25 (3H, t, J=7,7 Hz).

Stage 6. 2-[4-(2-Ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole (step 5).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,3 Hz), 7,30 (2H, d, J=8,3 Hz), make 6.90 (1H, s), 6,69 (1H, s), 3,62 (2H, t, J=7.0 Hz), 3,01 (2H, d, J=7,0 Hz), of 2.81 (2H, q, J=7.5 Hz), to 2.66 (3H, s), a 2.36 (3H, s), 1,25 (3H, t, J=7.5 Hz).

Stage 7. 2-[4-(2-Ethyl-4,6-d is methyl-1 H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 6).

1H-NMR (CDCl3) δ 7,40 (2H, d, J=8,2 Hz), 7,27 (2H, d, J=8,2 Hz), 6.89 in (1H, s)of 6.71 (1H, s), of 3.07 (2H, t, J=6.9 Hz), 2.77-to 2,89 (4H, m)to 2.67 (3H, s), a 2.36 (3H, s), 1,25 (3H, t, J=7,6 Hz).

Stage 8. 2-Ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 7).

TPL 108-112°C; MS (ESI) m/z 491 (M+N)+;1H-NMR (CDCl3) δ of 7.75 (2H, d, J=8,2 Hz), 7.18 in-7,29 (6H, m), 6.89 in (1H, s), to 6.67 (1H, s), 6,62 (1H, Sirs), 3,51 (2H, Sirs), of 2.86 (2H, Sirs), was 2.76 (2H, q, J=7.4 Hz), 2.63 in (3H, s), is 2.37 (3H, s), of 2.33 (3H, s)of 1.20 (3H, t, J=7,4 Hz).

Example 94

5,6-Dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-1H-benzimidazole

Stage 1. 2-[(4,5-dimethyl-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 45, from 4,5-dimethyl-2-nitroaniline and 4-bromophenylacetate alcohol.

1H-NMR (CDCl3) δ 9,39 (1H, Sirs), of 7.96 (1H, s), 7,27 (2H, d, J=8,4 Hz), 7,21 (2H, d, J=8,4 Hz), 7,01(1H, C)3,91 (2H, q, J=6.4 Hz), 2,90 (2H, t, J=6.4 Hz), measuring 2.20 (3H, s), are 2.19 (3H, s).

Stage 2. 2-[(2-Amino-4,5-l]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[(4,5-dimethyl-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ? 7.04 baby mortality (2H, d, J=8,4 Hz)6,86 (1H, s), only 6.64 (2H, d, J=8,4 Hz), is 6.61 (1H, s), with 3.79 (2H, t, J=6.6 Hz), was 2.76 (2H, t, J=6.6 Hz), 2,19 (3H, s)a 2.12 (3H, s).

Stage 3. 2-[4-(2-Ethyl-5,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[(2-amino-4,5-dimethylaniline)phenyl]ethanol (step 2) and propionitrile.

MS (EI) m/z 350 (M+).

Stage 4. 2-[4-(2-Ethyl-5,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-ethyl-5,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 7,52 (1H, s), 7,44 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), 6.87 in (1H, s), of 4.00 (2H, t, J=6.6 Hz), a 3.01 (2H, t, J=6.6 Hz), was 2.76 (2H, q, J=7.5 Hz), a 2.36 (3H, s)to 2.29 (3H, s)is 1.31 (3H, t, J=7.5 Hz).

Stage 5. 2-[4-(2-Ethyl-5,6-dimethyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26 from 2-[4-(2-ethyl-5,6-dimethyl-1 H-benzimidazole-1-yl)phenyl]ethanol (step 4).

TLC Rf = 0.70 and (hexane/ethyl acetate = 1:1).

Stage 6. 2-[4-(2-Ethyl-5,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-5,6-dimethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ 7,53 (1H, s), 7,40 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8.1 Hz), 6.87 in (1H, s), 3,17 (2H, t, J=7,3 Hz)of 3.00 (2H, t, J=7,3 Hz), was 2.76 (2H, q, J=7.5 Hz), a 2.36 (3H, s)to 2.29 (3H, s)is 1.31 (3H, t, J=7.5 Hz).

Stage 7. 2-Ethyl-5,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-5,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ 7,79 (2H, d, J=8.1 Hz), of 7.48 (1H, s), 7,29-to 7.15 (6H, m)6,86 (1H, s), 6,60 (1H, Sirs), 3,57-3,55 (2H, m), 2.91 in-2,89 (2H, m), 2,70 (2H, q, J=7.5 Hz), 2,39 (3H, s)to 2.35 (3H, s), and 2.27 (3H, s), 1,25 (3H, t, J=7.5 Hz).

Example 95

Sodium salt of 5,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-5,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1Hbe the of imidazole (example 94).

1H-NMR (DMSO-d6) δ of 7.60 (2H, d, J=8.1 Hz), 7,39-to 7.32 (5H, m), 7,13 (2H, d, J=8.1 Hz), 6,86 (1H, s), and 3.16 (2H, m), 2,73-of 2.64 (4H, m)to 2.29 (3H, s), and 2.27 (3H, s), of 2.23 (3H, s)of 1.20 (3H, t, J=7.4 Hz); IR(KBr) Vmax1599, 1516, 1468, 1404, 1283, 1236, 1130, 1086 cm-1.

Example 96

5,6-Dichloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[4-(4,5-Dichloro-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, based on 2,4,5-trichloronitromethane and 4-aminophenylacetamido alcohol.

MS (EI) m/z 327 (M+).

Stage 2. 2-[4-(2-Amino-4,5-dichloroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[4-(4,5-dichloro-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,16 (1H, s), 7,11 (2H, d, J=8.0 Hz), 6.87 in (1H, s), 6,74 (2H, d, J=8.0 Hz), 5,10 (1H, Sirs), 3,90-of 3.60 (2H, m), and 2.79 (2H, t, J=7,0 Hz).

Stage 3. 2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-amino-4,5-dichloroaniline)phenyl]ethanol (step 2) and propionitrile.

MS (EI) m/z 390 (M+);1H-NMR (CDCl3) δ to 7.84 (1H, s), was 7.45 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8.1 Hz), 7,16 (1H, s), 4,37 (2H, t, J=6.8 Hz), to 3.09 (2H, t, J=6 Hz), 2,77 (2H, q, J=7.5 Hz), a 2.36 (2H, q, J=7.5 Hz), of 1.35 (3H, t, J=7.5 Hz), of 1.16 (3H, t, J=7.5 Hz).

Stage 4. 2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ to 7.84 (1H, s), 7,47 (2H, d, J=8.0 Hz), 7,28 (2H, d, J=8.0 Hz), 7,18 (1H, s), 4,10-of 3.94 (2H, m), a 3.01 (2H, t, J=6.4 Hz), 2,77 (2H, q, J=7.5 Hz), of 1.34 (3H, t, J=7.5 Hz).

Stage 5. 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

MS (EI) m/z 359 (M+);1H-NMR (CDCl3) δ a 7.85 (1H, s), 7,46 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8.1 Hz), 7,17 (1H, s), 3,62 (2H, t, J=7.0 Hz), to 3.02 (2H, t, J=7.0 Hz), was 2.76 (2H, q, J=7.5 Hz), of 1.34 (3H, t, J=7.5 Hz).

Stage 6. 2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ to 7.84 (1H, s), the 7.43 (2H, d, J=8,4 Hz), 7,27 (2H, d, J=8,4 Hz), 7,22 (1H, s), 3,14 (2H, t, J=7.2 Hz), of 2.97 (2H, t, J=7.2 Hz), was 2.76 (2H, q, J=7,6 Hz), 2,10 (2H, Sirs), of 1.34 (3H, t, J=7,6 Hz).

Stage 7. 5,6-is ALOR-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1 H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ 8,01 (1H, s), of 7.70 (2H, d, J=8,3 Hz), 7,46 (2H, d, J=8,3 Hz), of 7.36-7.29 trend, (3H, m) of 7.24 (2H, d, J=8,3 Hz), for 6.81 (1H, Sirs), 3,57-of 3.46 (2H, m), 3,06-is 2.88 (4H, m), of 2.38 (3H, s)of 1.43 (3H, t, J=6,9 Hz).

Example 97

2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4 of example 96).

1H-NMR (CDCl3) δ a 7.92 (2H, d, J=8,4 Hz), the 7.85 (1H, s), 7,37 (2H, d, J=8,4 Hz), 7,35 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), 7,16 (1H, s), 4.72 in (1H, Sirs), to 4.38 (2H, t, J=6.8 Hz), 3,03 (2H, t, J=6.8 Hz), 2,75 (2H, q, J=7.5 Hz), 2,44 (3H, s)of 1.34 (3H, t, J=7.5 Hz).

Example 98

5,6-Dichloro-2-ethyl-1-(4-{2-[hydroxy({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 1-[4-(2-{(Tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino}ethyl)phenyl]-5,6-dichloro-2-ethyl-1H-benzimidazole

To a stirred mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (example 96, 100 mg, 0.3 mmol), N,O-bis-tert-butoxycarbonyloxyimino (Baillie, L. C.; Batsanov, A.; Bearder, J. R.; Whiting, D. A. J.Chem. Soc. Perkin Trans. 1, 1998,20, 3471., 140 mg, 0.6 mmol) and triphenylphosphine (158 mg, 0.6 mmol) in THF (10 ml) was added diethyl azodicarboxylate (DEAD) (0.1 ml, 0.6 mmol). The mixture was stirred in nitrogen atmosphere at room temperature for 2.5 hours. The solvent was removed and the residue was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (1:1), to obtain 174 mg (amounts.) the connection specified in the header, in the form of a yellow amorphous substance.

1H-NMR (CDCl3) δ to 7.84 (1H, s), 7,46 (2H, d, J=8,4 Hz), 7,25 (2H, d, J=8,4 Hz), 7,16 (1H, s)to 3.92 (2H, t, J=6,7 Hz), 3,05 (2H, t, J=6,7 Hz), was 2.76 (2H, q, J=7,6 Hz), and 1.56 (9H, s)of 1.46 (9H, s)of 1.33 (3H, t, J=7,6 Hz).

Stage 2. N-{2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl}hydroxylamine

A mixture of 1-[4-(2-{(tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino}ethyl)phenyl]-5,6-dichloro-2-ethyl-1H-benzimidazole (stage 1,174 mg, 0.3 mmol) and 2 N. hydrochloric acid (3 ml) in ethyl acetate (20 ml) was stirred at room temperature for 1 day. The reaction mixture was poured into water (100 ml), neutralized with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated saline (50 ml), dried (Na2SO4) and concentrated to obtain 162 mg (colwid) the connection specified in the header, in the form of a yellow oil.

1H-NMR (CDl 3) δ 10,35 (2H, Sirs), 7,89 (1H, s), 7,46 is 7.50 (2H, m), 7,29 (2H, d, J=6.8 Hz), 7,17 (1H, s), 3,37 (2H, t, J=6.9 Hz), of 3.12 (2H, t, J=6.9 Hz), 2,80 (2H, q, J=6.9 Hz), of 1.34 (3H, m).

Stage 3. 5,6-Dichloro-2-ethyl-1-(4-{2-[hydroxy({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The interaction was carried out according to the method described for stage 10 of example 1 from N-{2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl}hydroxylamine (stage 2).

MS (ESI) m/z 547 (M+N)+;1H-NMR (CDCl3) δ a 7.92 (2H, d, J=8,4 Hz), 7,79 (2H, d, J=7,2 Hz), 7,34 was 7.45 (2H, m), 7,13-to 7.18 (4H, m), 3,85 (1H, Sirs), was 3.05 (2H, Sirs), 2,66 is 2.80 (4H, m), of 2.38 (3H, s)of 1.32 (3H, t, J=7.4 Hz); IR (KBr) Vmax1654, 1517, 1452, 1164, 1095, 869 cm-1.

Example 99

5,6-Dichloro-2-ethyl-1-(4-{CIS-3-[({[(4-were)sulfonyl]amino}carbonyl)amino]cyclobutyl}phenyl)-1H-benzimidazole

Stage 1. TRANS-3-phenylcyclohexyl benzoate

To a stirred solution of CIS-3-phenylcyclohexanol (Eckehard, V.D.,et al. Chem. Ber., 1993, 126, 2759., 4.6 g, 30.2 mmol), triphenylphosphine (3.3 g, 59,1 mmol) and benzoic acid (7,6 mg of 62.3 mmol) was added diethyl azodicarboxylate (DEAD) (10,9 g of 62.3 mmol) at room temperature. The resulting mixture was stirred at room temperature for 40 minutes, then the mixture was concentrated. The residue was dissolved in diethyl ether (100 ml) and washed with saturated aqueous sodium bicarbonate (50 ml), water (50 ml) and the us is breeding brine (50 ml). The organic layer was dried (Na2SO4) and concentrated. Was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (10:1), obtaining of 6.52 g (86%) of the compound indicated in the title, in the form of a light yellow oil.

1H-NMR (CDCl3) δ 7,71-7,20 (10H, m), 5,49-5,41 (1H, m), 3,82-and 3.72 (1H, m), 2,78-of 2.64 (4H, m).

Stage 2. TRANS-3-phenylcyclohexanol

To a solution of TRANS-3-phenylcyclohexyl benzoate (step 1, 6.5 g, 26.0 mmol) in methanol (100 ml) was added 4 N. aqueous LiOH solution (20 ml, 80 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was concentrated. The residue was dissolved in water (100 ml) and was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated saline (100 ml), dried (Na2SO4) and concentrated. Was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (5:1), with the 3.65 g (93%) of the compound indicated in the title, in the form of a colorless oil.1H-NMR (CDCl3) δ 7,34-7,16 (5H, m), 4,60-4,51 (1H, m), 3,69-3,59 (1H, m), 2,55-is 2.37 (4H, m).

Stage 3. TRANS-3-(4-nitrophenyl)cyclobutanol

To a mixture of nitric acid (fuming, 2,3 ml) and acetic anhydride (25 ml) was added dropwise a mixture of TRANS-3-phenylcyclopropane (stage 2, 3.7 g, 24.6 mmol) and sulfuric acid in acetic anhydride (25 ml) at -23°C. Polucen the th mixture was stirred in an ice bath for 1.5 hours. The mixture was poured into ice water (200 ml) and was extracted with dichloromethane (2 x 100 ml). The organic layer was washed with water and saturated saline solution (100 ml), then dried (Na2SO4) and concentrated. The oily residue was dissolved in methanol (100 ml) was added 4 N. aqueous LiOH (50 ml). The resulting mixture was stirred at room temperature for 10 minutes, then concentrated. The residue was dissolved in water (100 ml) and was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated saline solution, dried (Na2SO4) and concentrated. Was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (2:1), to obtain 2.7 g (56%) of the compound indicated in the title, in the form of a light yellow oil.

MS (EI) m/z 193 (M+);1H-NMR (CDCl3) δ 8,18 (2H, d, J=8.6 Hz), 7,38 (2H, d, J=8.6 Hz), 4,62-to 4.52 (1H, m), 3,81-3,71 (1H, m), 2,54 at 2.45 (4H, m).

Stage 4. TRANS-3-(4-AMINOPHENYL)cyclobutanol

To a stirred solution of TRANS-3-(4-nitrophenyl)cyclobutanol (stage 3, 1.0 g, 4.9 mmol) in methanol (20 ml) was added 10% Pd-C (50 mg). The mixture was stirred at room temperature in a hydrogen atmosphere for 2.5 hours. The palladium catalyst was removed by filtration and washed with methanol (100 ml) and ethyl acetate (100 ml). The filtrate was concentrated under reduced pressure to obtain 0.9 g (colwid) connection, asanoha in the header, in the form of a light yellow solid. MS (EI) m/z 163 (M+);1H-NMR (CDCl3) δ 7,03 (2H, d, J=8,3 Hz), of 6.66 (2H, d, J=8,3 Hz), 4,56-4,47 (1H, m), to 3.58-of 3.48 (3H, m), 2,48-2,31 (2H,m)of 1.73 (1H, d, J=5,1 Hz).

Stage 5. TRANS-3-[4-(4,5-dichloro-2-nitroaniline)phenyl]cyclobutanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, based on 2,4,5-trichloronitromethane and TRANS-3-(4-AMINOPHENYL)cyclobutanol (stage 4).

1H-NMR (CDCl3) δ 9,40 (1H, Sirs), of 8.27 (1H, s), 7,33 (2H, d, J=8.1 Hz), 7,22 (2H, d, J=8.1 Hz), 7,19 (1H, s), 4.63 to-4,55 (1H, m), of 3.73-3,63 (1H, m), 2.57 m) is 2.43 (4H, m).

MS (EI) m/z: 352 (M+).

Stage 6. TRANS-3-[4-(2-amino-4,5-dichloroaniline)phenyl]cyclobutanol

The connection specified in the header received in accordance with the method described for stage 3 of example 6, on the basis of TRANS-3-[4-(4,5-dichloro-2-nitroaniline)phenyl]cyclobutanol (stage 5).

1H-NMR (CDCl3) δ 7,16 (1H, s), 7,12 (2H, d, J=8.6 Hz), 6,86 (1H, s), of 6.75 (2H, d, J=8.6 Hz), to 5.08 (1H, Sirs), 4,58 figure-4.49 (1H, m), of 3.77 (2H, Sirs), 3,62-to 3.52 (1H, m), 2,50-of 2.34 (4H, m).

Stage 7. TRANS-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]cyclobutylamine

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from TRANS-3-[4-(2-amino-4,5-dichloroaniline)phenyl]cyclobutanol (stage 6) and propionitrile.

TLC Rf= 0,56 (ethyl acetate/hexane = 1:1).

Stage 8. T the ANS-3-[4-(5,6-dichloro-2-ethyl-1 H-benzimidazole-1-yl)phenyl]cyclobutanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from TRANS-3-[4-(2-amino-4,5-dichloroaniline)phenyl]cyclobutylamine (stage 7).

MS (EI) m/z 360(M+).1H-NMR (CDCl3) δ a 7.85 (1H, Sirs), was 7.45 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8.1 Hz), 7,18 (1H, Sirs)and 4.65-4,55 (1H, m), 3,83-to 3.73 (1H, m), 2,77 (2H, q, J=7.5 Hz), 2.63 in-2,48 (4H, m)of 1.34 (3H, t, J=7.5 Hz).

Stage 9. CIS-3-[4-(5,6-dichloro-2-ethyl-1N-benzimidazole-1-yl)phenyl]cyclobutene

To a stirred solution of TRANS-3-[4-(5,6-dichloro-2-ethyl-1N-benzimidazole-1-yl)phenyl]cyclobutanol (stage 8, 572 mg, 1.6 mmol), triphenylphosphine (623 mg, 2.4 mmol) and diphenylphosphoryl azide (DPPA) (655 mg, 2.4 mmol) in THF (8 ml) was added diethylazodicarboxylate (415 mg, 2.4 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours, then the mixture was diluted with ethyl acetate (100 ml) and washed with water (100 ml) and saturated saline (100 ml). The organic layer was dried (Na2SO4) and concentrated. Purification with flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (2:1), gave 506 mg (83%) of the compound indicated in the title, in the form of a colorless solid product.

MS (EI) m/z: 385 (M+);1H-NMR (CDCl3) δ to 7.84 (1H, Sirs), 7,42 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), 7,17 (1H, Sirs), 3,98-3,88 (1H,m), 3,37-of 3.25 (1H, m), 2,89 is 2.75 (2H, m), 2,77 (2H, q, J=7,6 Hz), 2,34-of 2.23 (2H, m)of 1.34 (3H, t, J=7,6 Hz).

Stage 10. CIS-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]cyclobutylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, on the basis of CIS-3-[4-(5,6-dichloro-2-ethyl-1-benzimidazole-1-yl)phenyl]cyclobutylamine (stage 9).

MS (EI) m/z 359 (M+);1H-NMR (CDCl3) δ to 7.84 (1H, Sirs), 7,41 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), 7,17 (1H, Sirs), 3,55-of 3.43 (1H, m), 3,24-of 3.12 (1H, m), 2,87-by 2.73 (4H, m), 1.91 a and 1.80 (2H, m)of 1.34 (3H, t, J=7.5 Hz).

Stage 11. 5,6-Dichloro-2-ethyl-1-(4-{CIS-3-[({[(4-were)sulfonyl]amino}carbonyl)amino]cyclobutyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from CIS-3-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]cyclobutylamine (stage 10).

MS (ESI) m/z 557 (M+H)+;1H-NMR (CDCl3) δ a 7.85 (1H, Sirs), 7,79 (2H, d, J=8,4 Hz), 7,42 (2H, d, J=8.1 Hz), was 7.36 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8,4 Hz), 7,17 (1H, Sirs), of 4.35-4.26 deaths (1H, m), 3,35-of 3.25 (1H, m), 2,93-and 2.83 (2H, m), 2,78 (2H, q, J=7,6 Hz), the 2.46 (3H, s), 2,19-2,07 (2H, m)of 1.34 (3H, J=7,6 Hz).

Example 100

5,6-Dichloro-1-(4-{1,1-dimethyl-2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-1H-benzimidazole

Stage 1. 2-[4-(4,5-Dichloro-2-nitroaniline)phenyl]-2-methylpropionitrile

The connection specified in the header of the received ACC is accordance with the method, described for stage 3 of example 1, based on 2,4,5-trichlorethylene and 2-(4-AMINOPHENYL)-2-methylpropionitrile (Axton, C. A.; et al.J. Chern. Soc. Perkin Trans. 1, 1992, 17, 2203).

1H-NMR (CDCl3) δ 9,38 (1H, W), 8,31 (1H, s), 7,54 (2H, d, J=8,58 Hz), 7,30-7,22 (3H, m)of 1.75 (6H,s).

Stage 2. 2-[4-(2-Amino-4,5-dichloroaniline)phenyl]-2-methylpropionitrile

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[4-(4,5-dichloro-2-nitroaniline)phenyl]-2-methylpropionitrile (stage 1).

1H-NMR (CDCl3) δ 7,41 (1H, s), 7,30 (2H, d, J=8,4 Hz), to 7.09 (1H, s), make 6.90 (1H, s), to 6.80 (2H, d, J=8,4 Hz), with 5.22 (2H, s)of 1.62 (6H, s).

Stage 3. 2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]-2-methylpropionitrile

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-(2-amino-4,5-dichloroaniline)phenyl]-2-methylpropionitrile (stage 2) and propionitrile.

1H-NMR (CDCl3) δ to $ 7.91 (1H, s), 7,78 (2H, d, J=8,4 Hz), was 7.45 (2H, d, J=8,4 Hz), 7,24 (1H, s), and 2.83 (2H, q, J=7.5 Hz), 1,89 (6H, s)of 1.42 (3H, t, J=7,3 Hz).

Stage 4. 5,6-Dichloro-1-(4-{1,1-dimethyl-2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-1H-benzimidazole

A mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]-2-methylpropionitrile (stage 3, 102 mg, 0.28 mmol), PtO2(one portion), chloroform (0.5 ml) in ethanol (15 ml) was stirred and the atmosphere of hydrogen (4.5 kg/cm2) at room temperature. After 8 hours the mixture was filtered through a thick layer of celite and the filtrate was concentrated. The residue is suspended in dichloromethane (10 ml). To the suspension was added n-toluensulfonyl isocyanate (0.3 ml, a 1.96 mmol) and triethylamine (0.3 ml, 2.1 mmol) at room temperature. After 0.5 hours the mixture was concentrated. The residue was dissolved in dichloromethane (100 ml) and washed with 10% aqueous citric acid solution (50 ml), water (50 ml) and saturated saline (50 ml). The organic layer was dried (MgSO4) and concentrated. The residue was purified using preparative TLC (ethyl acetate/hexane = 2:1) to give 62 mg (37%) of the compound indicated in the title, in the form of a white solid.1H-NMR (CDCl3) δ 7,83 (1H, s), to 7.67 (2H, d, J=9.3 Hz), 7,55 (2H, d, J=9.3 Hz), 7,38-7,22 (4H, m), 7,18 (1H, s), of 3.45 (1H, W), was 2.76 (2H, q, J=8,4 Hz), was 2.34 (3H, s)to 1.37 (6H, s)is 1.31 (3H, t, J=8,2 Hz).

Example 101

Stage 1. Ethyl [4-(4,5-dichloro-2-nitroaniline)phenyl]acetate

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from ethyl 2,4,5-trichloronitromethane and 4-aminophenylacetate.

1H-NMR (CDCl3) δ 9,41 (1H, s), 8,32 (1H, s), 7,37 (2H, d, J=8,4 Hz), 7,28 (1H, s), 7,22 (2H, d, J=8,3 Hz), 4,19 (2H, q, J=7,1 Hz), 3,66 (2H, s)of 1.29 (3H, t, J=7,1 Hz).

Stage 2. Ethyl[4-(2-amino-4,5-dichloroaniline)phenyl]acetate

The connection specified in the header received in accordance with the FPIC of the BOM, described for step 2 of example 28, from ethyl[4-(4,5-dichloro-2-nitroaniline)phenyl]acetate (stage 1).

1H-NMR (CDCl3) δ 7,16 (1H, s), to 7.15 (2H, d, J=7.5 Hz), 6,86 (1H, s), 6,72 (2H, d, J=7,1 Hz), 5,12 (1H, Sirs), is 4.15 (2H, q, J=7.0 Hz), with 3.79 (2H, W), of 3.54 (2H, s)of 1.26 (3H, t,J=7,1 Hz).

Stage 3. Ethyl [4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]acetate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from ethyl [4-(2-amino-4,5-dichloroaniline)phenyl]acetate (stage 2) and propionitrile.

1H-NMR (CDCl3) δ to 7.84 (1H, s), 7,52 (2H, d, J=8,2 Hz), 7,30 (2H, d, J=8,4 Hz), 7,19 (1H, s), 4,22 (2H, q, J=7,1 Hz in), 3.75 (2H, s), 2,77 (2H, q, J=7.5 Hz), of 1.34 (3H, t, J=7.5 Hz), 1,32 (3H, J=7,1 Hz).

Stage 4. [4-(5,6-Dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]acetic acid

To a stirred solution of ethyl [4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]acetate (stage 3, of 1.30 g, 3.4 mmol) in methanol was added 2 N. aqueous NaOH (3.4 ml) at room temperature. After 1 hour the mixture was concentrated and the residue was diluted in water (200 ml) and the mixture was washed with diethyl ether (100 ml). The aqueous layer was acidified using 2 N. hydrochloric acid and was extracted with ethyl acetate/THF (about./about., 1:1, 300 ml). The organic extract was washed with water (200 ml), saturated brine (200 ml) and dried (MgSO4). Removal of solvent gave 1,02 g (86%) of the compound indicated in the title VI is e white powder.

1H-NMR (CDCl3) δ 7,94 (1H, s), 7,56 was 7.45 (4H, m), 7,26 (1H, s), and 3.72 (2H, s), of 2.72 (2H, q, J=7,3 Hz)to 1.22 (3H, t, J=7.5 Hz).

Stage 5. 2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ndimethylacetamide

A mixture of [4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]acetic acid (stage 4, 0,81 g, 2.3 mmol) and thionyl chloride (10 ml) was stirred for 0.5 hours and then concentrated. To the residue was added ammonium hydroxide (28% NH3in water, 50 ml) and the mixture was extracted with ethyl acetate/THF (about./about., 1:1, 200 ml). The extract was washed with saturated brine (2 x 100 ml), dried (MgSO4) and concentrated. The residue was purified using flash chromatography on a column of silica gel, elwira dichloromethane/methanol (20:1), to obtain 349 mg (44%) of the compound indicated in the title, in the form of a yellow solid.1H-NMR (CDCl3) δ to 7.93 (1H, s), 7,58 (1H, W), 7,51 (2H, d, J=8,4 Hz), 7,47 (2H, d, J=8,4 Hz), 7,27 (1H, s), 7,00 (1H, W), 3,51 (2H, s), 2,71 (2H, q, J=7.5 Hz), to 1.21 (3H, t, J=7.5 Hz).

Stage 6. 2-[4-(5,6-Dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]-N-({[(4-were)sulfonyl]amino}carbonyl)ndimethylacetamide

A mixture of [2-4-(5,6-dichloro-2-ethyl-1H-benzimidazole-1-yl)phenyl]ndimethylacetamide (stage 5, 105 mg, 0.30 mmol), p-toluensulfonate (0,07 ml, 0.45 mmol), toluene (10 ml) and THF (5 ml) is refluxed. After 6 hours, add 0.1 ml toluensulfonate and the mixture is heated for 3 hours. See the camping is cooled and left to stand at room temperature for 2 days. The mixture is concentrated and the residue purified using preparative TLC (ethyl acetate) to obtain 150 mg (92%) of the compound indicated in the title, in the form of colorless amorphous solid.1H-NMR (CDCl3) δ 9,78 (1H, s), 7,95 (2H, d, J=8,3 Hz), to 7.84 (1H, s), 7,54 (2H, d, J=8,4 Hz), 7,34 (2H, d, J=8.0 Hz), 7,32 (2H, d, J=8,4 Hz), 7,18 (1H, s), of 3.78 (2H, s), 2,77 (2H, q, J=7.5 Hz), is 2.41 (3H, s), of 1.35 (3H, t, J=7.5 Hz).

Example 102

5,6-Dichloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[4-(5,6-Dichloro-1H-benzimidazole-1-yl)phenyl]ethyl formate

A mixture of 2-[(4,5-dichloro-2-aniline)phenyl]ethanol (450 mg, of 1.42 mmol) and formic acid (7 ml) was stirred while boiling under reflux for 4 hours. After cooling, the mixture was podslushivaet 2 N. aqueous solution of NaOH and was extracted with ethyl acetate (50 ml). The extracts were dried (MgSO4) to obtain 480 mg (colwid) the connection specified in the header, in the form of a brown oil.1H-NMR (CDCl3) δ 8,10 (1H, s), 8,08 (1H, s), 7,95 (1H, s), to 7.61 (1H, s), 7,49-7,41 (4H, m), 4,47 (2H, t, J=6.8 Hz), 3,10 (2H, t, J=6,8 Hz).

Stage 2. 2-[4-(5,6-Dichloro-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(5,6-dichloro-1H-benzimidazole-1-yl)phenyl]ethyl formate (stage 1).

1H-NMR (CDCl3) δ 8,08 (1H,s), of 7.96 (1H, s), to 7.61 (1H, s), 7,49-7,40 (4H, m), of 3.97 (2H, q, J=6.4 Hz), 2,99 (2H, t, J=6.4 Hz).

Stage 3. 2-[4-(5,6-Dichloro-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(5,6-dichloro-1H-benzimidazole-1-yl)phenyl]ethanol (step 2).

MS (EI) m/z 332 (M+).

Stage 4. 2-[4-(5,6-Dichloro-1H-benzimidazole-1-yl)phenethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(5,6-dichloro-1H-benzimidazole-1-yl)phenyl]utilised (stage 3).

1H-NMR (CDCl3) δ of 8.09 (1H, s), of 7.96 (1H, s), a 7.62 (1H, s), 7,45-7,38 (4H, m), 3,06 (2H, m), 2,87 (2H, t, J=6.6 Hz).

Stage 5. 5,6-Dichloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(5,6-dichloro-1H-benzimidazole-1-yl)phenyl]ethylamine (step 3).

1H-NMR (CDCl3) δ 8,11 (1H, s), of 7.96 (1H, s), 7,72 (2H, d, J=8,4 Hz), 7,58 (1H, s), 7,38 (4H, s), 7,28 (2H, d, J=8,4 Hz), 6,72 (1H, m), of 3.56 (2H, q, J=6.9 Hz), of 2.92 (2H, t, J=6.9 Hz), of 2.38 (3H, s).

Example 103

Sodium salt of 5,6-dichloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the way the, described in example 2, on the basis of 5,6-dichloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 102).

1H-NMR (DMSO-d6) δ 8,55 (1H, s), of 7.97 (1H, s), 7,71 (1H, s), 7,50-7,44 (4H, m), 7,29 (2H, d, J=8,4 Hz), 7,01 (2H, d, J=8,4 Hz), to 3.02 (2H, m), 2,61 (2H, m)of 2.16 (3H, s); IR (KBr) Vmax1601, 1516, 1487, 1450, 1128, 1084 cm-1.

Example 104

6-Chloro-5-trifluoromethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[(5-Chloro-4-trifluoromethyl-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 2,4-dichloro-5-triftormetilfosfinov and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ RS 9.69 (1H, Sirs), 8,58 (1H, s), 7,37 (2H, d, J=8,4 Hz), 7.23 percent (2H, d, J=8,4 Hz), 7,19 (1H, s), 3,93 (2H, t, J=6.4 Hz), to 2.94 (2H, t, J=6.4 Hz).

Stage 2. 2-[(2-Amino-5-chloro-4-triptoreline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[(5-chloro-4-trifluoromethyl-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,17-to 7.15 (3H, m), 7,05 (1H, s), 6,92-to 6.88 (2H, m); of 5.48 (1H, Sirs), 3,85 (2H, t, J=6.6 Hz), and 2.83 (2H, t, J=6.6 Hz).

Stage 3. 2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header, the floor is made in accordance with the method, described for stage 5 of example 1 from 2-[(2-amino-5-chloro-4-triptoreline)phenyl]ethanol (step 2) and propionitrile.

MS (EI) 424 (M+).

Stage 4. 2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 8,11 (1H, s)to 7.50 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), 7,21 (1H, s), a 4.03-3,98 (2H, m), to 3.02 (2H, t, J=6.4 Hz), and 2.79 (2H, q, J=7.5 Hz), of 1.36 (3H, t, J=7.5 Hz).

Stage 5. 2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ 8,11 (1H, s), 7,49 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), 7,20 (1H, s), 3,63 (2H, t, J=6.9 Hz), 3,03 (2H, t, J=6.9 Hz), and 2.79 (2H, q, J=7.4 Hz), of 1.36 (3H, t, J=7,4 Hz).

Stage 6. 2-4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) ´ 8,11 (1H, s), was 7.45 (2H, d, J=8,3 Hz), 7,29-7,26 (2H, m), 7.23 percent (1H, s), 3,11 (2H, t, J=7.0 Hz), of 2.92 (2H, t, J=7,0 Hz), and 2.79 (2H, q, J=7.5 Hz), of 1.36 (3H, t, J=7.5 Hz).

Stage 7. 2-Ethyl-6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ of 8.09 (1H, s), 7,74 (2H, d, J=8,4 Hz), 7,42 (2H, d, J=8,2 Hz), 7,30-7,26 (4H, m), 7,18 (1H, s)6,76 (1H, m)and 3.59 (2H, q, J=7.0 Hz), 2,96 (2H, t, J=7,0 Hz), and 2.79 (2H, q, J=7,6 Hz)of 1.34 (3H, t, J=7,6 Hz).

Example 105

Sodium salt of 6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (example 104).

1H-NMR (DMSO-d6) δ of 8.15 (1H, s), to 7.59 (2H, d, J=8,4 Hz), 7,46-7,39 (4H, m), 7,33 (1H, s), 7,12 (2H, d, J=8,4 Hz)and 3.15 (2H, m), 2,78-a 2.71 (4H, m)of 1.24 (3H, t, J=7.5 Hz); IR (KBr) Vmax1601, 1518, 1431, 1398, 1348, 1306, 1128, 1084 cm-1.

Example 106

4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenethyl-(4-were)sulfonylureas

The connection specified in the header received is in accordance with the method, described in example 3 from 2-[4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4 of example 104).

TPL 170-173°C;1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,94-to $ 7.91 (2H, m), 7,41-7,24 (6H, m), 7,19 (1H, s), 4,39 (2H, t, J=6.8 Hz), totaling 3.04 (2H, t, J=6.8 Hz), 2,78 (2H, q, J=7,6 Hz), 2,44 (3H, s)of 1.35 (3H, t, J=7,6 Hz); IR (KBr) Vmax1746, 1518, 1342, 1232, 1159, 1132, 1086 cm-1.

Example 107

Sodium salt of 4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenethyl-[4-were)sulfonylamino

The connection specified in the header received in accordance with the method described in example 2 from 4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenethyl-(4-were)sulfanilamide (example 106).

1H-NMR (DMSO-d6) δ of 8.15 (1H, s), to 7.59 (2H, d, J=8.1 Hz), 7,47 (4H, s), 7,34 (1H, s), to 7.15 (2H, d, J=8.1 Hz), of 3.96 (2H, t, J=6.6 Hz), of 2.86 (2H, t, J=6.6 Hz), a 2.75 (2H, q, J=7.4 Hz), 2,28 (3H, s)of 1.24 (3H, t, J=7,4 Hz).

Example 108

5-Chloro-6-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2-[(4-Chloro-5-methyl-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 2,5-dichloro-4-methylnitrobenzene and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 9,40 (1H, s), to 8.20 (1H, s), 7,31 (2H, d, J=8,4 Hz), 7,21 (2H, d, J=8,4 Hz), 7,05 (1H, s), 3,93-3,91 (2H, m), only 2.91 (2H, t, J=6 Hz), to 2.29 (3H, s).

Stage 2. 2-[(2-Amino-4-chloro-5-methylaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[(4-chloro-5-methyl-2-nitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,06 (2H, d, J=8.6 Hz), 6,93 (1H, s), 6,79 (1H, s), to 6.67 (2H, d, J=8.6 Hz), 3,80 (2H, d, J=6.4 Hz), 2,77 (2H, t, J=6.4 Hz), of 2.21 (3H, s).

Stage 3. 2-[4-(5-Chloro-2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[(2-amino-4-chloro-5-methylaniline)phenyl]ethanol (step 2) and propionitrile.

MS (EI) m/z 370 (M+).

Stage 4. 2-[4-5-Chloro-2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(5-chloro-2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ 7,74 (1H, s), 7,47 (2H, d, J=8,3 Hz), 7,27 (2H, d, J=8,3 Hz), 6,93 (1H, s), of 4.00 (2H, t, J=6.6 Hz), to 3.02 (2H, t, J=6.6 Hz), was 2.76 (2H, q, J=7.5 Hz), 2,39 (3H, s)of 1.32 (3H, t, J=7.5 Hz).

Stage 5. 2-[4-(5-Chloro-2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-[4-(5-chloro-2-ethyl-6-methyl-1H

1H-NMR (CDCl3) δ of 7.75 (1H, s), was 7.45 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), 7,27 (1H, s), 3,62 (2H, t, J=7.0 Hz), to 3.02 (2H, t, J=7.0 Hz), was 2.76 (2H, q, J=7.5 Hz), 2.40 a (3H, s)of 1.33 (3H, t, J=7.5 Hz).

Stage 6. 2-[4-(5-Chloro-2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(5-chloro-2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]utilised (stage 5).

1H-NMR (CDCl3) δ of 7.75 (1H, s), 7,42 (2H, d, J=8,3 Hz), 7,27 (2H, d, J=8,3 Hz), 6,93 (1H, s), 3,10 (2H, t, J=7.0 Hz), 2,90 (2H, t, J=7.0 Hz), was 2.76 (2H, q, J=7.5 Hz), 2.40 a (3H, s)of 1.33 (3H, t, J=7.5 Hz).

Stage 7. 2-Ethyl-5-chloro-6-methyl-1-(4-{2-[([[(4-were)sulfonyl]amino]carbonyl)amino]ethylphenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(5-chloro-2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethylamine (step 6).

1H-NMR (CDCl3) δ 7,75-7,72 (3H, m), 7,38-of 7.23 (6H, m)6,91 (1H, s), 6.73 x-6,69 (1H, m), 3,62-3,55 (2H, m)to 2.94 (2H, t, J=6.8 Hz), a 2.75 (2H, q, J=7,6 Hz), is 2.40 (3H, s), is 2.37 (3H, s)of 1.30 (3H, t, J=7,6 Hz).

Example 109

Sodium salt of 5-chloro-6-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-5-chloro-6-methyl-1-(4-{2-[([[(4-methylphe the Il)sulfonyl]amino]carbonyl)amino]ethyl}phenyl)-1 H-benzimidazole (example 108).

1H-NMR (DMSO-d6) δ to 7.68 (1H, s), 7,60 (2H, d, J=8.1 Hz), 7,41-to 7.35 (4H, m), 7,13 (2H, d, J=8.1 Hz), 7,05 (1H, s), 3,17-3,15 (2H, m), 2,75-to 2.65 (4H, m), of 2.34 (3H, s), and 2.27 (3H, s)of 1.20 (3H, t, J=7.5 Hz); IR (KBr) Vmax1599, 1516, 1456, 1402, 1128, 1084, 1001 cm-1.

Example 110

6-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl])-5-[(methylsulphonyl)amino]-1H-benzimidazole

Stage 1. 2-[4-(5-Chloro-2,4-dinitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 2,4-dichloro-1,5-dinitrobenzene and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 9,81 (1H, Sirs), 9,07 (1H, s), 7,40 (2H, d, J=8,3 Hz), 7,25 (2H, d, J=8,3 Hz), 7,17 (1H, s), of 3.95 (2H, t, J=6.6 Hz), 2,95 (2H, t, J=6.6 Hz).

Stage 2. 2-[4-(2-Amino-5-chloro-4-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 40, from 2-[4-(5-chloro-2,4-dinitroaniline)phenyl]ethanol (step 1).

1H-NMR (CDCl3) δ 7,54 (1H, s), from 7.24 (2H, d, J=8.6 Hz), 7,11 (1H, s), 7,03 (2H, d, J=8.6 Hz), USD 5.76 (1H, Sirs), the 3.89 (2H, t, J=6.4 Hz), the 3.65 (2H, Sirs), 2,87 (2H, t, J=6.4 Hz), 1,28(1H, s).

Stage 3. 2-[4-(6-Chloro-2-ethyl-5-nitro-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1, based on the C 2-[4-(2-amino-5-chloro-4-nitroaniline)phenyl]ethanol (step 2) and propionitrile.

TLC Rf = 0.8 in (hexane/ethyl acetate = 1:2).

Stage 4. 2-[4-(6-Chloro-2-ethyl-5-nitro-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-amino-5-chloro-4-nitroaniline)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ a 8.34 (1H, s)to 7.50 (2H, d, J=8.0 Hz), 7,28 (2H, d, J=8.0 Hz), 7,19 (1H, s), of 4.00 (2H, t, J=6.3 Hz), to 3.02 (2H, t, J=6.3 Hz), and 2.79 (2H, q, J=7,6 Hz)of 1.62 (1H, s)of 1.36 (3H, t, J=7,6 Hz).

Stage 5. 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-nitro-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(6-chloro-2-ethyl-5-nitro-1H-benzimidazole-1-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ a 8.34 (1H, s)to 7.50 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,4 Hz), 7,19 (1H, s), a-3.84 (2H, t, J=7.0 Hz), up 3.22 (2H, t, J=7.0 Hz), 2,80 (2H, q, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz).

Stage 6. 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-ylamine

The connection specified in the header received in accordance with the method described for stage 4 of example 89, on the basis of 6-chloro-1-[4-(2-chloroethyl)phenyl-2-ethyl-5-nitro-1H-benzimidazole (step 5).

1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8.6 Hz), 7,29 (2H, d, J=8.6 Hz), 7,16 (1H, s), 7,02 (1H, s), of 3.96 (2H, Sirs), 3,81 (2H, t, J=7,1 Hz), 3,19 (2H, t, J=7,1 Hz), is 2.74 (2H, q, J=7.5 Hz), of 1.33 (3H, t, J=7.5 Hz).

Stage 7. N-{6-Chloro-1-[4-(2-chloroethyl)the dryer is l]-2-ethyl-1 H-benzimidazole-5-yl}methanesulfonamide

The connection specified in the header received in accordance with the method described for stage 5 of example 40, on the basis of 6-chloro-1-[4-(chlorethyl)phenyl-2-ethyl-1H-benzimidazole-5-ylamine (stage 6).

1H-NMR (CDCl3) δ of 7.70 (1H, s), 7,55 (2H, d, J=7.9 Hz), to 7.50 (2H, d, J=7.9 Hz), 7,13 (1H, s), of 3.95 (2H, t, J=7,0 Hz), and 3.16 (2H, t, J=7.0 Hz), of 2.97 (3H, s), 2,71 (2H, q, J=7,6 Hz)to 1.21 (3H, t, J=7,6 Hz).

Stage 8. N-{1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}methanesulfonamide

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from N-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}methanesulfonamide (stage 7).

1H-NMR (CDCl3) δ 7,47 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 7,16 (1H, s), is 6.78 (1H, s), 3,63 (2H, t, J=6.9 Hz), 2,98 was 3.05 (5H, m), 2,77 (2H, q, J=7.4 Hz), of 1.35 (3H, t, J=7,4 Hz).

Stage 9. N-{1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}methanesulfonamide

The connection specified in the header received in accordance with the method described for stage 7 of example 37, on the basis of N-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}methanesulfonamide (stage 8).

1H-NMR (CDCl3) δ 8,03 (1H, s), the 7.43 (2H, d, J=8,4 Hz), 7,26 (2H, d, J=8,4 Hz), 7,17 (1H, s)to 3.33 (2H, Sirs), is 3.08 (2H, t, J=7.0 Hz), 2,96 (3H, s), is 2.88 (2H, t, J=7.0 Hz), 2,77 (2H, q, J=7,6 Hz)of 1.35 (3H, t, J=7,6 Hz).

Stage 10. 6-Chloro-2-ethyl-1-(4-{2-[({[(methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-[(methylsulphonyl)amino]-1 H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from N-{1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}methanesulfonamide (stage 9).

TPL 101-123°C; MS (ESI) m/z 590 (M+N)+;1H-NMR (CDCl3) δ of 8.04 (1H, s), 7,73 (2H, d, J=8,2 Hz), 7,42 (2H, d, J=8,2 Hz), 7,25-7,33 (4H, m), 7,16 (1H, s), of 6.68 (1H, Sirs), to 3.58 (2H, t, J=7.2 Hz), 2.93 which are 2.98 (5H, m), 2,77 (2H, q, J=7.5 Hz), a 2.45 (3H, s), 1,35 (3H, t, J=7.5 Hz); IR (KBr) Vmax1654, 1517, 1467, 1336, 1151, 1089, 972 cm-1.

Example 111

6-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

Stage 1. 2-Chloro-4-[4-(2-hydroxyethyl)aniline]-5-nitrobenzonitrile

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 2,4-dichloro-5-nitrobenzonitrile (Grivsky, E. M.; Hitching, G. H.Ind. Chim. Belge., 1974, 39. 490) and 4-aminophenylacetamido alcohol.

1H-NMR (CDCl3) δ 9,81 (1H, Sirs), 8,56 (1H, s), 7,39 (2H, d, J=8,3 Hz), 7.23 percent (2H, d, J=8,3 Hz), to 7.15 (1H, s), 3,93 (2H, t, J=6.2 Hz), to 2.94 (2H, t, J=6.2 Hz), of 1.62 (1H, Sirs).

Stage 2. 5-Amino-2-chloro-4-[4-(2-hydroxyethyl)aniline]benzonitrile

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-chloro-4-[4-(2-hydroxyethyl)aniline]-5-nitrobenzonitrile(stage 1).

1H-NMR CDCl 3) δ of 7.23 (4H, d, J=8,3 Hz), 6,99-7,33 (2H, m), 3,88 (2H, t, J=6,1 Hz), of 3.56 (1H, Sirs), 2,87 (2H, t, J=6,1 Hz).

Stage 3. 2-[4-(6-Chloro-5-cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1, starting from 5-amino-2-chloro-4-[4-(2-hydroxyethyl)aniline]benzonitrile (stage 2) and propionitrile.

TLC Rf = 0,5 (hexane/ethyl acetate = 1:2).

Stage 4. 6-Chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(6-chloro-5-cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ of 8.04 (1H, s), 7,52 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 7,19 (1H, s), was 4.02 (2H, t, J=6.5 Hz), 3,03 (2H, t, J=6.5 Hz), 2,80 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

Stage 5. 6-Chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide

To a mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile (stage 4, 2.4 g, 7.4 mmol), DMSO (0.7 ml, 8,8 mmol) and methanol (100 ml) was added 30% aqueous hydrogen peroxide solution (1.3 ml, 11 mmol) and 0.2 M aqueous solution of NaOH (0.7 ml, 0.14 mmol). The mixture was stirred at 50°C for 2 hours. The solvent was removed and the precipitate was collected by filtration. The precipitate was washed with water and dried, propanganda pressure to obtain 1.9 g (76%) indicated in the title compounds as a pale pink solid. 1H-NMR (DMSO-d6) δ of 7.69 (1H, Sirs), to 7.61 (1H, s), 7,33-7,40 (4H, m), to 6.95 (1H, s), with 4.64 (1H, Sirs)and 3.59 (2H, t, J=6.4 Hz), is 2.74 (2H, t, J=6.4 Hz), 2,62 (2H, q, J=7.4 Hz), is 1.11 (3H, t, J=7,4 Hz).

Stage 6. 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (stage 5).

1H-NMR (DMSO-d6) δ 7,71 (1H, Sirs), a 7.62 (1H, s), of 7.36-7,47 (5H, m), to 6.95 (1H, s), 3,85 (2H, t, J=7,1 Hz), 3,06 (2H, t, J=7,1 Hz), 2,63 (2H, q, J=7,6 Hz)of 1.11 (3H, t, J=7,6 Hz).

Stage 7. 1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide (stage 6).

1H-NMR (DMSO-d6) δ 7,80 (1H, Sirs), 7,71 (1H, s), 7,46-EUR 7.57 (5H, m),? 7.04 baby mortality (1H, s), the 3.65 (2H, t, J=6.9 Hz), 2,98 (2H, t, J=6.9 Hz), of 2.72 (2H, q, J=7.5 Hz), to 1.21 (3H, t, J=7.5 Hz).

Stage 8. 1-[4-(2-amino-ethyl]phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide (stage 7).

1H-NMR (CDCl3) δ 7,80 (1H, s), 7,71 (1H, s), 39-7,50 (5H, m), was 7.08 (1H, s), 2,49-2,89 (6H, m)to 1.21 (3H, t, J=7,4 Hz).

Stage 9. 6-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide (step 8).

TPL 152-163°C; MS (ESI) m/z 540 (M+N)+;1H-NMR (DMSO-d6) δ 7,81 (1H, Sirs), 7,72 to 7.75 (3H, m), 7,51 (1H, Sirs), 7,33-7,44 (6H, m), 7,06 (1H, s), 3,26 (2H, Sirs), 2,68 is 2.80 (4H, m), of 2.34 (3H, s)of 1.23 (3H, t, J=7.5 Hz); IR (KBr) Vmax3395, 1664, 1519, 1396, 1161, 1089, 991 cm-1.

Example 112

6-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxylic acid

A mixture of 6-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide (example 111, 140 mg, 0.26 mmol) and KOH (63 mg, 0.8 mmol) in methanol (10 ml) was stirred at 100°C for 1 day. The mixture was poured into water, acidified 2 N. hydrochloric acid and was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated saline solution (30 ml), dried (Na2SO4) and concentrated. The residue was purified using flash chromatography on a column of silica gel, elwira dichloromethane/methanol (10:1), to obtain 36 mg (25%) of the compound indicated in the title the information, in the form of a white solid.

TPL 145-150°C; MS (ESI) m/z 541 (M+N)+;1H-NMR (DMSO-d6) δ 8,10 (1H, s), 7,76 (2H, d, J=7.9 Hz), of 7.36-7,47 (6H, m), 7,10 (1H, s), or 3.28 (2H, m), 2,69-of 2.81 (4H, m), of 2.34 (3H, s)of 1.24 (3H, t, J=7.5 Hz); IR (KBr) Vmax3450, 1701, 1517, 1340, 1163, 1091, 900 cm-1.

Example 113

N-[6-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-yl]ndimethylacetamide

Stage 1. N-{6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}ndimethylacetamide

To a solution of 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-ylamine (stage 6 of example 110, 100 mg, 0.3 mmol) in pyridine (7 ml) was added dropwise acetylchloride one (0.03 ml, 0.33 mmol) under nitrogen atmosphere at 0°C and the reaction mixture was stirred at room temperature for 1.5 hours. The mixture was poured into water (20 ml) and was extracted with ethyl acetate (50 ml). The organic layer was washed 2 N. aqueous NaOH (30 ml), saturated brine (30 ml), then dried (Na2SO4). After removal of solvent the crude product was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (1:3), to obtain 110 mg (98%) indicated in the title compound as a white solid.

1H-NMR (CDCl3) δ 8,66 (1H, s), 7,56 (1H, Sirs), was 7.45 (2H, d, J=8,2 Hz), 7,29 (2H, d, J=8,2 Hz), 7,12 (1H, s), 3,82 (2H, t, J=7,1 Hz), 3,19 (2H, t, J=7,1 Hz), 2,77 (2H, q, J=7,6 Hz), and 2.26 (3H, s)of 1.34 (3H, the, J=7,6 Hz).

Stage 2. N-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}ndimethylacetamide

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from N-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}ndimethylacetamide (stage 1).

1H-NMR (DMSO-d6) δ 8,66 (1H, s), 7,55 (1H, Sirs), was 7.45 (2H, d, J=8.1 Hz), 7,30 (2H, d, J=8.1 Hz), 7,11 (1H, s), 3,62 (2H, t, J=7,1 Hz), to 3.02 (2H, t, J=7,1 Hz), was 2.76 (2H, q, J=7,6 Hz), and 2.26 (3H, s)of 1.34 (3H, t, J=7,6 Hz).

Stage 3. N-{1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}ndimethylacetamide

The connection specified in the header received in accordance with the method described for stage 7 of example 37, on the basis of N-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}ndimethylacetamide (stage 2).

1H-NMR (CDCl3) δ 8,66 (1H, s), 7,55 (1H, Sirs), 7,42 (2H, d, J=6.6 Hz), 7,27-7,29 (2H, m), 7,12 (1H, s), is 3.08 (2H, t, J=6.9 Hz), is 2.88 (2H, t, J=6.9 Hz), a 2.75 (2H, q, J=7,4 Hz), and 2.26 (3H, s)of 1.34 (3H, t, J=7,4 Hz).

Stage 4. N-[6-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-yl]ndimethylacetamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from N-{1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}ndimethylacetamide (stage 3).

TPL 125-133°C; MS (ESI) m/z 554 (M+N)+;1H-NMR (CDCl3) δ 8,64 (1H, s), 7,74 (2H, d, J=8 Hz), at 7.55 (1H, Sirs), 7,25-7,39 (1H, s), was 7.08 (1H, s), 3,53-3,61 (2H, m)to 2.94 (2H, t, J=7,1 Hz)of 2.75 (2H, q, J=7.4 Hz), is 2.41 (3H, s), and 2.27 (3H, s)of 1.32 (3H, t, J=7.4 Hz); IR (KBr) Vmax3390, 1676, 1517, 1240, 1161, 1089, 1018, 972 cm-1.

Example 114

6-Ethyl-5-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole

Stage 1. 2-[(6-Nitro-1,3-benzodioxol-5-yl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 45, starting from 5-amino-6-nitro-1,3-benzodioxole and 4-bromophenylacetate alcohol.

1H-NMR (CDCl3) δ 10,07 (1H, Sirs), a 7.62 (1H, s), 7,29 (2H, d, J=8.5 Hz), 7,20 (2H, d, J=8.5 Hz), to 6.58 (1H, s), 5,98 (2H, s), 3,90 (2H, t, J=6.6 Hz), 2,90 (2H, t, J=6.6 Hz).

Stage 2. 2-{4-[(6-Amino-1,3-benzodioxol-5-yl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-{4-[(6-nitro-1,3-benzodioxol-5-yl)amino]phenyl}ethanol (step 1).

1H-NMR (CDCl3) δ 7,26 (1H, s),? 7.04 baby mortality (2H, d, J=8,2 Hz), 6,60 (2H, d, J=8,2 Hz), to 6.39 (1H, s), by 5.87 (2H, s), 4,96 (1H, Sirs), of 3.80 (2H, t, J=6.4 Hz), to 3.64 (2H, Sirs), was 2.76 (2H, t, J=6.4 Hz).

Stage 3. 2-[4-(6-Ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazole-5-yl)-phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(6-amino-1,3-benzodioxol-5-yl)amino]phenyl}ethanol (step ) and propyl alcohol.

TLC Rf = 0,5 (hexane/ethyl acetate = 1:2).

Stage 4. 2-[4-(6-Ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazole-5-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-{4-[(6-amino-1,3-benzodioxol-5-yl)amino]phenyl}ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), 7,19 (1H, s), 6,53 (1H, s)5,94 (2H, s), 3,98 (2H, t, J=6.4 Hz), 2,99 (2H, t, J=6.4 Hz), 2,73 (2H, q, J=7.4 Hz), is 1.31 (3H, t, J=7,4 Hz).

Stage 5. 5-[4-(2-Chloroethyl)phenyl]-6-ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(6-ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazole-5-yl)phenyl]ethanol (step 4).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8.1 Hz), 7,19 (1H, s), is 6.54 (1H, s)5,94 (2H, s), 3,81 (2H, t, J=7,1 Hz), 3,19 (2H, t, J=7,1 Hz), of 2.72 (2H, q, J=7,6 Hz)is 1.31 (3H, t, J=7,6 Hz).

Stage 6. 2-[4-(6-Ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazole-5-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1, starting from 5-[4-(2-chloroethyl)phenyl]-6-ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazole (stage 5).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), 7,19 (1H, s), 6,53 (1H, s), to 5.93 (2H, s), of 3.60 (2H, t, J=7,1 Hz)of 3.00 (2H, t, J=7,1 Hz), 2,73 (2H, q, J=7,6 Hz)is 1.31 (3H, t, J=7,6 Hz).

Stage 7. 2-[4-(6-Ethyl-5H-[1,3]dioxolo[4,5-f]be imidazol-5-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(6-ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazole-5-yl)phenyl]utilised (stage 6).

1H-NMR (CDCl3) δ 7,40 (2H, d, J=8,2 Hz), 7,22-7,28 (2H, m), 7,19 (1H, s), is 6.54 (1H, s), to 5.93 (2H, s), 3,05 (2H, t, J=6.8 Hz), of 2.86 (2H, t, J=6.8 Hz), 2,73 (2H, q, J=7,6 Hz)is 1.31 (3H, t, J=7,6 Hz).

Stage 8. 6-Ethyl-5-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(6-ethyl-5H-[1,3]dioxolo[4,5-f]benzimidazole-5-yl)phenyl]ethylamine (step 7).

MS (ESI) m/z 507 (M+H)+;

1H-NMR (DMSO-d6) δ of 7.75 (2H, d, J=8.1 Hz), 7,35-7,37 (6H, m), 7,16 (1H, s), 6,55 (1H, s), 5,97 (2H, s), was 2.76 (2H, t, J=6.9 Hz), 2,65 (2H, q, J=7,6 Hz), 2,50 (2H, Sirs), was 2.34 (3H, s)of 1.18 (3H, t, J=7,6 Hz).

Example 115

Sodium salt of 6-ethyl-5-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 6-ethyl-5-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole (example 114).

TPL 140-155°C; IR (KBr) Vmax3384, 2873, 1600, 1519, 1460, 1155, 1128, 1085, 1037, 945, 813 cm-1.

Example 116

2-Ethyl-1-(4-{2-[({[(4-were)su is hanil]amino}carbonyl)amino]ethyl}phenyl)-6,7-dihydro-1 H-[1,4]like[2,3-f]benzimidazole

Stage 1. 7-Nitro-2,3-dihydro-1,4-benzodioxin-6-amine

To a mixture of 6,7-dinitro-2,3-dihydrobenzo[1,4]dioxin (Takakis, I. M.; Hadjimihalakis, P. M.J. Heterocyclic. Chem., 1991, 28, 625., 13 g of 57.8 mmol) and acetic acid (150 ml) was added iron powder (9.6 g, 172,5 mmol) at room temperature, the mixture is then boiled under reflux for 30 minutes. After cooling, the mixture was filtered through a thick layer of celite and the filtrate was concentrated. The residue was purified using flash chromatography on a column of silica gel, elwira hexane/ethyl acetate (gradient elution from 1:1 to 1:2), with 3,22 g (28%) of the compound indicated in the title, in the form of an orange solid.

1H-NMR (CDCl3) δ to 7.67 (1H, s), 6,23 (1H, s), to 5.85 (2H, Sirs), 4,19-to 4.33 (4H, m).

Stage 2. 2-{4-[(7-Nitro-2,3-dihydro-1,4-benzodioxin-6-yl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 45, from 7-nitro-2,3-dihydro-1,4-benzodioxin-6-amine (stage 1) and 4-bromophenylacetate alcohol.

1H-NMR (CDCl3) δ to 7.77 (1H, s), 7,26 (2H, d, J=8,4 Hz), 7,19 (2H, d, J=8,4 Hz), only 6.64 (1H, s), 4,20-or 4.31 (4H, m)to 3.89 (2H, t, J=6.4 Hz), is 2.88 (2H, t, J=6.4 Hz).

Stage 3. 2-{4-[(7-Amino-2,3-dihydro-1,4-benzodioxin-6-yl)amino]phenyl}ethanol

The connection specified in the header received in accordance what about the way described for step 2 of example 28, from 2-{4-[(7-nitro-2,3-dihydro-1,4-benzodioxin-6-yl)amino]phenyl}ethanol (step 2).

1H-NMR (CDCl3) δ 7,02-7,05 (2H, m), 6,62-of 6.65 (3H, m), 6,33 (1H, s)5,00 (1H, Sirs), 4,15-4,24 (4H, m), with 3.79 (2H, t, J=6.6 Hz), 3,53 (2H, Sirs), was 2.76 (2H, t, J=6.6 Hz).

Stage 4. 2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)amino]phenyl}ethanol (step 3) and propionitrile.

TLC Rf = 0,5 (hexane:ethyl acetate = 1:2).

Stage 5. 2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-{4-[(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)amino]phenyl}ethylpropylamine (stage 4).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8.1 Hz), 7,25-7,28 (3H, m), to 6.58 (1H, s), 4,21-4,27 (4H, m), of 3.97 (2H, t, J=6.6 Hz), 2,98 (2H, t, J=6.6 Hz), is 2.74 (2H, q, J=7,3 Hz)is 1.31 (3H, t, J=7,3 Hz).

Stage 6. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-6,7-dihydro-1H- [1,4]like[2,3-f]benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole-1-yl)phenyl]ethanol (stage 5).

1Mr. YAM is (CDCl 3) δ 7,40 (2H, d, J=8.1 Hz), 7,26-7,39 (3H, m), to 6.58 (1H, s), 4,25 (4H, s), 3,80 (2H, t, J=7,3 Hz), 3,20 (2H, t, J=7,3 Hz), is 2.74 (2H, q, J=7,6 Hz)is 1.31 (3H, t, J=7,6 Hz).

Stage 7. 2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole-1-yl)phenyl]utilised

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole (stage 6).

1H-NMR (CDCl3) δ 7,40 (2H, d, J=8,3 Hz), 7.24 to 7,29 (3H, m), to 6.57 (1H, s), is 4.21-4.26 deaths (4H, m)and 3.59 (2H, t, J=7,0 Hz)to 2.99 (2H, t, J=7.0 Hz), 2,73 (2H, q, J=7.5 Hz), of 1.30 (3H, t, J=7.5 Hz).

Stage 8. 2-[4-(2-Ethyl-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 2-[4-(2-ethyl-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole-1-yl)phenyl]utilised (stage 6).

1H-NMR (CDCl3) δ 77,40 (2H, d, J=8,3 Hz), 7.24 to 7,27 (3H, m), 6,62 (1H, s), is 4.21 (4H, s), 3,24-3,26 (2H, m), 3,11 (2H, t, J=6.9 Hz), of 2.72 (2H, q, J=7.4 Hz), of 1.30 (3H, t, J=7,4 Hz).

Stage 9. 2-Ethyl-1-(4-{2-[({[(4-were))sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole-1-yl)phenyl]ethylamine (step 8).

MS (EI) m/z 521 (M+H) +;1H-NMR (CDCl3) δ 7,76 (2H, d, J=8,4 Hz), 7.18 in-7,31 (7H, m), only 6.64 (1H, Sirs), 6,56 (1H, Sirs), 4,24 (4H, s), of 3.56 (2H, t, J=6.9 Hz), 2,90 (2H, t, J=6.9 Hz), 2,70 (2H, q, J=7,6 Hz)to 2.41 (3H, s)of 1.27 (3H, t, J=7,6 Hz).

Example 117

Sodium salt of 2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole (example 116).

TPL 162-173°C;1H-NMR (DMSO-d6) δ 7,83 (2H, d, J=8.0 Hz), 7,58 (2H, d, J=8.6 Hz), 7,54 (2H, d, J=8.0 Hz), 7,35 (2H, d, J=8.6 Hz), 7,29 (1H, s), of 6.68 (1H, s), 4,42 (4H, s)to 3.38 (2H, Sirs), to 2.94 (2H, t, J=6.9 Hz), of 2.86 (2H, q, J=7,6 Hz), 2.49 USD (3H, s)of 1.39 (3H, t, J=7,6 Hz); IR (KBr) Vmax3360, 2875, 1596, 1516, 1468, 1335, 1167, 1130, 1064, 920 cm-1.

Example 118 example 161

The compounds described in these examples were obtained in accordance with the following method: to a solution of the necessary commercially available sulfonamida (0.05 mmol) in DMF (1 ml) was added a suspension of NaH (0.1 mmol) in DMF (0.5 ml) and the mixture was shaken for 5 minutes. To this mixture was added a solution of phenyl-2-[4-(2-ethyl-5,7-dimethyl-3N-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 of example 18, 7 mg, 0.05 mmol) in DMF (0.5 ml) and the mixture was shaken at room temperature for 30 minutes. the donkey removal of DMF in a stream of nitrogen, the residue was dissolved in water (3 ml) and was placed on a 0.5 g/3 ml BondElute SCX. The solid phase is washed with MeOH (5 ml) and then was suirable 10% HCl/MeOH (3 ml). The eluate was concentrated under reduced pressure to get the connection specified in the header.

Example 118

Hydrochloride 3-(4-{2-[({[(3,4-dichlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 546,6 (M+N)+.

Example 119

Hydrochloride of 2-ethyl-3-{4-[2-({[({3-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 523,3 (M+N)+.

Example 120

Hydrochloride 3-(4-{2-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 512,5 (M+N)+.

Example 121

Hydrochloride of 2-ethyl-3-{4-[2-({[({4-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 523,3 (M+H)+.

Example 122

The hydrochloride of N-[4-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)phenyl]-2,2-dimethylpropanamide

MS (ESI) m/z 577,5 (M+N)+.

Example 123

Hydrochloride 3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 512,4 (M+N)+.

Example 124

Hydrochloride 3-(4-{2-[({[(3-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-H-imidazo[4,5-b]pyridine

MS (ESI) m/z 512,5 (M+N)+.

Example 125

Hydrochloride 3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[45-b]pyridine

MS (ESI) m/z 518,6 (M+N)+.

Example 126

Hydrochloride 3-(4-{2-[({[(5-bromo-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 564,2 (M+N)+.

Example 127

Hydrochloride of 2-ethyl-3-{4-[2-({[({2-methyl-5-nitro-phenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI)m/z 537,3 (M+N)+.

Example 128

Hydrochloride 3-(4-{2-[({[(3,4-acid)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 538,4 (M+N)+.

Example 129

Hydrochloride 3-(4-{2-[({[(4-butylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 534,5 (M+N)+.

Example 130

Hydrochloride of 2-ethyl-3-(4-{2-[({[(4-methoxyphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 508,4 (M+N)+.

Example 131

Hydrochloride of 2-ethyl-5,7-dimethyl-3-[4-(2-{[({[5-(phenylsulfanyl)-2-thienyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 592,4 (M+N)+.

Example 132

Hydrochloride 3-(4-{2-[({[(3,5-dichlorophenyl)sulfo the yl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 546,6 (M+N)+.

Example 133

Hydrochloride 3-(4-{2-[({[(2-bromophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 558,0 (M+N)+.

Example 134

Hydrochloride 3-(4-{2-[({[(4,5-dichloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 552,6 (M+N)+.

Example 135

Hydrochloride 3-[4-(2-{[({[2-(2,4-dichlorophenoxy)phenyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 638,8 (M+N)+.

Example 136

Hydrochloride 3-(4-{2-[({[(5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z us $ 530, 3 (M+N)+.

Example 137

Hydrochloride 3-(4-{2-[({[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 523,2 (M+N)+.

Example 138

Hydrochloride 3-(4-{2-[({[(4-cyanophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 503,2 (M+N)+.

Example 139

Hydrochloride 3-(4-{2-[({[(3,4-differenl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 514,3 (M+N)+.

Example 140

Hydrochloride 3-(4-{2-[({[(2,5-is ALOR-3-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 552,3 (M+N)+.

Example 141

The hydrochloride of N-[5-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)-1,3,4-thiadiazole-2-yl]ndimethylacetamide

MS (ESI) m/z 543,0 (M+N)+.

Example 142

Hydrochloride 3-{4-[2-({[({4-chloro-3-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 557,2 (M+N)+.

Example 143

Hydrochloride 3-(4-{2-[({[(4-butoxyphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 550,4 (M+N)+.

Example 144

Hydrochloride 3-[4-[4-(2-{[({[2,6-dichloro-4-(trifluoromethyl)phenyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 614,4 (M+N)+.

Example 145

Hydrochloride 3-[4-(2-{[({[4-(1-substituted)phenyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 612,4 (M+N)+.

Example 146

Hydrochloride 3-(4-{2-[({[(4,5-dibromo-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 642,0 (M+H)+.

Example 147

Hydrochloride of 2-ethyl-5,7-dimethyl-3-[4-(2-{[({[5-(2-thienylmethyl)-2-thienyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 598,2 (M+N)+.

Example 148

MS (ESI) m/z 534,4 (M+H)+.

Example 149

Hydrochloride 3-(4-{2-[({[(4-amino-3-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 527,3 (M+N)+.

Example 150

Hydrochloride of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2,4,5-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 580,4 (M+N)+.

Example 151

Hydrochloride 3-(4-{2-[({[(2,5-acid)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 538,3 (M+N)+.

Example 152

Hydrochloride 3-(4-{2-[({[(6-ethoxy-1,3-benzothiazol-2-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 579,1 (M+N)+.

Example 153

Hydrochloride 3-(4-{2-[({[(2-amino-4-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 527,2 (M+N)+.

Example 154

Hydrochloride of 2-ethyl-5,7-dimethyl-3-[4-(2-{[({[5-(2-thienylmethyl)-2-thienyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine

MS (ESI)m/z 630,2 (M+N)+.

Example 155

Hydrochloride 3-[4-(2-{[({[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 580,2 (M+N)+.

Example 156

Hydrochlori is 3-{4-[2-({[(2,3-dihydro-1,4-benzodioxin-6-ylsulphonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 536,2 (M+N)+.

Example 157

Hydrochloride of 2-ethyl-5,7-dimethyl-3-[4-(2-{[({[2-(phenylsulfanyl)phenyl]sulfonyl}amino)carbonyl]amino}ethyl)phenyl]-3H-imidazo[4,5-b]pyridine

MS (ESI)m/z 586,3 (M+N)+.

Example 158

Hydrochloride 3-(4-{2-[({[(4-chloro-2,5-dimetilfenil)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 540,3 (M+H)+.

Example 159

Hydrochloride 3-(4-{2-[({[(3-bromo-5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 598,1 (M+H)+.

Example 160

Hydrochloride of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-vinylphenol)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 504,4 (M+N)+.

Example 161

The hydrochloride of methyl 2,4-dichloro-5-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)benzoate

MS (ESI) m/z 604,5 (M+H)+.

Example 162 example 194

The compounds described below were obtained in accordance with the following method: to a mixture of the necessary commercially available carbonic acid and dichloromethane was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (WSC) (0.05 mmol, 0.5 ml), and then to the reaction mixture was added a solution of 3-amino-4,6-dimethyl-2-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}aniline)pyridine*(0,038 mmol) in dichloromethane (0.5 ml) at the room temperature. The reaction mixture was heated for 3 days at room temperature, then was stirred for 1 day at 40°C. After removal of solvent the residue was dissolved in MeOH (1 ml)and the solution was filtered through a membrane filter. The filtrate was purified via preparative LC/MS (Shiseido capcell pack C18 UG80 (a 4.6 x 50 mm), elwira MeOH/0.1% of HCOOH (about./about., from 20/80 to 90/10)), with the connection specified in the header.

*3-Amino-4,6-dimethyl-2-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}aniline)pyridine was obtained in the following way.

Stage 1. 3-{4-[(4,6-Dimethyl-3-nitro-2-pyridinyl)amino[phenyl}propionic acid

To a solution of 2-chloro-4,6-dimethyl-3-nitropyridine (17.9 g, 96 mmol) and methyl 3-(4-AMINOPHENYL)propanoate (19 g, 96 mmol) in DMSO (100 ml) was added N,N-diisopropylethylamine (26 g, 200 mmol) and the reaction mixture was heated at 140°C during the night. The reaction mixture was distributed between water (400 ml) and ethyl acetate/toluene (about./about., 2:1, 300 ml). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate/toluene (about./about., 2:1, 200 ml). The combined organic extracts were washed with saturated brine (200 ml), dried (Na2SO4) and concentrated. To a solution of the residual oil in methanol (100 ml) was added 2 N. aqueous NaOH (150 ml, 300 mmol) and the resulting mixture was stirred at room temperature for 2 hours. Volatile components is UNT was removed under reduced pressure and the residue was washed with ethyl acetate (200 ml). The aqueous phase was acidified using 2 N. hydrochloric acid (200 ml, 400 mmol) and was extracted with ethyl acetate (3 x 200 ml). The extracts were washed with saturated brine (200 ml), dried (Na2SO4) and concentrated, obtaining of 23.2 g (77%) of the compound indicated in the title, in the form of a light brown solid.

1H-NMR (CDCl3) δ to 9.57 (1H, s), 7,56 (2H, d, J=8,4 Hz), 7,19 (2H, d, J=8,4 Hz), of 6.52 (1H, s), 2,95 (2H, t, J=7.5 Hz), to 2.66 (2H, t, J=7.5 Hz), to 2.55 (3H, s), 2,43 (3H, s).

Stage 2. Phenyl 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethylcarbamate

To a stirred solution of 3-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}propionic acid (stage 1, 10 g, and 31.7 mmol) in dioxane (200 ml) was added diphenylphosphoryl (DPPA) (7,54 ml, 35 mmol) and triethylamine (4,87 ml, 35 mmol). The reaction mixture was heated at 120°C for 2 hours. To the reaction mixture was added phenol (6.6 g, 70 mmol) and the reaction mixture is boiled under reflux. After 3 hours the reaction mixture was added an additional amount of phenol (3,3 g, 35 mmol). The resulting mixture was heated at the boiling point under reflux overnight. The volatile component was removed and the residue was divided between 10% aqueous solution of citric acid (200 ml) and ethyl acetate (300 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (300 ml). The combined organic extrathyroidal water (300 ml) and saturated saline (300 ml), then was dried (Na2SO4) and concentrated. The crude product was purified using flash chromatography on a column of silica gel, elwira hexane/EtOAc (2:1), to obtain 10.3 g (77%) of the compound indicated in the title, in the form of an orange solid.

1H-NMR (CDCl3) δ 9,60 (IB, C)to 7.61 (2H, d, J=8.6 Hz), 7,38-to 7.32 (2H, m), 7.24 to 7,16 (3H, m), 7,14-to 7.09 (2H, m), 6,54 (IB, C), is 5.06 (1H, Sirs), to 3.58-3,50 (2H, m), 2,89 (2H, t, J=6.9 Hz), of 2.56 (3H, s), is 2.44 (3H, s).

Stage 3. 4,6-Dimethyl-2-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}aniline)-3-nitropyridine

To a stirred solution of phenyl 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethylcarbamate (stage 2, 10.0 g, 24.6 mmol) and p-toluensulfonate (6.3 g, to 36.8 mmol) in DMF (100 ml) was added sodium hydride (2.0 g, 50 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (300 ml) and was extracted with ethyl acetate/toluene (about./about., 2:1, 2 x 300 ml). The organic extracts were washed with water (100 ml) and saturated saline (200 ml), then dried (Na2SO4). Removal of solvent gave the crude product. Recrystallization from ethyl acetate gave 9.6 g (81%) of the compound indicated in the title, in the form of a brown solid. The original liquid was concentrated, and the residue was purified using flash chromatography on a column of silica gel, elwira hexane/acilac what tatom (1:1), with the receipt of 1.9 g (16%) of the compound indicated in the title, in the form of a brown solid.

1H-NMR (CDCl3) δ of 9.75 (1H, s), a 7.62 (2H, d, J=8,4 Hz), to 7.59 (2H, d, J=8,4 Hz), 7,26 (2H, d, J=8,4 Hz), to 7.15 (2H, d, J=8,4 Hz), 6,62-6,50 (2H, m), 3,55-of 3.42 (2H, m), 2,80 (2H, t, J=6.9 Hz), of 2.56 (3H, s), 2,43 (3H with), 2,39 (3H, s).

Stage 4. 3-Amino-4,6-dimethyl-2-(4-{2-[(({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}aniline)pyridine

To a solution of 4,6-dimethyl-2-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}aniline)-3-nitropyridine (stage 3, 11.4 g, 23.6 mmol) in methanol (250 ml) was added 10% Pd-C (2.0 g). The resulting mixture was stirred in an atmosphere with an average pressure of hydrogen (to 4.0 kgf/cm2) for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was recrystallized from ethyl acetate, to obtain 9.0 g (85%) of the compound indicated in the title, in the form of a pale white solid.

1H-NMR (CDCl3) δ of 7.69 (2H, d, J=8.0 Hz), 7,26 (2H, d, J=8.0 Hz), 7,00-to 6.95 (4H, m), is 6.61 (1H, s), 6,24 (1H, Sirs), 3,44-to 3.38 (2H, m), 2,70 (2H, t, J=6,7 Hz), 2,39 (3H, s), of 2.33 (3H,s), are 2.19 (3H,s).

Example 162

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[3-oxo-3-(2-thienyl)propyl]-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 602,48 (M+N)+.

Example 163

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(phenoxymethyl)-3H-imidazo[4,5-b]is iridine

MS (ESI) m/z 570,5 (M+N)+.

Example 164

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonylamino}carbylamine]ethyl}phenyl)-2-[2-(3-pyridinyl)ethyl]-3H-imidazo[4,5-b]pyridine

MS (ESI)m/z 569,49 (M+N)+.

Example 165

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(3-oxo-3-phenylpropyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 596,28 (M+N)+.

Example 166

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(3-phenylpropyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 582,52 (M+H)+.

Example 167

Formate 2-(ethoxymethyl)-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 522,46 (M+H)+.

Example 168

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[(phenylsulfanyl)methyl]-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 586,49 (M+N)+.

Example 169

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-pentyl-3H-imidazo[4,5-b]pyridine

MS (ESI)m/z 534,51 (M+N)+.

Example 170

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(2-phenylethyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 568,51 (M+N)+.

Example 171

Formate 2-(3-butenyl)-5,7-dime the Il-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 516,45 (M+H)+.

Example 172

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(3-thienylmethyl-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 560,44 (M+H)+.

Example 173

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(4-pentenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 530,46 (M+N)+.

Example 174

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(2-thienylmethyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 560,44 (M+N)+.

Example 175

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(3-pyridinylmethyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 555,48 (M+N)+.

Example 176

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[(2E)-2-pentenyl]-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 532,48 (M+N)+.

Example 177

Formate 2-benzyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 554,48 (M+N)+.

Example 178

Formate 2-(cyanomethyl)-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI)m/z 503,41 (M+N)+.

Example 179

Formate 2-(methoxymethyl)-5,7-dimethyl-3-(4-{2-[({[(4-m is terphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 508,44 (M+N)+.

Example 180

Formate 2-heptyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 562,33 (M+N)+.

Example 181

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-octyl-3H-imidazo[4,5-b]pyridine

MS (ESI)m/z 576,37 (M+N)+.

Example 182

Formate 5,7-dimethyl-2-(4-methylpentyl)-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 548,53 (M+N)+.

Example 183

Formate 2-[(benzyloxy)methyl]-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 584,52 (M+H)+.

Example 184

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(2-phenoxyethyl)-3H-imidazo[4,5-b]pyridine

MS (ESI)m/z 584,33 (M+N)+.

Example 185

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[3-(2-thienyl)propyl]-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z to 588.5 (M+N)+.

Example 186

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were))sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(2-naphthylmethyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 604,37 (M+N)+.

Example 187

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)su is hanil]amino}carbonyl)amino]ethyl}phenyl)-2-(4-phenylbutyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 596,42 (M+N)+.

Example 188

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(5-fenilpentil)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 610,45 (M+N)+.

Example 189

Formate 2-(2-ethoxyethyl)-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 536,38 (M+N)+.

Example 190

Formate 2-(2,3-dihydro-1H-inden-2-ylmethyl)-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 594,45 (M+N)+.

Example 191

Formate 2-(cyclopropylmethyl)-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 518,45 (M+N)+.

Example 192

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(methylsulfanyl)ethyl]-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 538,44 (M+N)+.

Example 193

Formate 2-hexyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 548,44 (M+N)+.

Example 194

Formate 5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(4-pentenyl)-3H-imidazo[4,5-b]pyridine

MS (ESI) m/z 532,42 (M+N)+.

Example 195

6-Chloro-5-tzia is o-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1 H-benzimidazole

Stage 1. 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carbonitrile

The interaction was carried out according to the method described for stage 7 of example 1 from 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile (example 111, step 4).

1H-NMR (CDCl3) δ 8,07 (1H, s)to 7.50 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), 7,19 (1H, s), 3,83 (2H, t, J=7,1 Hz), up 3.22 (2H, t, J=7,1 Hz), and 2.79 (2H, q, J=7.5 Hz), of 1.37 (3H, t, J=7.5 Hz).

Stage 2. 1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile

The interaction was carried out according to the method described for stage 8 of example 1 from 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carbonitrile (stage 1).

1H-NMR (CDCl3) δ 8,07 (1H, s), 7,49 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 7,18 (1H, s)to 3.64 (2H, t, J=7.0 Hz), totaling 3.04 (2H, t, J=7,0 Hz), and 2.79 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

Stage 3. 1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile

The interaction was carried out according to the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile (stage 2).

1H-NMR (CDCl3) δ of 8.06 (1H, s), 7,46 (2H, d, J=8.1 Hz), 7,26 (2H, d, J=8.1 Hz), 7,19 (1H, s)to 3.09 (2H, t, J=7,1 Hz), 2,89 (2H, t, J=7,1 Hz), and 2.79 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

Stage 4. 6-Chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]am is but}carbonyl)amino]ethyl}phenyl-1H-benzimidazole

The interaction was carried out according to the method described for stage 10 of example 1 from 1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile (stage 3).

TPL 219-224°C;

IR (KBr) v: 3388, 2229, 1708, 1618, 1514, 1466, 1344, 1161, 1089 cm-1.

MS (ESI) m/z 522 (M+H)+, 520(M-H)-;1H-NMR (DMSO-d6) δ scored 8.38 (1H, s), to 7.77 (211, d, J=8,2 Hz), 7,31-7,49 (6H, m), 7,32 (1H, s), 6,53 (1H, Sirs), 3,26 of 3.28 (2H, m), 2,69-of 2.81 (4H, m)to 2.35 (3H, s), 1,25 (3H, t, J=7,6 Hz).

The method of synthesis of compounds of example 196 - example 197

The compounds described below were obtained in accordance with the following method: to a mixture of the necessary commercially available carbonic acid and dichloromethane (DCM) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (WSC) (0.05 mmol, 0.5 ml), then a solution of 3-amino-4,6-dimethyl-2-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}aniline)pyridine (0,038 mmol) in DCM (0.5 ml) at room temperature. The reaction mixture was stirred for 3 days at room temperature, then for one day at 40°C. After removal of solvent the residue was dissolved in MeOH (1 ml) and the solution was filtered through a membrane filter. The filtrate was purified via preparative LC/MS (Shiseido capcell pack UG80 Cl8 (20 x 50 mm), elwira MeOH/0.1% of HCOOH (about./about., from 20/80 to 90/10), with the connection specified in the header.

Example 196

Formate N-{[(2-{4-[5,7-dimethyl-2-(4-methyl who entyl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI) m/z 548,53 (M+H)+.

Example 197

Formate N-{[(2-{4-[5,7-dimethyl-2-(3-oxo-3-phenylpropyl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI)m/z 596,28 (M+N)+.

The method of synthesis of compounds of example 198 example 216

The compounds described below were obtained in accordance with the following method: carboxylic acid (0.06 mmol) was diluted with N,N-diisopropylethylamine (DIEA) (0,106 mmol) and dichloromethane (DCM) (0.3 ml). To this mixture was added 1-hydroxybenzotriazole hydrate (HOBT) (0.06 mmol) in N,N-dimethylformamide (DMF) (0,02 ml). To the reaction mixture were added 3-amino-4,6-dimethyl-2-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}aniline)pyridine (0,044 mmol) in DCM (0.3 ml) and DMF (0,08 ml), then O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexaflurophosphate (HBTU) (0.13 mmol) in DMF (0.25 ml). The reaction solution was stirred for 6 hours at room temperature, then was heated at 40°C during the night. After removal of solvent the residue was dissolved in MeOH (0.8 ml). The solution was placed on a Varian cartridge BondElute® SCX (500 mg/3 ml), which was pre-treated with 2 ml MeOH. Solid-phase matrix was washed in 5 ml MeOH and then suirable 2 n ammonia/MeOH (3 ml). After removal of solvent the product was used in the reaction in the next stage.

The intermediate product of the 1st stage was diluted in EtOH (2 ml), then the reaction is ionic solution was added excess amount of 2 N. aqueous NaOH (1 ml). The reaction mixture was stirred at 40-70°C during the night. After completion of the reaction the solvent was removed. To the residue was added 2 N. aqueous solution of HCl (1 ml, set pH equal to 7.0). The aqueous layer was extracted with DCM (1 ml X 3). The organic layer was concentrated to obtain a residue. The crude product was purified via preparative LC/MS (Shiseido capcellpack UG 80 C18 (20 x 50 mm), elwira MeOH/0.1% of HCOOH (about./about., from 20/80 to 90/10), with the connection specified in the header, in the form of formate.

Example 198

Formate N-{5-[5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine-2-yl]pentyl}ndimethylacetamide

MS (ESI) m/z 591,33 (M+N)+.

Example 199

Formate N-{[(2-{4-[5,7-dimethyl-2-(5-oxo-5-fenilpentil)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI) m/z 624,37 (M+N)+.

Example 200

Formate N-{[(2-{4-[2-(2-cyclopenten-1-ylmethyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI) m/z 544,40 (M+H)+.

Example 201

Formate N-{[(2-{4-[2-(1-cyclopenten-1-ylmethyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI)m/z 544,40 (M+N)+.

Example 202

Formate (2Z)-3-[5,7-dimethyl-3-(4-{2-[({[(4-were) sulfonyl]amino}carbonyl)amino]the Teal}phenyl)-3H-imidazo[4,5-b]pyridine-2-yl]-N-propyl-2-propenamide

MS (ESI) m/z 575,44 (M+N)+.

Example 203

Formate N-{[(2-{4-[5,7-dimethyl-2-(1-methyl-3-oxo-3-phenylpropyl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI) m/z 610,49 (M+N)+.

Example 204

Formate N-{[2-{4-[5,7-dimethyl-2-(3,3,3-Cryptor-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI)m/z 574,43 (M+N)+.

Example 205

Formate N-({[2-(4-{2-[2-(diethylamino)ethyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide

MS (ESI) m/z 563,49 (M+N)+.

Example 206

Formate N-{[2-(4-{2-[2-(4-forfinal)ethyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide

MS (ESI) m/z 586,46 (M+N)+.

Example 207

Formate 3-[5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine-2-yl]-N,N-diethylpropane

MS (ESI) m/z 591,50 (M+N)+.

Example 208

Formate N-[({2-[4-(5,7-dimethyl-2-tetrahydro-3-furanyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

MS (ESI)m/z 534,41 (M+N)+.

Example 209

Formate N-{[(2-4-[5,7-dimethyl-2-(1-methylbutyl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI)m/z 534,45 (M+N)+.

Primer

Formate N-{[(2-{4-[2-(cyclopentylmethyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI) m/z 546,46 (M+N)+.

Example 211

Formate N-{[(2-{4-[5,7-dimethyl-2-(2-methylcyclopropyl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI)m/z 518,41(M+N)+.

Example 212

Formate N-[({2-[4-(5,7-dimethyl-2-{3-[4-(metiloksi)phenyl]-3H-oxopropyl}-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

MS (ESI) m/z 626,45 (M+N)+.

Example 213

Formate N-({[2-(4-{2-[3-(3,4-dimetilfenil)propyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide

MS (ESI) m/z 610,28 (M+H)+.

Example 214

Formate N-([2-(4-{2-[(Z)-2-(4-forfinal)ethynyl]-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide

MS (ESI) m/z 584,41 (M+N)+.

Example 215

Formate N-[({2-[4-(5,7-dimethyl-2-{(Z)-2-[2-(metiloksi)phenyl]ethynyl}-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

MS (ESI)m/z 596,29 (M+N)+.

Example 216

Formate N-{[(2-{4-[2-(5-hexenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI) m/z 544,33 (M+N)+.

The method of synthesis of compounds of example 217 - PR is a measure 220

The compounds described below were obtained in accordance with the following method: to a solution of 3-amino-4,6-dimethyl-2-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}aniline)pyridine (0,044 mmol) in dichloromethane (DCM) (0.2 ml) and DMF (0.05 ml) was added pyridine (0,103 mmol) in DCM (0.2 ml) and excess of acid chloride of acid (of 0.066 mmol - 0,088 mmol) at room temperature. The reaction mixture was stirred at room temperature until disappearance of starting compound (4-6 hours). After completion of the reaction, to the reaction mixture was added MeOH (0.2 ml), then was stirred for 1 hour. The solvent was removed using a vacuum centrifuge. The residue, which was dissolved MeOH (0.8 ml), was placed on a Varian cartridge BondElutet® SCX (500 mg/3 ml), which was pre-treated with 2 ml MeOH. Solid-phase matrix was washed in 5 ml MeOH and then suirable 2 n ammonia/MeOH (3 ml). The eluate was concentrated in vacuum to obtain an intermediate product. The intermediate product of the 1st stage was dissolved EtOH (2 ml), and then to the reaction solution was added an excess amount of 2 N. aqueous NaOH (1 ml). The reaction mixture was stirred at 70°C during the night. After removal of solvent the residue was added 2 N. aqueous HCl for neutralization. The aqueous layer was extracted with DCM (1 ml X 5 times). The organic layer was dried with sodium sulfate, then concentrated. The crude product of cleansing and using preparative LC/MS (Shiseido capcellpack UG 80 C18 (20 x 50 mm), elwira MeOH/0.1% of HCOOH (about./about., from 20/80 to 90/10), with the connection specified in the header, in the form of formate.

Example 217

Formate, 4-methyl-N[({2-[4-(2,5,7-trimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]benzosulfimide

MS (ESI) m/z 478,31 (M+N)+.

Example 218

Formate N-{[(2-{4-[2-(2,2-dimethylpropyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

MS (ESI)m/z 534,40 (M +H)+.

Example 219

Formate N-[({2-[4-(2-cyclobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

MS (ESI)m/z 518,38 (M+H)+.

Example 220

Formate N-[({2-[4-(2-cyclopentyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

MS (ESI)m/z 532,44 (M+N)+.

Example 221

P-toluensulfonate 4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenethyl(4-were)sulfonylamino

A mixture of 4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenethyl(4-were)sulfanilamide (example 106, 150 mg, 0,265 mmol), p-toluensulfonate acid (50.5 mg, 0,265 mmol) in acetone (3% H2Oh, 0.3 ml) was stirred at room temperature for 16 hours. The precipitated crystals solids were filtered, washed with acetone (0.05 ml x5) and dried in vacuum at 40°C for 2 hours, is getting 158 mg (81%) compound specified in the header, in the form of a white solid.

TPL: 234,8°C.

1H-NMR (CDCl3) δ 8,66 (1H, Sirs), 8,35 (1H, s), a 7.85 (2H, d, J=8.1 Hz), 7,81 (2H, d, J=8,4 Hz), 7,53 (2H, d, J=8,4 Hz), 7,39-to 7.35 (3H, m), 7,29 (2H, d, J=7.9 Hz), 7,19 (2H, d, J=7.9 Hz), 4,35 (2H, t, J=6.2 Hz), of 3.13 (2H, q, J=7,6 Hz), totaling 3.04 (2H, t, J=6.3 Hz), 2,42 (3H, s), a 2.36 (3H, s)of 1.43 (3H, t, J=7,4 Hz).

Example 222

Bansilalpet 4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenethyl(4-were)sulfonylamino

The connection specified in the header received in accordance with the method described in example 221 on the basis of 4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenethyl(4-were)sulfanilamide (example 106).

TPL: 194,9°C.

1H-NMR (CDCl3) δ 8,83 (1H, Sirs), 8,39 (1H, s), 7,99-of 7.95 (2H, m), 7,81 (2H, d, J=8,4 Hz), 7,54 (2H, d, J=8,4 Hz), 7,41 and 7.36 (6H, m), 7,29 (2H, d, J=8,4 Hz), 4,34 (2H, t, J=6,1 Hz), 3,14 (2H, q, J=7,6 Hz), 3,03 (2H,, t, 3=6,1 Hz)to 2.41 (3H, s)of 1.42 (3H, t, J=7,4 Hz).

Example 223

Methanesulfonate of 4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 221 on the basis of 4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenethyl(4-were)sulfanilamide (example 106).

TPL: 172,2°C.

1H-NMR (CDCl3) δ 9,03 (1H, Sirs), charged 8.52 (1H, s), 7,81 (2H, d, J=8,2 Hz), 7,56 (2H, d, J=8,2 Hz), 7,40 (2H,d, J=8.1 Hz), 7,39 (1H, s), 7,29 (2H, d, J=8.1 Hz), 4,35 (2H, t, J=6.3 Hz), and 3.16 (2H, q, J=7,6 Hz), 3,06 (2H, t, J=6.3 Hz), to 2.94 (3H, s)to 2.41 (3H, s)of 1.45(3H, t, J=7,6 Hz).

Example 224

p-Toluensulfonate 5-acetyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole

A mixture of 5-acetyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole (example 78, 43 mg of 0.085 mmol), p-toluensulfonate acid (16.2 mg, of 0.085 mmol) in ethanol (0.1 ml) was stirred at room temperature for 16 hours. The precipitated crystals are solids were filtered, washed with ethanol (0.05 ml x 5) and dried in vacuum at 40°C for 2 hours, to obtain 54 mg (91%) of the compound indicated in the title, in the form of a white solid.

TPL: 166,7°C.

1H-NMR (CDCl3) δ 9,85 (1H, Sirs), and 8.50 (1H, s), 8,02 (1H, d, J=8,9 Hz), 7,86 (2H, d, J=8.1 Hz), to 7.68 (2H, DD, J=1,8, 8,2 Hz), 7,47 (2H, d, J=8,4 Hz), of 7.36-7,31 (3H, m), 7,22 (2H, d, J=8,4 Hz), 7,17 (2H, d, J=8,4 Hz), 7,00 (1H, Sirs), 3,47-3,39 (2H, m) of 3.14 (2H, q, J=7,3 Hz), is 2.88 (2H, t, J=6.3 Hz), 2,58 (3H, s)to 2.35 (3H,s), of 2.34 (3H,s)of 1.45 (3H, t, J=7,6 Hz).

Example 225

Bansilalpet 5-acetyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole

The connection specified in the header received in accordance with the method described in example 224, starting from 5-acetyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazo is a (example 78).

TPL: 117,7°C.

1H-NMR (CDCl3) δ 9,62 (1H, Sirs), charged 8.52 (1H, s), 8,05-of 7.96 (3H, m), to 7.67 (2H, d, J=8,2 Hz), 7,49-the 7.43 (5H, m), 7,37-to 7.32 (3H, m), 7,19 (2H, d, J=8,2 Hz), 6,92-to 6.88 (1H, m), 3,48-of 3.42 (2H, m) 3,17 (2H, q, J=7,6 Hz), 2,89 (2H, t, J=6,1 Hz), 2,61 (3H, s)to 2.35 (3H,s), for 1.49 (3H, t, J=7,6 Hz).

Example 226

4-chloro-2-ethyl-6-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine

Stage 1. Tert-butyl 2-{4-[(2-chloro-6-methyl-3-nitro-4-pyridinyl)amino]phenyl}ethylcarbamate

A mixture of 2,4-dichloro-6-methyl-3-nitropyridine (Chorvat, Robert J. et al.,J. Med. Chem., 1999,42, 833., 7.5 g, and 36.2 mmol), tert-butyl ether [2-(4-AMINOPHENYL)ethyl]carbamino acid (Stark, Peter A. et al.,J. Med. Chem., 1992,35, 4264., 1,14 g of 4.83 mmol) in N,N-diisopropylethylamine (50 ml) was boiled under reflux for 16 hours. After cooling, the mixture was concentrated. The residue was diluted with dichloromethane (200 ml) and washed with saturated aqueous NaHCO3(50 ml x 2). The organic layer was dried (MgSO4) and concentrated. Purified column flash chromatography, elwira hexane/ethyl acetate (1:1), to obtain 310 mg (16%) of the compound indicated in the title, in the form of an orange solid.

1H-NMR (CDCl3) δ 8,19 (1H, s), 7,28 (2H, d, J=8,4 Hz), 7,16 (2H, d, J=8,3 Hz), 6,69 (1H, s), to 4.62 (1H, Sirs), 3,43-3,37 (2H, m), 2,84 (2H, t, J=7.0 Hz), is 2.37 (3H, s)of 1.44 (9H, s).

Stage 2. Tert-butyl 2-{4-[(3-amino-2-chloro-6-methyl-4-pyridine)amino]Fe is Il}ethylcarbamate

The connection specified in the header received in accordance with the method described for stage 1 of example 6, from tert-butyl 2-{4-[(2-chloro-6-methyl-3-nitro-4-pyridinyl)amino]phenyl}ethylcarbamate (stage 1).

1H-NMR (CDCl3) δ to 7.18 (2H, d, J=8,3 Hz), 7,03 (2H, d, J=8,2 Hz), 6,76 (1H, s), of 6.02 (1H, Sirs), br4.61 (1H, Sirs), 3,40-3,37 (4H, m), 2,78 (2H, t, J=7.0 Hz), of 2.33 (3H, s)of 1.44 (9H, s).

Stage 3. Tert-butyl 2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylcarbamate

A mixture of tert-butyl 2-{4-[(3-amino-2-chloro-6-methyl-4-pyridinyl)amino]phenyl}ethylcarbamate (stage 2,238 mg, 0,63 mmol), Propionaldehyde (70 mg, from 0.76 mmol) in toluene (4.6 ml) and dichloromethane (0.6 ml) was boiled under reflux for 1 hour. After cooling, the mixture was diluted with ethyl acetate (100 ml) and washed with 1 N. aqueous solution of NaOH (30 ml x 2) and saturated saline (30 ml). The organic layer was dried (MgSO4) and concentrated. Sediment and monohydrate p-toluensulfonate acid (5 mg, was 0.026 mmol) in toluene (5.0 ml) was boiled under reflux for 16 hours. After cooling, the mixture was diluted with dichloromethane (100 ml) and washed with saturated aqueous NaHCO3(30 ml) and saturated saline (30 ml). The organic layer was dried (MgSO4) and concentrated. Was purified using PTLC, elwira hexane/ethyl acetate (1:1), to obtain 90 mg (34%) of the connection specified in reception is e, in the form of a brown oil.

1H-NMR (CDCl3) δ 7,44 (2H, d, J=8,2 Hz), 7,27 (2H, d, J=8,2 Hz), for 6.81 (1H, s), and 4.75 (1H, Sirs), 3,52-3,44 (2H, m)to 2.94 (2H, t, J=7,1 Hz), 2,82 (2H, q, J=7,6 Hz)to 2.55 (3H, s)of 1.46 (9H, s)of 1.32 (3H, t, J=7,6 Hz).

Stage 4. 2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c]pyridine-1-ylphenyl]ethanamine

To a stirred solution of tert-butyl 2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylcarbamate (stage 3, 90 mg, 0.22 mmol) in dichloromethane (8.5 ml) was added triperoxonane acid (1.0 ml, at 13.0 mmol) at 0°C and the mixture was stirred at 0°C for 30 minutes, then at room temperature for 5 hours. The mixture was concentrated and diluted with dichloromethane (50 ml), washed with saturated aqueous NaHCO3(10 ml) and saturated saline (10 ml). The organic layer was dried (MgSO4) and concentrated. Cleaning with PTLC, elwira with ethyl acetate, gave 50 mg (73%) of the compound indicated in the title, in the form of a brown oil.

1H-NMR (CDCl3) δ was 7.45 (2H, d, J=8,2 Hz), 7,27 (2H, d, J=8,2 Hz), for 6.81 (1H, s)to 3.09 (2H, t, J=6.9 Hz), 2,89 (2H, t, J=6.8 Hz), and 2.83 (2H, q, J=7.4 Hz), to 2.55 (3H, s)is 1.31 (3H, t, J=7,4 Hz).

Stage 5. 4-Chloro-2-ethyl-6-methyl-1-[4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo [4,5-c]pyridine

The connection specified in the header, received as described for stage 10, based on 2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c]pyridine-1-is)phenyl]ethanamine (stage 4).

TPL: 163°C. MS (ESI) m/z: 512 [(MH)+], 510 [(M-H)-].

1H-NMR (CDCl3) δ 7,73 (2H, d, J=8,2 Hz), 7,38-7,21 (6H, m), 6,78 (1H, s), 3,53-3,51 (2H, m), 2.91 in-2,89 (2H, m), and 2.79 (2H, q, J=7.2 Hz), 2,52 (3H, s), is 2.37 (3H, s)of 1.29 (3H, t, J=7.2 Hz).

Example 227

2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol (step 4 of example 42).

TPL: 158°C.

MS (ESI) m/z: 493[(MH)+], 491[(M-H)-].

1H-NMR (DMSO-d6) δ 7,72 (2H, d, J=8,2 Hz), 7,47 (2H, d, J=8.6 Hz), the 7.43 (2H, d, J=8.6 Hz), 7,34 (2H, d, J=8.0 Hz), of 6.96 (1H, s), 4,18 (2H, t, J=6.6 Hz), to 2.94 (2H, t, J=6.4 Hz), was 2.76 (3H, s), is 2.74 (2H, q, J=7,3 Hz), 2,50 (3H, s)to 2.35 (3H, s)of 1.23 (3H, t, J=7,3 Hz).

Example 228

2-[4-(8-Ethyl-2,6-dimethyl-9H-purine-9-yl)phenyl]ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[(6-Chloro-2-methyl-5-nitro-4-pyrimidinyl)amino]phenyl}ethanol

To a stirred solution of 4,6-dichloro-2-methyl-5-nitro-pyrimidine (Albert et al.,J. Chem. Soc., 1954, 3832, 7.5 g, 36,1 mmol) in THF (150 ml) was added 4-aminophenylamino alcohol (2,47 g, 18.0 mmol), triethylamine (3,65 g, 36,1 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction extinguished with water (10 ml) and the mixture was extracted with ethyl acetate (100 ml x 3). The organic layer was washed with saturated solely the solution (50 ml), dried (MgSO4) and concentrated. Purified column flash chromatography, elwira hexane/ethyl acetate (gradient elution from 1:1 to 1:2), to obtain 4.0 g (72%) of the compound indicated in the title, in the form of a yellow solid.

1H-NMR (CDCl3) δ 9,34 (1H, s)to 7.50 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,8 Hz)to 3.89 (2H, t, J=6.6 Hz), 2,90 (2H, t, J=6.4 Hz), to 2.57 (3H, s).

Stage 2. Diethyl 2-(6-{[4-(2-hydroxyethyl)phenyl]amino}-2-methyl-5-nitro-4-pyrimidinyl)propanedioic

To a stirred solution of 2-{4-[(6-chloro-2-methyl-5-nitro-4-pyrimidinyl)amino]phenyl}ethanol (step 1, 2.0 g, 6,48 mmol) in acetone (61 ml) was added diethylmalonate (1,53 g, 9,54 mmol) at 0°C, was then added dropwise an aqueous solution of NaOH (11 N., 2 ml, 22 mmol) in 20 minutes. After the addition the mixture was stirred at room temperature for 1 hour. The reaction extinguished with water (120 ml) and adding acetic acid, has established a pH equal to 8.0. The mixture was extracted with ethyl acetate (100 ml x 3). The organic layer was washed with saturated saline (50 ml), dried (MgSO4) and concentrated. The removal of excess quantities of diethylmalonate by azeotropic distillation with toluene gave 3,26 g (72%) of the compound indicated in the title, in the form of a brown oil.

MS (EI) m/z: 432 (M+).

1H-NMR (CDCl3) δ 10,15 (1H, s), 7,55 (2H, d, J=8,4 Hz), 7,27 (2H, d, J=8,4 Hz), are 5.36 (1H, s), or 4.31 (4H, q, J=7,1 Hz), 3,90 (2H, t, J=6.6 Hz), 2,9 (2H, t, J=6.4 Hz), of 2.56 (3H, s)of 1.32 (6H, t, J=7,1 Hz).

Stage 3. 2-{4-[(2,6-Dimethyl-5-nitro-4-pyrimidinyl)amino]phenyl}ethanol

A mixture of diethyl 2-(6-{[4-(2-hydroxyethyl)phenyl]amino}-2-methyl-5-nitro-4-pyrimidinyl)propanoate (stage 2, 2.0 g, 6,48 mmol) in 2 N. aqueous HCl (15 ml) was boiled under reflux for 5 hours. After cooling, the reaction extinguished saturated aqueous NaHCO3(100 ml) and was extracted with ethyl acetate (100 ml x 3). The organic layer was washed with saturated saline (50 ml), dried (MgSO4) and concentrated. Purified column flash chromatography, elwira hexane/ethyl acetate (gradient elution from 1:1 to 0:100), with the receipt of 1.33 g (71%) of the compound indicated in the title, in the form of a yellow solid.

MS (EI) m/z: 288(M+).

1H-NMR (CDCl3) δ 9,81 (1H, s), 7,56 (2H, d, J=8,4 Hz), 7,27 (2H, d, J=8,4 Hz), 3,92-3,86 (2H, m), 2,89 (2H, t, J=6.4 Hz), was 2.76 (3H, s), of 2.56 (3H, s).

Stage 4. 2-{4-[(5-Amino-2,6-dimethyl-4-pyrimidinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 6, from 2-{4-[(2,6-dimethyl-5-nitro-4-pyrimidinyl)amino]phenyl}ethanol (step 3).

MS (EI) m/z: 258 (M+).

1H-NMR (DMSO-d6) δ to 8.14 (1H, s), 7,63 (2H, d, J=8.6 Hz), 7,12 (2H, d, J=8,4 Hz), of 4.67 (2H, Sirs), to 3.58 (2H, t, J=7,3 Hz)to 2.67 (2H, t, J=7.2 Hz), 2,28 (3H, s), measuring 2.20 (3H, s).

Stage 5. 2-[4-(8-Ethyl-2,6-dimethyl-9H-purine-9-is)phenyl]ethyl propanoate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(5-amino-2,6-dimethyl-4-pyrimidinyl)amino]phenyl}ethanol (step 4).

1H-NMR (CDCl3) δ 7,44 (2H, d, J=8,2 Hz), 7,31 (2H, d, J=8,2 Hz), 4,37 (2H, t, J=6.9 Hz), 3,06 (2H, t, J=6.8 Hz), 2,84 (3H, s), 2,82 (2H, q, J=7.4 Hz), 2,70 (3H, s)to 2.35 (2H, q, J=7,6 Hz)is 1.31 (3H, t, J=7,6 Hz)and 1.15 (3H, t, J=7,6 Hz).

Stage 6. 2-[4-(8-Ethyl-2,6-dimethyl-9H-purine-9-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(8-ethyl-2,6-dimethyl-9H-purine-9-yl)phenyl]ethyl of propanoate (stage 5).

1H-NMR (CDCl3) δ 7,46 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,3 Hz), 3,99-to 3.92 (2H, m)to 2.99 (2H, t, J=6.4 Hz), 2,85 (3H, s), and 2.83 (2H, q, J=7.5 Hz), 2,70 (3H, s)of 1.32 (3H, t, J=7,3 Hz).

Stage 7. 2-[4-(8-Ethyl-2,6-dimethyl-9H-purine-9-yl-phenyl]ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(8-ethyl-2,6-dimethyl-9H-purine-9-yl)phenyl]ethanol (step 6).

TPL 162°C.

MS (ESI) m/z: 494 [(MH)+], 492 [(M-H)-].

1H-NMR (CDCl3) δ 7,94 (2H, d, J=8,4 Hz), 7,34 (2H, d, J=8.1 Hz), 7,24 (2H, d, J=8.6 Hz), 7,18 (2H, d, J=8,4 Hz), 4,36 (2H, t, J=6.4 Hz), of 2.97 (2H, t, 1=6.2 Hz), of 2.86 (3H, s), and 2.79 (2H, q, J=7,6 Hz)of 2.64 (3H, ), is 2.44 (3H, s)of 1.28 (3H, t, J=7,6 Hz).

Example 229

2-[4-(4,6-Dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]e is Il(4-were)sulfonylureas

Stage 1. 2-[4-(4,6-Dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylbenzoic

A mixture of 2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2 of example 42, 500 mg, 1.94 mmol), benzoic acid (4,45 g of 36.4 mmol), anhydride benzoic acid (4.8 g, of 21.2 mmol) was heated at 120°C for 4 hours. After cooling, the mixture was diluted with dichloromethane (100 ml). The solution was washed with a saturated aqueous solution of NaHCO3(50 ml), saturated brine (50 ml), dried (MgSO4) and concentrated. Purified column flash chromatography, elwira with ethyl acetate, obtaining 813 mg (94%) of the compound indicated in the title, in the form of a white solid.

MS (EI) m/z: 447 (M+).

1H-NMR (CDCl3) δ 8,02-7,21 (14H, m), 6.87 in (1H, s), br4.61 (2H, t, J=7.0 Hz), 3,18 (2H, t, J=6.8 Hz), 2,96 (3H, s), 2,61 (3H, s).

Stage 2. 2-[4-(4,6-Dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl benzoate (step 1).

1H-NMR (CDCl3) δ EUR 7.57-to 7.18 (9H, m), 6.87 in (1H, s), of 3.95 (2H, t, J=6.6 Hz), 2,96 (2H, t, J=6.6 Hz), to 2.94 (3H, s)at 2.59 (3H, s).

Stage 3. 2-[4-(4,6-Dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfonylureas

The connection specified in the header, the floor is Ali in accordance with the method, described in example 3 from 2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol (step 2).

TPL: 194°C.

MS (ESI) m/z: 541 [(MH)+], 539 [(M-H)-].

1H-NMR (CDCl3) δ 7,89 (2H, d, J=8,2 Hz), 7,46-6,95 (11H, m), 6,77 (1H, s), 4,35 (2H, t, J=6.0 Hz), 3,03 (3H, s), 2,96 (2H, t, J=6.0 Hz), of 2.56 (3H, s), 2,42 (3H, s).

Example 230

2-[4-(2-Butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfonylureas

Stage 1. 2-[4-(2-Butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylpentane

The connection specified in the header received in accordance with the method described for stage 1 of example 229, on the basis of 2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2 of example 42).

1H-NMR (CDCl3) δ 7,44 (2H, d, J=8.1 Hz), 7,26 (2H, d, J=8,2 Hz), of 6.71 (1H, s), to 4.38 (2H, t, J=6.9 Hz), of 3.07 (2H, t, J=6.9 Hz), is 2.88 (3H, s), 2,78 (2H, t, J=7,6 Hz), of 2.56 (3H, s), of 2.33 (2H, t, J=7.4 Hz), 1,74-of 1.55 (4H, m), 1.41 to 1,24 (4H, m)of 0.91 (3H, t, J=7.2 Hz), is 0.84 (3H, t, J=7.2 Hz).

Stage 2. 2-[4-(2-Butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylpentane (stage 1).

1H-NMR (CDCl3) δ 7,46 (2H, d, J=8,2 Hz), 7,25 (2H, d, J=8,2 Hz), 6,72 (1H, s), of 4.00 (2H, t, J=6.6 Hz), to 3.02 (2H, t, J=6.4 Hz), is 2.88 (3H, s), 2,78 (2H, t, J=7,6 Hz)to 2.54 (3H, s), 1,76-of 1.64(2H, m), 1,39-1,25 (2H, m)of 0.85 (3H, t, J=7,4 Hz).

Stage 3. 2-[4-(2-Butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol (step 2)

TPL 162°C.

MS (ESI) m/z: 521 [(MH)+], 519 [(M-H)-].

1H-NMR (CD3OD) δ of 7.97 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=7.9 Hz), 7,18 (2H, d, J=8,4 Hz), at 6.84 (2H, d, J=8,4 Hz), 6,60 (1H, s), 4,34 (2H, t, J=5.5 Hz), 3,03 (3H,s), 2,96 (2H, t, J=5.5 Hz), a 2.71 (2H, t, J=7.5 Hz), 2,52 (3H, s), 2,43 (3H, s), 1,72-of 1.62 (2H, m), 1,36-1,24 (2H, m), is 0.84 (3H, t, J=7,3 Hz).

Example 231

p-Toluensulfonate 2-[4-(2-butyl-4,6-dimethyl-1H-imidazo [4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfonylamino

To a solution of 2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfanilamide (example 230) in methanol was added TsOH (1.0 EQ.). The resulting mixture was stirred at room temperature for 5 minutes and concentrated. The residue solid was collected and dried under reduced pressure at 50°C, obtaining the connection specified in the header, in the form of a white solid.

1H-NMR (CDCl3) δ 7,89-7,86 (4H, m), 7,49 (2H, d, J=8,3 Hz), 7,30 (2H, d, J=8.1 Hz), 7,24 (2H, d, J=8,3 Hz), 7,18 (2H, d, J=7.9 Hz), 7,03 (1H, s), 4,34 (2H, t, J=6.2 Hz), of 3.12 (3H,s), to 3.02 (2H, t, J=6.2 Hz), 2,80 (3H, s), 2,77 (2H, t, J=8,1 Hz), 42 (3H, C)of 2.34 (3H, s), 1,78 by 1.68 (2H, m), 1,39-of 1.27 (2H, m)0,86 (3H, t, J=7,3 Hz).

Example 232

2-[4-(4,6-Dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[4,6-Dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl 2-methylpropanoate

The connection specified in the header received in accordance with the method described for stage 1 of example 229, on the basis of 2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2, example 42).

1H-NMR (CDCl3) δ 7,44 (2H, d, J=8,4 Hz), 7,26 (2H, d, J=8,4 Hz), of 6.66 (1H, s), to 4.38 (2H, t, J=7.0 Hz), is 3.08 (2H, t, J=6.8 Hz), 3,12-to 3.02 (1H, m), 2,89 (3H, s)to 2.55 (3H, s), 2,61-2,48 (1H, m)of 1.33 (6H, d, J=7,0 Hz)and 1.15 (6H, d, J=7,0 Hz).

Stage 2. 2-{4-[4,6-Dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-{4-[4,6-dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl 2-methylpropanoate (stage 1).

1H-NMR (CDCl3) δ 7,46 (2H, d, J=8,2 Hz), 7,25 (2H, d, J=8,3 Hz), of 6.68 (1H, s), of 4.00 (2H, t, J=6.6 Hz), 3,13 totaling 3.04 (1H, m), to 3.02 (2H, t, J=6.6 Hz), is 2.88 (3H, s), of 2.53 (3H, s)of 1.33 (6H, d, J=7,0 Hz).

Stage 3. 2-{4-[4,6-Dimethyl-2-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3, and based on the 2-{4-[4,6-dimethyl-2-(1-methylethyl)-1 H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethanol (step 2).

TPL: 213°C.

MS (ESI) m/z: 507 [(MH)+], 505 [(M-H)-].

1H-NMR (CD3OD) δ 7,80 (2H, d, J=8,4 Hz), 7,51 (2H, d, J=8.6 Hz), 7,34 (2H, d, J=8.6 Hz), 7,29 (2H, d, J=8.1 Hz), 7,01 (1H, s), 4.26 deaths (2H, t, J=6.6 Hz), 3,15-to 3.09 (1H, m)of 3.00 (2H, t, J=6.4 Hz), 2,90 (3H, s), of 2.58 (3H, s), a 2.36 (3H, s)of 1.33 (6H, d, J=6,8 Hz).

Example 233

2-{4-[2-(1,1-Dimethylethyl)-4,6-dimethyl-1H-imidazo-[4,5-c]pyridin-1-yl]phenyl]ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[2-(1,1-Dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl 2,2-dimethylpropanoate

The connection specified in the header received in accordance with the method described for stage 1 of example 229, on the basis of 2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2 of example 42).

1H-NMR (CDCl3) δ 7,41 (2H, d, J=8,4 Hz), 7,26 (2H, d, J=8,4 Hz), 6.35mm (1H, s), to 4.38 (2H, t, J=6.6 Hz), is 3.08 (2H, t, J=6.6 Hz), 2,87 (3H, s)of 2.50 (3H, s)of 1.34 (9H, s)of 1.17 (9H, s).

Stage 2. 2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl 2,2-dimethylpropanoate (stage 1).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8.6 Hz), 6,38 (1H, s), of 4.00 (2H, t, J=6.4 Hz), a 3.01 (2H, t, J=6.6 Hz), 2,87 (3H, s)of 2.50 (3H, s)of 1.34 (9H, s).

Study the 3. 2-{4-[2-(1,1-Dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethanol (step 2).

TPL: 226°C.

MS (ESI) m/z: 521 [(MH)+], 519 [(M-H)-].

1H-NMR (DMSO-d6) δ 7,71 (2H, d, J=8,3 Hz), 7,46 (2H, d, J=8.6 Hz), 7,41 (2H, d, J=8.6 Hz), 7,35 (2H, d, J=8.1 Hz), 6,55 (1H, s), 4,20 (2H, t, J=7.0 Hz), 2,95 (2H, t, J=7.0 Hz), is 2.74 (3H, s), is 2.44 (3H, s), 2,36 (3H, s)of 1.27 (9H, s).

Example 234

2-[4-(2-Cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl (4-were)sulfonylureas

Stage 1. 2-[4-(2-Cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl cyclohexanecarboxylate

The connection specified in the header received in accordance with the method described for stage 1 of example 229, on the basis of 2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2 of example 42).

1H-NMR (CDCl3) δ 7,44 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), of 6.65 (1H, s), 4,39 (2H, t, J=6.8 Hz), is 3.08 (2H, t, J=6.8 Hz), is 2.88 (3H, s)to 2.54 (3H, s), 2.71 to 1,21 (22H, m).

Stage 2. 2-[4-(2-Cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(2-cyclohexyl-46-dimethyl-1 H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl of cyclohexanecarboxylate (stage 1).

1H-NMR (CDCl3) δ 7,46 (2H, d, J=8,2 Hz), 7,25 (2H, d, J=8,2 Hz), of 6.68 (1H, s)to 4.01 (2H, t, J=6.4 Hz), to 3.02 (2H, t, J=6.4 Hz), is 2.88 (3H, s), 2,72-2,70 (1H, m), of 2.54 (3H, s), 2,30-1,15 (10H, m).

Stage 3. 2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(2-cyclohexyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol (step 2).

TPL: 168°C.

MS (ESI) m/z:547 [(MH)+], 545 [(M-H)-].

1H-NMR (CD3OD) δ of 7.97 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8.1 Hz), 7,19 (2H, d, J=8,3 Hz), 6,77 (2H, d, J=8,2 Hz), 6,53 (1H, s)to 4.33 (2H, t, J=5.3 Hz), to 3.09 (3H,s), of 2.97 (2H, t, J=5.5 Hz), 2,65 is 2.55 (1H, m), of 2.50 (3H, s), 2,42 (3H, s), 1.77 in-1,18 (10H, m).

Example 235

2-{4-[4,6-Dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl (4-were)sulfonylureas

Stage 1. 2-[4-[4,6-Dimethyl-2-3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl 4-phenylbutanoate

The connection specified in the header received in accordance with the method described for stage 1 of example 229, on the basis of 2-{4-[(3-amino-2,6-dimethyl-4-pyridinyl)amino]phenyl}ethanol (step 2 of example 42).

1H-NMR (CDCl3) δ 7,39 (2H, d, J=8,2 Hz), 7,30-to 7.15 (10H, m), 7,06 (2H, d, J=6.4 Hz), 6,70 (1H, s), 4,37 (2H, t, J=7,1 Hz), 3,06 (2H, t, J=6.9 Hz), is 2.88 (3H, s), 2,80 (2, t, J=7,6 Hz), 2,68-2,60 (4H, m), of 2.54 (3H, s), a 2.36 (2H, t, J=7.4 Hz), 2,09 is 1.91 (4H, m).

Stage 2. 2-{4-[4,6-Dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl 4-phenylbutanoate (stage 1).

1H-NMR (CDCl3) δ 7,41 (2H, d, J=8,2 Hz), 7,25-to 7.15 (5H, m), 7,07 (2H, d, J=6.8 Hz), 6,72 (1H, s)to 3.99 (2H, t, J=6,6 Hz)of 3.00 (2H, t, J=6.3 Hz), is 2.88 (3H, s), of 2.81 (2H, t, J=7,6 Hz)of 2.64 (2H, d, J=7,6 Hz), to 2.55 (3H, s), 2,11-2,00 (2H, m).

Stage 3. 2-{4-[4,6-Dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethanol (step 2).

TPL: 175°C.

MS (ESI) m/z: 583 [(MH)+], 581 [(M-H)-].

1H-NMR (CDCl3) δ to 7.95 (2H, d, J=8,3 Hz), 7,30-7,14 (7H, m), 7,03 (2H, d, J=8.1 Hz), for 6.81 (2H, d, J=8.0 Hz), only 6.64 (1H, s)to 4.33 (2H, t, J=5.7 Hz), of 3.00 (3H, s), 2,95 (2H, t, J=5.7 Hz), of 2.72 (2H, t, J=7.5 Hz), 2,62 (2H, t, J=7.4 Hz), of 2.51 (3H, s)to 2.41 (3H, s), 2,07-of 1.97 (2H, m).

Example 236

p-Toluensulfonate 4-methyl-N-{[(2-{4-[5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}benzosulfimide

Stage 1. 2-{4-[5-(Methoxy)-2-(1H-pyrazole-3-yl)-1HBenson Gasol-1-yl]phenyl}ethanol

A mixture of 2-(4-{[2-amino-4-(metiloksi)phenyl]amino}phenyl)ethanol (step 2 of example 71, of 1.95 g, 7.56 mmol), pyrazole-3-carbaldehyde (726 mg, 7.56 mmol) in ethanol (45 ml) was boiled under reflux for 2 hours. After cooling, the mixture was concentrated. A mixture of the residue, leads to compounds, which lead (4.61 in) 8,32 mmol) in benzene (50 ml) was stirred at room temperature for 16 hours. The mixture was suppressed saturated aqueous NaHCO3(150 ml). The mixture was extracted with ethyl acetate (150 ml x 4). The organic layer was washed with water (100 ml x 5), saturated brine (50 ml), dried (MgSO4) and concentrated. Purified column flash chromatography, elwira dichloromethane/methanol (gradient elution from 20:1 to 10:1), to obtain 408 mg (16%) of the compound indicated in the title, in the form of a yellow solid.

MS (EI) m/z: 334 (M+).

1H-NMR (DMSO-d6) δ and 7.6 (1H, Sirs), the 7.43 (2H, d, J=7,7 Hz), 7,29-of 7.23 (3H, m),? 7.04 baby mortality (1H, d, J=8,8 Hz), make 6.90 (1H, d, J=8,8 Hz), 6,34 (1H, Sirs), 3,85-3,81 (5H, m), of 2.92 (2H, t, J=6.6 Hz).

Stage 2. 1-[4-(2-Chloroethyl)phenyl]-5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-{4-[5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 1).

MS (EI) m/z: 352 (M+)

1H-NMR (CDCl3) δ 8,96 (0,5H, s), 8,11 (0,5H, d, J=29 Hz), 7,50 (0,5H, d, J=2.0 Hz), 7,46-7,34 (5H, m), 7,05 (1H, DD, J=16.5, and an 8.8 Hz), 6,93 (1H, DDD, J=1,4, 9,0,2,4 Hz), of 6.71 (0,5H, DD, J=2,9, 1.1 Hz), of 5.81 (1H, s), 3,85 (3H, s), 3,82 (2H, t, J=7.0 Hz), up 3.22 (2H, t, J=7,0 Hz).

Stage 3. 1-[4-(2-azidoethyl)phenyl]-5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole (stage 2).

MS (EI) m/z:359 (M+).

1H-NMR (CDCl3) δ 14,05 (1H, Sirs), 7,53 is 7.50 (2H, m), 7,45 (2H, d, J=8,4 Hz), 7,37 (2H, d, J=8,4 Hz), 7,01 (1H, d, J=8.7 Hz), 6.89 in (1H, DD, J=8,7, 2.4 Hz), of 5.81 (1H, s), 3,85 (3H, s), 3,61 (2H, t, J=6.9 Hz), 3,03 (2H,, t, J=6.9 Hz).

Stage 4. 2-{4-[5-(Metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 1-[4-(2-azidoethyl)phenyl]-5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole (stage 3).

MS (EI)m/z: 333 (M+).

1H-NMR (CDCl3) δ 7,47 (1H, d, J=2.0 Hz), 7,43-7,29 (5H, m), 7,00 (1H, d, J=8,8 Hz), to 6.88 (1H, DD, J=9,0, 2.4 Hz), of 5.81 (1H, s), of 3.80 (3H, s)to 3.09 (2H, t, J=7,1 Hz), 2,90 (2H, t, J=6,8 Hz).

Stage 5. 4-Methyl-N-{[(2-{4-[5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}benzosulfimide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-{4-[5-(metiloksi)-2-(1H-p is razol-3-yl)-1 H-benzimidazole-1-yl]phenyl}ethylamine (stage 4).

MS (ESI) m/z:531 [(MH)+], 529[(M-H)-].

1H-NMR (CDCl3) δ to 7.77 (2H, d, J=8,3 Hz), 7,44 (1H,s), from 7.24 (2H, d, J=7.5 Hz), 7,14-7,07 (5H, m), 6,98 (1H, d, J=9.0 Hz), to 6.88 (1H, d, J=9.0 Hz), 6,10 (1H, s), 3,83 (3H, s), 3,57-3,55 (2H, m), 2,88-2,84 (2H, m), to 2.35 (3H, s).

Stage 6. 4-Methyl-N-{[(2-{4-[5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}benzosulfimide p-toluensulfonate mono-p-toluensulfonate

The connection specified in the header received in accordance with the method described in example 231, based on 4-methyl-N-{[(2-{4-[5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}benzosulfimide (stage 5).

1H-NMR (CDCl3) δ 12,65 (1H, s), 9,99 (1H, s), 7,87 (2H, d, J=8.1 Hz), 7,78 (2H, d, J=8,3 Hz)to 7.50 (2H, d, J=9.0 Hz), 7,39 (2H, d, J=8,4 Hz), 7,20 (2H, d, J=7.9 Hz), 7,18 (2H, d, J=8.1 Hz), 7,08-6,93 (5H, m), 6,44 (1H, s), 3,76 (3H, s), 3,42 is 3.40 (2H, m), 2,92-is 2.88 (2H, m), of 2.86 (6H, s).

Example 237

p-Toluensulfonate 2-{4-[5-metiloksi-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylamino

Stage 1. 2-{4-[5-(Metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 1 of example 236).

M (ESI) m/z: 532 [(MH) +], 530 [(M-H)-].

1H-NMR (DMSO-d6) δ of 7.75 (2H, d, J=8.1 Hz), 7,58 (2H, d, J=8.1 Hz), 7,38 (2H, d, J=7.8 Hz), 7,33-7,21 (3H, m), 7,22 (2H, d, J=8.1 Hz), of 6.96 (1H, d, J=8.1 Hz), to 6.88 (1H, d, J=8.1 Hz), 4.26 deaths-4,24 (2H, m), 3,82 (3H, ), 2,95-of 2.93 (2H, m), of 2.34 (3H, s).

Stage 2. Mono-p-toluensulfonate 2-{4-[5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylamino

The connection specified in the header received in accordance with the method described in example 231, on the basis of 2-{4-[5-(metiloksi)-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfanilamide (stage 1).

1H-NMR (CDCl3) δ 7,88 (2H, d, J=8,2 Hz), 7,80-the 7.65 (6H, m), 7,44 (2H, d, J=8.1 Hz), 7,38-7,26 (3H, m), 7,17 (2H, d, J=8.1 Hz), 7,10 (2H, d, J=7,6 Hz), 4,37-to 4.33 (2H, m), 3,03-to 2.99 (2H, m), 2,39 (3H, s)to 2.35 (3H, C)2,31 (3H, s).

Example 238

2-{4-[6-Chloro-2-(1,5-dimethyl-1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

Stage 1. 2-(4-{[5-Chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl-(4-were)sulfonylureas

To a stirred solution of 2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol (step 2 of example 104, 1.0 g, 2.77 mmol) in dichloromethane (45 ml) was added p-toluensulfonyl isocyanate (574 mg, only 2.91 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture is extinguished with water (100 ml). The organic layer was separated. The aqueous layer of the extras who were garofali dichloromethane (100 ml x 3). The combined organic layer was washed with saturated saline (50 ml), dried (MgSO4) and concentrated. Purified column flash chromatography, elwira hexane/ethyl acetate (gradient elution from 2:1 to 1:1), to obtain 1.51 g (98%) of the compound indicated in the title, in the form of an orange solid.

1H-NMR (CDCl3) δ 9,68 (1H, s), 8,58 (1H, s), to $ 7.91 (2H, d, J=8,4 Hz), 7,34 (2H, d, J=7.9 Hz), 7,27 (2H, d, J=7.9 Hz), 7,20 (2H, d, J=8,4 Hz), 7,17 (1H, s)to 4.33 (2H, t, J=7.0 Hz), 2,96 (2H, t, J=6.8 Hz), 2,45 (3H, s).

Stage 2. 2-(4-{[2-Amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl(4-were)sulfonylureas

To a stirred solution of 2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl (4-were)sulfanilamide (stage 1, 1.51 g, a 2.71 mmol) in methanol (250 ml) was added 5% sulfonated platinum coal (600 mg). The mixture was stirred at room temperature for 5 hours in an atmosphere of hydrogen (4 ATM). The palladium catalyst was removed by filtration and washed with dichloromethane (100 ml). The filtrate was concentrated under reduced pressure to get a 1.46 g (99%) of the compound indicated in the title, in the form of a brown oil.

1H-NMR (CDCl3) δ of 7.90 (2H, d, J=8,4 Hz), 7,33 (2H, d, J=8,2 Hz), 7,16 (1H, s), 7,07 (2H, d, J=8,2 Hz), 7,06 (1H, s)6,86 (2H, d, J=8,2 Hz), of 5.40 (2H, s), 4.26 deaths (2H, t, J=6.9 Hz), 2,85 (2H, t, J=7.2 Hz), 2,44 (3H, s).

Stage 3. 2-(4-{[5-Chloro-2-{[(1,5-dimethyl-1H-pyrazole-3-ylcarbonyl]amino-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl(4-were)sulfonylureas

To a stirred solution of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl(4-were)sulfanilamide (stage 2, 200 mg, 0,379 mmol) in dichloromethane (1.7 ml) was added a solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (63,8 mg, 0,455 mmol) and N,N-diisopropylethylamine (118 mg, 0,909 mmol) in dichloromethane (1.7 ml), and then to the mixture was added a solution of HOBt (61,5 mg, 0,455 mmol) and HBTU (431 mg, to 1.14 mmol) in DMF (2.5 ml) and the mixture was stirred at room temperature for 20 hours. The mixture is extinguished with water (100 ml). The mixture was extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with water (100 ml x 3)and saturated brine (50 ml), dried (MgSO4) and concentrated. Was purified using PTLC, elwira hexane/ethyl acetate (1:1), with 145 mg (59%) of the compound indicated in the title, in the form of a red solid.

1H-NMR (CDCl3) δ to 8.70 (1H, s), 7,87 (2H, d, J=8.1 Hz), 7,79 (1H, s), 7,28 (2H, d, J=8.1 Hz),? 7.04 baby mortality (2H, d, J=8,3 Hz), to 6.95 (2H, d, J=8,3 Hz), 6,72 (1H, s), 6,60 (1H, s), 4,22 (2H, t, J=6.8 Hz), of 3.78 (3H, s), 2,84 is 2.80 (2H, m), is 2.40 (3H, s), is 2.30 (3H, s).

Stage 4. 2-{4-[6-Chloro-2-(1,5-dimethyl-1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-l}ethyl(4-were)sulfonylureas

A mixture of 2-(4-{[5-chloro-2-{[(1,5-dimethyl-1H-pyrazole-3-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl(4-were)sulfanilamide (stage 3, 145 mg, 0,223 mmol) in 2 N. NaOH (1 ml) and ethanol is (2 ml) was stirred at 50° With over 85 hours. After cooling, the pH value was set equal to 4.0 by adding 2 N. HCl. The mixture was diluted with water (80 ml) and was extracted with dichloromethane (80 ml x 3). The combined organic layer was washed with saturated saline (50 ml), dried (MgSO4) and concentrated. Was purified using PTLC, elwira hexane/ethyl acetate (1:3), 30 mg (21%) of the compound indicated in the title, in the form of a red solid.

MS (ESI) m/z: 632 [(MH)+], 630 [(M-H)-].

1H-NMR (CDCl3) δ of 8.15 (1H, s), of 7.90 (2H, d, J=8,4 Hz), 7,34-7,24 (6H, m), 7,19 (1H, s), of 5.81 (1H, s), and 4.40 (2H, t, J=6.8 Hz), 3,76 (3H, s), totaling 3.04 (2H, t, J=6.4 Hz), is 2.41 (3H, s), measuring 2.20 (3H, s).

Example 239

N-[({2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

Stage 1. 2-Butyl-1-[4-(2-chloroethyl)phenyl]-4,6-dimethyl-1H-imidazo[4,5-c]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanol (step 2 example 230).

MS (EI) m/z: 341 (M+).

1H-NMR (CDCl3) δ was 7.45 (2H, d, J=8,2 Hz), 7,28 (2H, d, J=8,2 Hz), was 6.73 (1H, s), 3,82 (2H, t, J=7,1 Hz), up 3.22 (2H, t, J=7,1 Hz), 2,89 (3H, s), and 2.79 (2H, t, J=8,2 Hz), 2,58 (3H, s), 1,76-of 1.64 (2H, m), 1,39-1,25 (2H,, m)is 0.84 (3H, t, J=7.2 Hz).

Stage 2. 1-[4-(2-Azidoethyl)phenyl]-2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine

The connection specified in the header, received in accordance with the method described for stage 8 of example 1 from 2-butyl-1-[4-(2-chloroethyl)phenyl]-4,6-dimethyl-1H-imidazo[4,5-c]pyridine (stage 1).

MS (EI) m/z: 348 (M+).

1H-NMR (CDCl3) δ 7,46 (2H, d, J=8,2 Hz), 7,29 (2H, d, J=8.6 Hz), 6,72 (1H, s), 3,62 (2H, t, J=6.8 Hz), 3,03 (2H, t, J=6.8 Hz), is 2.88 (3H, s), 2,78 (2H, t, J=7,6 Hz)to 2.55 (3H, s), 1,74-to 1.63 (2H, m), 1,38-1,24 (2H,, m)is 0.84 (3H, t, J=7,3 Hz).

Stage 3. 2-4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 1-[4-(2-azidoethyl)phenyl]-2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine (stage 2)

MS (EI) m/z: 322 (M+).

1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8,3 Hz), 7,26 (2H, d, J=8.1 Hz), 6,72 (1H, s), 3,10 totaling 3.04 (2H, m), 2,90-of 2.86 (5H, m), 2,78 (2H, t, J=7,7 Hz)to 2.55 (3H, s), 1,74-of 1.64 (2H, m), 1,35-1,25 (2H, m), is 0.84 (3H, t, J=7,3 Hz).

Stage 4. N-[({2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}aminocarbonyl]-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylamine (step 3).

MS (ESI)m/z:520 [(MH)+], 518 [(M-H)-].

1H-NMR (CDCl3) δ to 7.77 (2H, d, J=8.1 Hz), 7,37 (2H, d, J=7.9 Hz), 7,27 (2H, d, J=7.8 Hz), 7,19 (2H, d, J=7.5 Hz), 6,76 (1H, s), 3,57-3,51 (2H, m), of 2.92 (2H, t, J=6.6 Hz), is 2.88 (3H, s), was 2.76 (2H, t, J=7.5 Hz), 2,52 (3H, s), of 2.38(3H, C), 1,73-of 1.62 (2H, m), 1,36 is 1.23 (2H, m)of 0.82 (3H, t, J=7,3 Hz).

Stage 5. Mono-p-toluensulfonate N-[({2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described in example 231, on the basis of N-[({2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide (stage 4).

1H-NMR (CDCl3) δ 9,85 (1H, Sirs), 7,78 (4H, d, J=8.1 Hz), was 7.45 (2H, d, J=7.9 Hz), 7,27-7,13 (6H, m), 7,01 (1H, s), 3,45-,343 (2H, m), 3,03 (3H, s), 2,89-2,87 (2H, m), 2,79-by 2.73 (5H, m), a 2.36 (3H, s), of 2.34 (3H, s), 1,74-of 1.65 (2H, m), 1,35 is 1.23 (2H, m), is 0.84 (3H, t, J=7.2 Hz).

Example 240

Monohydrochloride 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethyl(4-were)sulfonylamino

To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethyl(4-were)sulfanilamide (example 7, 694 mg, 1.37 mmol) in methanol (4 ml) was added 10% HCl in methanol (2 ml) at room temperature. This mixture was concentrated and treated with diethyl ether obtaining 624 mg (90%) of the compound indicated in the title, in the form of a light yellow solid.

1H-NMR (DMSO-d6) δ 11,92 (1H, Sirs), 7,76 (2H, d, J=7.9 Hz), 7,49-7,39 (6H, m), 7,26 (1H, Sirs), 4,98-4,88 (1H, m), 2,94-and 2.83 (4H, m), 2.63 in (3H, s)to 2.46 (3H, s), of 2.34 (3H, s)of 1.23 (3H, t, J=7.5 Hz), of 1.12 (3H, d, J=6,1 Hz).

MS (ESI) m/z: 507 [(MN)+], 505 (M-H) -].

Example 241

N-{[(2-{4-[5,7-dimethyl-2-(3-phenylpropyl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

A mixture of n-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (stage 4 of example 162, 86 mg, 0,19 mmol), 4-phenylalkanoic acid (37 mg, 0.23 mmol) and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (40 mg, 0.21 mmol) was stirred at room temperature for 5 days. The mixture was concentrated to obtain an orange syrup. This product was dissolved in toluene (8 ml), was added monohydrate p-toluensulfonate acid (3 mg, 0.02 mol)and then stirred at the boiling point under reflux for 5 hours. The mixture was diluted with dichloromethane and washed with diluted hydrochloric acid. The organic layer was concentrated. Was purified by TLC, elwira hexane/ethyl acetate (1:3), to obtain 32 mg (29%) of the compound indicated in the title, in the form of a colorless solid.

1H-NMR (CDCl3) δ a 7.85 (2H, d, J=8,4 Hz), 7,31-7,01 (11H, m)6,91 (1H, s), 3,52 is-3.45 (2H, m), and 2.83 (2H, t, J=6.4 Hz), 2.71 to to 2.65 (2H, m)of 2.64 (3H, s), 2,58 of $ 2.53 (2H, m), is 2.41 (3H, s), 2,39 (3H, s), 2.00 in 1,90 (2H, m,).

MS (ESI) m/z: 582 [(MH)+], 580 [(M-H)-].

Example 242

N-{[(2-{4-[5,7-dimethyl-2-(3-oxo-3-phenylpropyl)-3H-imidazo[4,5-B]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Connect the tion, specified in the header received in accordance with the method described in example 241, on the basis of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (stage 4 of example 162) and 3-benzoylpropionic acid.

1H-NMR (CDCl3) δ 8,04-7,14 (11H, m), 6.90 to (1H, s), 6,20-x 6.15 (1H, m), 3,50-to 3.38 (4H, m), 3,03-of 2.81 (4H, m), of 2.56 (3H, s), is 2.44 (3H, s)to 2.41 (3H, s).

MS (ESI) m/z: 596 [(MH)+], 594 [(M-H)-].

Example 243

2-[4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl 3-pyridinesulfonamide

Stage 1. 2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl phenyl carbonate

To a stirred solution of 2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4 of example 104, 3,90 g, 10.6 mmol) in dichloromethane (20 ml) and pyridine (2 ml) was added dropwise phenylcarbamate (1.6 ml, 12.7 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (50 ml), washed with water (50 ml). The organic layer was dried over Na2SO4and concentrated under reduced pressure. Purified column flash chromatography, elwira hexane/ethyl acetate (3:1), obtaining of 4.2 g (82%) of the compound indicated in the title, in the form of a colorless syrup.

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,53-to 7.15 (10H, m), 4,56 (2H, t, J=6.8 Hz), 3,20 (2H, t, J=6.8 G is), and 2.79 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

MS (EI) m/z: 488 (M+).

Stage 2. 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl 3-pyridinesulfonamide

To a stirred solution of 3-pyridinesulfonamide (Rafik, Karaman; et al.,J. Am. Chem. Soc., 1992, 114, 4889, 120 mg, from 0.76 mmol) in DMF (3 ml) was added NaH (60% oil dispersion, 27 mg of 0.68 mmol) at room temperature. After 10 minutes, was added phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1, 313 mg, 0.64 mmol) and the mixture was stirred for 9 hours at 80°C. the Mixture was diluted with ethyl acetate (50 ml) and washed with water and saturated salt solution. The organic layer was dried (Na2SO4) and concentrated. Purification by TLC, elwira dichloromethane/methanol (6:1), and TLC, elwira dichloromethane/methanol (10:1)gave 67 mg (19%) of the compound indicated in the title, in the form of a colorless solid.

1H-NMR (CDCl3) δ 9,18 (1H, s), 8,73-8,72 (1H, m), 8,32-8,29 (1H, m), of 8.09 (1H, s), 7,40-to 7.15 (6H, m), 4,33-the 4.29 (2H, m), 2,99 vs. 2.94 (2H, m), 2,78-a 2.71 (2H, m), 1,35-of 1.32 (3H, m).

MS (ESI) m/z: 553(MH+), 551([M-H]-).

Example 244

2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl 2-pyridinesulfonamide

The connection specified in the header received in accordance with the method described for step 2 of example 243, based on 2-pyridinesulfonamide (Naito,T.; et al., Chem. Phare. Bull., 1955, 3, 38) and 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 of example 243).

TPL: 127,0-130,0°C.

1H-NMR (CDCl3) δ 8,76-8,73 (1H, m), 8,24-8,21 (2H, m), 8,16 (1H, s), 8,03-of 7.97 (1H, m), 7,62-7,56 (1H, m), 7,37 (2H, d, J=8,2 Hz), 7.23 percent (2H, d, J=8,2 Hz), 7,17 (1H, s), 4,37 (2H, t, J=6.8 Hz), a 3.01 (2H, t, J=6,8 Hz), 2,77 (2H, q, J=7,6 Hz)of 1.35 (3H, t, J=7,6 Hz).

MS (ESI) m/z: 553 (MH+), 551 ([M-H]-).

Example 245

2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl)ethyl 4-pyridinesulfonamide

The connection specified in the header received in accordance with the method described for step 2 of example 243, based on 4-pyridinesulfonamide (Comrie, A. M.; et al., J. Chem. Soc.,1958, 3514) and 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 example 243).

1H-NMR (CDCl3) δ 8,82 (2H, d, J=5,2 Hz), 8,10 (1H, s), 7,87 (2H, d, J=4.9 Hz), 7,44 (2H, d, J=7.9 Hz), 7,27 (2H, d, J=7.9 Hz), 7,20 (1H, s), 4,34 (2H, t, J=7,3 Hz), totaling 3.04 (2H, t, J=7,3 Hz), 2,78 (2H, q, J=7,6 Hz), of 1.36 (3H, t, J=7,6 Hz).

MS (ESI) m/z: 553 (MH+), 551 ([M-H]-).

Example 246

2-[4-(5-acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1-methylethyl(4-were)sulfonylureas

Stage 1. 1-(4-{[4-(2-hydroxypropyl)phenyl]amino}-3-nitrophenyl)alanon

The connection specified in the header received in accordance with the method described for stage 1 of example 162, on the basis of 1-(4-chloro-3-nitrophenyl)ethanone and 1-(4-AMINOPHENYL)-2-propane is La (stage 1 example 6).

1H-NMR (CDCl3) δ 9,85 (1H, Sirs), 8,83-8,82 (1H, m), 7,99-of 7.95 (1H, m), 7,33 (2H, d, J an 8.4 Hz), 7,24 (2H, d, J=8,4 Hz), 7,18 (1H, d, J=9.0 Hz), 4,13-Android 4.04 (1H, m), 2,87-of 2.72 (2H, m), 2,58 (3H, s)of 1.29 (3H, d, J=6,2 Hz).

Stage 2. 1-(3-Amino-4-{[4-(2-hydroxypropyl)phenyl]amino}phenyl)alanon

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 1-(4-{[4-(2-hydroxypropyl)phenyl]amino}-3-nitrophenyl)ethanone (stage 1).

MS (EI) m/z: 284(M+).

Stage 3. 2-[4-(5-Acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1-methylethylamine

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 1-(3-amino-4-{[4-(2-hydroxypropyl)phenyl]amino}phenyl)ethanone (stage 2).

1H-NMR (CDCl3) δ to 8.41-to 8.40 (1H, m), 8,83-8,82 (1H, m), 7,92-7,89 (1H, m), the 7.43 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 7,12-to 7.09 (1H, m), 5.25-inch-by 5.18 (1H, m), 3,07-is 2.88 (2H, m), 2,80 (2H, q, J=7,3 Hz), 2,68 (3H, ), 2,34-of 2.26 (2H, m)to 1.37 (3H, q, J=7.5 Hz), 1,32 (3H, d, J=6.2 Hz), 1,10 (3H, t, J=7.5 Hz).

Stage 4. 1-{2-Ethyl-1-[4-(2-hydroxypropyl)phenyl]-1H-benzimidazole-5-yl}alanon

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(5-acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1-methylethylacetate (stage 3).

1H-NMR (CDCl3) δ 8,39 (1H, s), 7,89-7,86 (1H, m), 7,47 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), 7,13-7,10 (1H, m), 4,23-4,13 (1H, m), 2,94-2,6 (2H, m)2,80 (2H, q, J=7.5 Hz), to 2.66 (3H, s), of 1.39 and 1.33 (6H, m).

Stage 5. 2-[4-(5-Acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1-methylethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 1-{2-ethyl-1-[4-(2-hydroxypropyl)phenyl]-1H-benzimidazole-5-yl}ethanone (stage 4).

1H-NMR (CDCl3) δ to 8.40 (1H, d, J=l l Hz), to $ 7.91-7,86 (3H, m), 7,32-7,24 (4H, m), 7,17 (2H, d, J=7.9 Hz), 7,07 (1H, d, J=8,4 Hz), 5,09-to 5.03 (1H, m), 2,99 is 2.75 (2H, m), 2,77 (2H, q, J=7.5 Hz), to 2.67 (3H, s), 2,37 (3H, s)of 1.33 (3H, t, J=7.5 Hz), to 1.21 (3H, d, J=6,1 Hz).

MS (ESI) m/z:520 (MH+), 518 ([M-H]-).

Example 247

2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl(4-were)sulfonylureas

Stage 1. 1-(4-{[5-Chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol

The connection specified in the header received in accordance with the method described for stage 1 of example 162, on the basis of 2,4-dichloro-5-nitrobenzotrifluoride and 1-(4-AMINOPHENYL)-2-propanol (step 1 of example 6).

1H-NMR (CDCl3) δ RS 9.69 (1H, Sirs), 8,58 (1H, s), of 7.36 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), 7,20 (1H, s), 4,13-4,06 (1H, m), 2,88-by 2.73 (2H, m), 1,48 (1H, d, J=4, 2 Hz), of 1.30 (3H, d, J=6.2 Hz).

Stage 2. 1-(4-{[2-Amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 1-4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol (step 1).

1H-NMR (CDCl3) δ 7,17 (1H, s), to 7.15 (2H, d, J=8,4 Hz), 7,06 (1H, s), make 6.90 (2H, d, J=8,4 Hz), 4,05-3,98 (1H, m), 2,79-2,61 (2H, m)of 1.26 (3H, d, J=6.3 Hz).

Stage 3. Propanoate 2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol (stage 2).

MS (EI) m/z: 438 (M+).

Stage 4. 1-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-2-propanol

The connection specified in the header received in accordance with the method described in stage 6 of example 1 from 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethylacetate (stage 3).

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,47 (2H, d, J=8,4 Hz), 7,28 (211, d, J=8,4 Hz), 7,21 (1H, s), 4,20-4,10 (1H, m), 2.95 and-and 2.83 (2H, m), and 2.79 (2H, q, J=7.5 Hz), and 1.56 (1H, d, J=4, 2 Hz), of 1.36 (3H, t, J=7.5 Hz), of 1.34 (3H, d, J=6.2 Hz).

Stage 5. 2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl-(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-2-propanol (stage 4).

1H-NMR (CDCl3) δ of 8.09 (1H, s), 7,87 (2H, d, J=8,4 Hz), 7,41 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), 7,21 (1H, s), 5,06-5,00 (1H, m), 3.04 from-to 2.74 (4H, m), 40 (3H, C)of 1.36 (3H, t, J=7.5 Hz), of 1.23 (3H, d, J=6.2 Hz).

MS (ESI) m/z: 580(MH+), 578 ([M-H]-).

Example 248

(1S)-2-[4-(5-Acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1-methylethyl(4-were)sulfonylureas

Stage 1. (2S)-1-(4-nitrophenyl)-2-propanol and (1R)-1-methyl-2-4-nitrophenyl ethyl propanoate

To a mixture of 1-(4-nitrophenyl)-2-propanol (Schadt, F. L. et al.,J. Am. Chem. Soc.,1978, 100, 228., 2.5 g of 13.8 mmol) and propionic anhydride (1.8 g, of 13.8 mmol) in benzene (34 ml) was added lipase PS/celite (0.5 g, Bianichi, D. et al.J. Org. Chem. 1988, 53, 5531). The resulting mixture was stirred at room temperature for 72 hours. The reaction mixture was filtered through a thick layer of celite. The filtrate was washed with a saturated aqueous solution of hydrogencarbonate sodium and saturated salt solution. The organic layer was dried (MgSO4) and concentrated. Purified column flash chromatography, elwira hexane/diethyl ether (4:1 to 1:1), obtaining 1,91 g (58%) of (1R)-1-methyl-2-(4-nitrophenyl)ethyl of propanoate in the form of a light yellow oil and 1.14 g (46%) of (2S)-1-(4-nitrophenyl)-2-propanol as a colourless solid (93% EE). Recrystallization of 1.14 g of (2S)-1-(4-nitrophenyl)-2-propanol from hexane/diethyl ether gave 617 mg of colorless product in the form of needles (99% e. e.).

(1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate.

1H-NMR (CDCl3) δ 8,16 (2H, d, J=8,8 Hz), 7,37 (2H, d, J=8,8 Hz), 5,22-5,11 (1H, m), 3.04 from-2,87 (2H, m), 2,30-2,19 (2H, m)of 1.26 (3H, d, J=6,1 Hz)of 1.07 (3H, t, J=7.5 Hz).

(2S)-1-(4-nitrophenyl)-2-propanol.

1H-NMR (CDCl3) δ 8,18 (2H, d, J=8,8 Hz), 7,39 (2H, d, J=8,8 Hz), 4,14-Android 4.04 (1H, m), 2,92-and 2.79 (2H, m), 1,49 (1H, d, J=4.0 Hz), of 1.28 (3H, d, J=6,1 Hz).

[α]23D+31,0° (c 1,00, diethyl ether).

Stage 2. (2S)-1-(4-AMINOPHENYL)-2-propanol

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from (2S)-1-(4-nitrophenyl)-2-propanol (step 1).

1H-NMR (CDCl3) δ 7,00 (2H, d, J=8,4 Hz), of 6.65 (2H, d, J=8,4 Hz), 3,99-to 3.89 (1H, m), of 3.60 (2H, Sirs) 2,73-2,52 (2H, m)to 1.22 (3H, d, J=6.2 Hz).

Stage 3. 1-[4-({4-[(2S)-2-Hydroxypropyl]phenyl}amino)-3-nitrophenyl]alanon

The connection specified in the header received in accordance with the method described for stage 1 of example 162, on the basis of 1-(4-chloro-3-nitrophenyl)ethanone and (2S)-1-(4-AMINOPHENYL)-2-propanol (stage 2).

1H-NMR (CDCl3) δ 9,85 (1H, Sirs), 8,83-8,82 (1H, m), 7,99-of 7.95 (1H, m), 7,33 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), 7,18 (1H, 3 J=9.0 Hz), 4,13-Android 4.04 (1H, m), 2,87-of 2.72 (2H, m), 2,58 (3H, s)of 1.29 (3H, d, J=6.2 Hz).

Stage 4. 1-[3-amino-4-({4-[(2S)-2-hydroxypropyl]phenyl}amino)phenyl]alanon

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 1-[4-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-3-nitrophenyl]ethanone (stage 3).

MS (EI) m/z: 284 (M+).

Stage 5. (1S)-2-[4-(5-acetyl-2-ethyl-1Hbe imidazol-1-yl)phenyl]-1-methylethyl propanoate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 1-[3-amino-4-({4-[(2S)-2-hydroxypropyl]phenyl}amino)phenyl]ethanone (stage 4).

1H-NMR (CDCl3) δ to 8.41-to 8.40 (1H, m), 8,83-8,82 (1H, m), 7,92-7,89 (1H, m), the 7.43 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 7,12-to 7.09 (1H, m), 5.25-inch-by 5.18 (1H, m), 3,07-is 2.88 (2H, m), 2,80 (2H, q, J=7,3 Hz), 2,68 (3H, ), 2,34-of 2.26 (2H, m)to 1.37 (3H, q, J=7.5 Hz), 1,32 (3H, d, J=6.2 Hz), 1,10 (3H, t, J=7.5 Hz).

Stage 6. 1-(2-Ethyl-1-{4-[(2S)-2-hydroxypropyl]phenyl}-1H-benzimidazole-5-yl)alanon

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from (1S)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1-methylethylacetate (stage 5).

1H-NMR (CDCl3) δ 8,39 (1H, d, J=l l Hz), 7,87 (1H, DD, J=8,6,1,1 Hz), of 7.48 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), 7,12 (1H, d, J=8.6 Hz), 4,22-of 4.12 (1H, m), 2,94-2,89 (2H, m), 2,80 (2H; q, J=7.5 Hz), 2,69 (3H with), 2,42 (1H, Sirs), to 1.37 (3H, t, J=7.5 Hz), of 1.33(3H, d, J=6.2 Hz).

Stage 7. (1S)-2-[4-(5-Acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1-methylethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 1-(2-ethyl-1-{4-[(2S)-2-hydroxypropyl]phenyl}-1H-benzimidazole-5-yl)ethanone (stage 6).

1H-NMR (CDCl3) δ to 8.40 (1H, d, J=l l Hz), to $ 7.91-7,86 (3H, m), 7,32-7,24 (4H, m), 7,17 (2H, d, J=7.9 Hz), 7,07 (1H, d, J=8,4 Hz), 5,09-to 5.03 (1H, m), 2,99 is 2.75 (2H, m), 2,77 (2H, q, J=7.5 Hz), 267 (3H, C)is 2.37 (3H, s)of 1.33 (3H, t, J=7.5 Hz), to 1.21 (3H, d, J=6,1 Hz).

MS (ESI) m/z: 520(MH+), 518 ([M-H]-).

[α]24D- 3,09° (c 0,120, methanol).

Example 249

(1R)-2-[4-(5-Acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1-methylethyl (4-were)sulfonylureas

Stage 1. (2R)-1-(4-nitrophenyl)-2-propanol

To a solution of (1R)-1-methyl-2-(4-nitrophenyl)ethylpropane (stage 1 of example 248, 1,91 g, with 8.05 mmol) in ethanol (20 ml) was added 2 N. aqueous NaOH (5 ml) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, extracted with diethyl ether (2 x 50 ml). The organic layer was washed with saturated saline solution, dried (MgSO4) and concentrated. Purified column flash chromatography, elwira hexane/diethyl ether (1:1), obtaining of 1.16 g (80%) indicated in the title compounds as a colorless solid (79% EE). Recrystallization from hexane/diethyl ether gave 717 mg of colorless product in the form of needles (99% EE).

1H-NMR (CDCl3) δ 8,18 (2H, d, J=8,8 Hz), 7,39 (2H, d, J=8,8 Hz), 4,14-Android 4.04 (1H, m), 2,92-and 2.79 (2H, m), 1,49 (1H, d, J=4.0 Hz), of 1.28 (3H, d, J=6,1 Hz).

[α]23D-32,6° (c 1,00, diethyl ether).

Stage 2. (2R)-1-(4-AMINOPHENYL)-2-propanol

The connection specified in the header received in accordance with the method described on the I stage 4 of example 1, on the basis of (2R)-1-(4-nitrophenyl)-2-propanol (step 1).

1H-NMR (CDCl3) δ 7,00 (2H, d, J=8,4 Hz), of 6.65 (2H, d, J=8,4 Hz), 3,99-to 3.89 (1H, m), of 3.60 (2H, Sirs) 2,73-2,52 (2H, m)to 1.22 (3H, d, J=6.2 Hz).

Stage 3. 1-[4-({4-[(2R)-2-hydroxypropyl]phenyl}amino)-3-nitrophenyl]alanon

The connection specified in the header received in accordance with the method described for stage 1 of example 162, on the basis of 1-(4-chloro-3-nitrophenyl)ethanone and (2R)-1-(4-AMINOPHENYL)-2-propanol (stage 2).

1H-NMR (CDCl3) δ 9,85 (1H, Sirs), 8,83-8,82 (1H, m), 7,99-of 7.95 (1H, m), 7,33 (2H, d, J=8,4 Hz), 7,24 (2H; d, J=8,4 Hz), 7,18 (1H, d, J=9.0 Hz), 4,13-Android 4.04 (1H, m), 2,87-of 2.72 (2H, m), 2,58 (3H, s)of 1.29 (3H, d, J=6,2 Hz).

Stage 4. 1-[3-Amino-4-({4-[(2R)-2-hydroxypropyl]phenyl}amino)phenyl]alanon

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 1-[4-({4-[(2R)-2-hydroxypropyl]phenyl}amino)-3-nitrophenyl]ethanone (stage 3).

MS (EI) m/z: 284 (M+).

Stage 5. (1R)-2-[4-(5-Acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1-methylethyl propanoate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 1-[3-amino-4-(4-[(2R)-2-hydroxypropyl]phenyl}amino)phenyl]ethanone (stage 4).

1H-NMR (CDCl3) δ to 8.41-to 8.40 (1H, m), 8,83-8,82 (1H, m), 7,92-7,89 (1H, m), the 7.43 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 7,12-to 7.09 (1H, m), 5.25-inch-by 5.18 (1H, m), 3,07-is 2.88 (2H, m), 2,80 (2H, q, 3=1.3 Hz), 2,68 (3H, ), 2,34-of 2.26 (2H, m), 137 (3H, kV, J=7.5 Hz), 1,32 (3H, d, J=6.2 Hz), 1,10 (3H, t, J=7.5 Hz).

Stage 6. 1-(2-ethyl-1-{4-[(2R)-2-hydroxypropyl]phenyl}-1H-benzimidazole-5-yl)alanon

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from (1R)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1-methylethylacetate (stage 5).

1H-NMR (CDCl3) δ 8,39 (1H, d, J=l l Hz), 7,87 (1H, DD, J=8,6, 1.1 Hz), of 7.48 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), 7,12 (1H, d, J=8.6 Hz), 4,22-of 4.12 (1H, m), 2,94-2,89 (2H, m), 2,80 (2H, q, J=7.5 Hz), 2,69 (3H, s), 2,42 (1H, Sirs), to 1.37 (3H, t, J=7.5 Hz), of 1.33 (3H, d, J=6.2 Hz).

Stage 7. (1R)-2-[4-(5-acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1-methylethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 1-(2-ethyl-1-{4-[(2R)-2-hydroxypropyl]phenyl}-1H-benzimidazole-5-yl)ethanone (stage 6).

1H-NMR (CDCl3) δ to 8.40 (1H, d, J=l l Hz), to $ 7.91-7,86 (3H, m), 7,32-7,24 (4H, m), 7,17 (2H, d, J=7.9 Hz), 7,07 (1H, d, J=8,4 Hz), 5,09-to 5.03 (1H, m), 2,99 is 2.75 (2H, m), 2,77 (2H, q, J=7.5 Hz), to 2.67 (3H, s), 2,37 (3H, s)of 1.33 (3H, t, J=7.5 Hz), to 1.21 (3H, d, J=6,1 Hz).

MS (ESI) m/z: 520 (MH+), 518 ([M-H]-).

[α]24D+6,05° (c amount of 0.118, methanol).

Example 250

(1S)-2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl (4-were)sulfonylureas

Stage 1. (2S)-1-(4-{[5-Chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-disappear to the ol

The connection specified in the header received in accordance with the method described for stage 1 of example 162, on the basis of 2,4-dichloro-5-nitrobenzotrifluoride and (2S)-1-(4-AMINOPHENYL)-2-propanol (stage 2 of example 248).

1H-NMR (CDCl3) δ RS 9.69 (1H, Sirs), 8,58 (1H, s), of 7.36 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), 7,20 (1H, s), 4,13-4,06 (1H, m); 2,88-by 2.73 (2H, m), 1,48 (1H, d, J=4, 2 Hz), of 1.30 (3H, d, J=6.2 Hz).

Stage 2. (2S)-1-(4-{[2-Amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, on the basis of (2S)-1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol (step 1).

1H-NMR (CDCl3) δ 7,17 (1H, s), to 7.15 (2H, d, J=8,4 Hz), 7,06 (1H, s), make 6.90 (2H, d, J=8,4 Hz), 4,05-3,98 (1H, m), 2,79-2,61 (2H, m)of 1.26 (3H, d, J=6.3 Hz).

Stage 3. (1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethylamine

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from (2S)-1-(4-{[2-amino-5-chloro-4-(cryptomate)phenyl]amino}phenyl)-2-propanol (stage 2).

MS (EI) m/z: 438 (M+).

Stage 4. (2S)-1-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-2H-benzimidazol-1-yl]phenyl}-2-propanol

The connection specified in the header received in accordance with the stage 6 of example 1, based on propanoate (1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl] - dryer is l}-1-methylethylacetate (stage 3).

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,47 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), 7,21 (1H, s), 4,20-4,10 (1H, m), 2.95 and-and 2.83 (2H, m), and 2.79 (2H, q, J=7.5 Hz), and 1.56 (1H, d, J=4, 2 Hz), of 1.36 (3H, t, J=7.5 Hz), of 1.34 (3H, d, J=6.2 Hz).

Stage 5. (1S)-2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-methylethyl-(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3, on the basis of (2S)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-2-propanol (stage 4).

TPL: to 200.3°C.

1H-NMR (CDCl3) δ of 8.09 (1H, s), 7,87 (2H, d, J=8,4 Hz), 7,41 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), 7,21 (1H, s), 5,06-5,00 (1H, m), 3.04 from-to 2.74 (4H, m), is 2.40 (3H, s)of 1.36 (3H, t, J=7.5 Hz), of 1.23 (3H, d, J=6.2 Hz).

MS (ESI) m/z: 580 (MH+), 578 ([M-H]-).

[α]24D+ 1,31° (c 0,398, methanol).

ee: 98%.

Example 251

Mono-p-toluensulfonate-(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 231, on the basis of (1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl(4-were)sulfanilamide (stage 5 of example 250).

1H-NMR (DMSO-d6) δ 11,91 (1H, Sirs), 8,23 (1H, s), of 7.75 (2H, d, J=8,3 Hz), 7,50-7,37 (9H, m), 7,11 (2H,d, J=8.1 Hz), equal to 4.97-4,91 (1H, m), 2,92 was 2.76 (4H, m), is 2.30 (3H, s), and 2.27 (3H, s)of 1.24 (3H, t, J=7,3 Hz)to 1.14 (3H, the, J=6.2 Hz).

Example 252

(1R)-2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl (4-were)sulfonylureas

Stage 1 (2R)-1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol

The connection specified in the header received in accordance with the method described for stage 1 of example 162, on the basis of 2,4-dichloro-5-nitrobenzotrifluoride and (2R)-1-(4-AMINOPHENYL)-2-propanol (step 2 of example 249).

1H-NMR (CDCl3) δ RS 9.69 (1H, Sirs), 8,58 (1H, s), of 7.36 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), 7,20 (1H, s), 4,13-4,06 (1H, m), 2,88-by 2.73 (2H, m), 1,48 (1H, d, J=4, 2 Hz), of 1.30 (3H, d, J=6.2 Hz).

Stage 2. (2R)-1-(4-{[2-Amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, on the basis of (2R)-1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol (step 1).

1H-NMR (CDCl3) δ 7,17 (1H, s), to 7.15 (2H, d, J=8,4 Hz), 7,06 (1H, s), make 6.90 (2H, d, J=8,4 Hz), 4,05-3,98 (1H, m), 2,79-2,61 (2H, m)of 1.26 (3H, d, J=6.3 Hz).

Stage 3. (1R)-2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethylamine

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from (2R)-1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-propanol (stage 2).

MS (EI)m/z: 438(M+).

Stage 4. (2R)-1-{4-[6-chloro-2-ethyl-5-(t is iformity)-1 H-benzimidazole-1-yl]phenyl}-2-propanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from (1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethylacetate (stage 3).

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,47 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), 7,21 (1H, s), 4,20-4,10 (1H, m), 2.95 and-and 2.83 (2H, m), and 2.79 (2H, q, J=7.5 Hz), and 1.56 (1H, d, J=4, 2 Hz), of 1.36 (3H, t, J=7.5 Hz), of 1.34 (3H, d, J=6.2 Hz).

Stage 5. (1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl(4-were)sulfonylamino

The connection specified in the header received in accordance with the method described in example 3, on the basis of (2R)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-2-propanol (stage 4).

TPL: of 199, 9°C.

1H-NMR (CDCl3) δ 10,70 (1H, Sirs), 8,10 (1H, s), 7,89 (2H, d, J=8,3 Hz), 7,40 (2H, d, J=8,3 Hz), 7,30 (2H, d, J=8,3 Hz), 7,22 (2H, d, J=8,3 Hz), 7,20 (1H, s), 5,32-5,00 (1H, m), 3.04 from-2,82 (2H, m), 2,78 (2H, q, J=7.5 Hz), 2.40 a (3H, s)of 1.36 (3H, t, J=7.5 Hz), of 1.23 (3H, d, J=6.2 Hz).

MS (ESI)m/z: 580(MH+), 578([M-H]-).

[α]24D-2,19°(c 0,402, methanol)

ee: 97%.

Example 253

N-{[(2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. 1-[4-(2-Azithromy)phenyl]-6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole

To paramashiva is the PTO to a solution of {4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1 H-benzimidazole-1-yl]phenyl}-2-propanol (step 8 of example 247, 1,96 g, 5,12 mmol), triphenylphosphine (1.75 g, of 6.66 mmol) and diphenylphosphinite (1,83 mg of 6.66 mmol) in tetrahydrofuran (15 ml) was added diethylazodicarboxylate (1,16 mg of 6.66 mmol) at room temperature. The resulting mixture was stirred at the temperature for 3 hours, and then at the boiling point under reflux. The mixture was diluted with ethyl acetate and washed with water and saturated salt solution. The organic layer was dried (Na2SO4) and concentrated. Purified column flash chromatography, elwira hexane/ethyl acetate (2:1), and TLC, elwira hexane/ethyl acetate (1:1), with 769 mg (37%) of the compound indicated in the title, in the form of a light yellow syrup.

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,47 (2H, d, J=8,3 Hz), 7,30 (2H, d, J=8,3 Hz), 7,21 (1H, s), 3,85-of 3.77 (1H, m), 2,92-2,89 (2H, m), 2,80 (2H, q, J=7.5 Hz), of 1.37 (3H, d, J=6.6 Hz), of 1.36 (3H, t, J=7.5 Hz).

MS (ESI) m/z: 408 (MH+).

Stage 2. 2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azithromy)phenyl]-6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole (step 1).

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,44 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), 7,21 (1H, s), 3,49-3,26 (1H, m), 2,86-2,95 (2H, m), and 2.79 (2H, q, J=7.5 Hz), of 1.36(3H, t, J=7.5 Hz), of 1.20 (3H, d, J=6.2 Hz).

Stage 3. N-{[2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethylamine (stage 2).

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,73 (2H, d, J=8,4 Hz), 7,41 (2H, d, J=8,3 Hz), 7,29-of 7.23 (4H, m), 7,17 (1H, s), 4,20-4,11 (1H, m), 2,99-2,82 (2H, m), 2,78 (2H, q, J=7,3 Hz), of 2.38 (3H, s)of 1.35 (3H, t, J=7,3 Hz), of 1.24 (3H, d, J=6,6 Hz).

MS (ESI) m/z: 579 (MH+), 577 ([M-H]-).

Example 254

N-{[((1S)-2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. 1-[4-[(2s)-2-Azithromy)phenyl]-6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 1 of example 253, on the basis of (2R)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-2-propanol (stage 4 of example 252).

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,46 (2H, d, J=7.9 Hz), 7,29 (2H, d, J=7.9 Hz), 7,21 (1H, s), 3,84-of 3.77 (1H, m), 2,92-2,89 (2H, m), and 2.79 (2H, q, J=7,6 Hz), of 1.39 and 1.33 (6H, m).

Stage 2. (1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethylamine

The connection specified in the header received in soo is according to the way described for stage 7 of example 37, from 1-[4-[(2s)-2-azithromy)phenyl]-6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole (step 1).

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,44 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), 7,21 (1H, s), 3,49-3,26 (1H, m), 2,86-to 2.65 (2H, m), and 2.79 (2H, q, J=7.5 Hz), of 1.36 (3H, t, J=7.5 Hz), of 1.20 (3H, d, J=6.2 Hz).

Stage 3. N-{[((1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from (1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethylamine (stage 2).

TPL: 141,0-143,0°C.

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,73 (2H, d, J=8,3 Hz), 7,41 (2H, d, J=8,3 Hz), 7,30 (2H, d, J=8,3 Hz), 7,25 (2H, d, J=8,3 Hz), 7,17 (1H, s), to 6.58 (1H, d, J=7,7 Hz), 4,22-to 4.14 (1H, m), 2,82-of 2.30 (2H, m), 2,78 (2H,, kV, J=7,6 Hz), 2,39 (3H, s)of 1.35 (3H, t, J=7.5 Hz), 1,24 (3H, d, J=6,6 Hz).

MS (ESI) m/z: 579 (MH+), 691([M+CF3COOH-H]-).

[α]24D-5,08° (c 0,394, methanol)

ee:99%.

Example 255

N-{[((1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. 1-[4-[(2R)-2-azithromy)phenyl]-6-chloro-2-ethyl(trifluoromethyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 1 of example 253, IP is odya of (2S)-1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1 H-benzimidazole-1-yl]phenyl}-2-propanol (stage 4 of example 250).

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,46 (2H, d, J=7.9 Hz), 7,29 (2H, d, J=7.9 Hz), 7,21 (1H, s), 3,84-of 3.77 (1H, m), 2,92-2,89 (2H, m), and 2.79 (2H, q, J=7,6 Hz), of 1.39 and 1.33 (6H, m).

Stage 2. (1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-[(2R)-2-azithromy)phenyl]-6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole (step 1).

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,44 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), 7,21 (1H, s), 3,49-3,26 (1H, m), 2,86-to 2.65 (2H, m), and 2.79 (2H, q, J=7.5 Hz), of 1.36 (3H, t, J=7.5 Hz), of 1.20 (3H, d, J=6.2 Hz).

Stage 3. N-{[((1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from (1R)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-methylethylamine (stage 2).

TPL: 138,0-141,0°C.

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,73 (2H, d, J=8,3 Hz), 7,41 (2H, d, J=8,3 Hz), 7,30 (2H, d, J=8,3 Hz), 7,25 (2H, d, J=8,3 Hz), 7,17 (1H, s), to 6.58 (1H, d, J=7,7 Hz), 4,22-to 4.14 (1H, m), 2,82-of 2.30 (2H, m), 2,78 (2H,, kV, J=7,6 Hz), 2,39 (3H, s)of 1.35 (3H, t, J=7.5 Hz), 1,24 (3H, d, J=6,6 Hz).

MS (ESI) m/z: 579 (MH+), 691 ([M+CF3COOH-H]-).

[α]24D+3,43 °(c 0,408, meta is ol)

ee: 99%.

Example 256

2-{4-[6-Chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

Stage 1. 2-{4-[6-Chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol (step 2 of example 104, 2.28 g, of 5.85 mmol) and 1H-pyrazole-3-carbaldehyde (562 mg, 2,85 mmol) in ethanol (35 ml) was stirred at the boiling point under reflux for 1 hour. The mixture was concentrated and dissolved in benzene (40 ml). To this solution at room temperature was added leads to compounds, which lead (2.85 g, 6,44 mmol). After stirring at room temperature for 18 hours, to the mixture was added saturated aqueous sodium bicarbonate (50 ml) and ethyl acetate. The organic layer was separated and washed with saturated salt solution, dried (Na2SO4) and concentrated. Purified column flash chromatography, elwira dichloromethane/methanol (20:1 to 10:1), then dichloromethane/2-propanol (5:1), obtaining 979 mg (41%) of the compound indicated in the title, in the form of a light brown solid.

1H-NMR (CDCl3/CD3OD=4/1) δ to 8.12 (1H, Sirs), 7,74 (1H, s), to 7.59 (1H, Sirs), 7,47 (2H, d, J=7.9 Hz), 7,34-7,30 (3H, m), 6,36 (1H, Sirs), a 3.87 (2H, shirt, J=6,8 Hz), 2,95 (2H, t, J=6,8 Hz).

MS (ESI) m/z: 407 (MH+), 405 ([M-H]-).

Stud is I 2. 2-[4-[6-chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl=(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[6-chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)(-1H-benzimidazole-1-yl]phenyl}ethanol (step 1).

1H-NMR (CDCl3) δ 8,18 (1H, s), to $ 7.91 (2H, d, J=8,3 Hz), 7,54-7,53 (1H, m), 7,34-of 7.23 (8H, m), of 6.31 (1H, Sirs), and 4.40 (2H, t, J=6.4 Hz), a 3.01 (2H, t, J=6.4 Hz), 2,42 (3H, s).

MS (ESI) m/z: 604(MH+), 602([M-H]-).

Example 257

Mono-p-toluensulfonate 2-{4-[6-chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-(4-were)sulfonylamino

The connection specified in the header received in accordance with the method described in example 231, on the basis of 2-{4-[6-chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfanilamide (stage 2 of example 256).

1H-NMR (DMSO-d6) δ 8,24 (1H, s), to 7.77-7,74 (2H, m), of 7.48-7,38 (10H, m), 7,26 (1H, s), 7,11 (2H, d, J=7.9 Hz), 6,44 (1H, Sirs), 4,30-4,20 (2H, m), 2,98-of 2.93 (2H, m), of 2.33 (3H, s), and 2.27 (3H, s).

MS (ESI) m/z: 604 (MH+), 602 ([M-H]-).

Example 258

Monohydrochloride (1S)-2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-B]pyridine-3-yl)phenyl]-1-methylethyl-(4-were)sulfonylamino

Stage 1. (2S)-1-{4-[(4,6-Dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-propanol

The connection specified in the title is information, received in accordance with the method described for stage 1 of example 162, based on 2-chloro-4,6-dimethyl-3-nitropyridine (stage 2 of example 1) and (2S)-1-(4-AMINOPHENYL)-2-propanol (stage 2 of example 248).

1H-NMR (CDCl3) δ 9,58 (1H, Sirs), to 7.59 (2H, d, J=8.6 Hz), 7,19 (2H, d, J=8.6 Hz), 6,53 (1H, s), 4,05-3,98 (1H, m), 2.82 from 2.63 in (2H, m)to 2.55 (3H, s), 2,43 (3H, s)of 1.26 (3H, d, J=6.3 Hz).

Stage 2. (2S)-1-{4-[(3-Amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}-2-propanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, on the basis of (2S)-1-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-propanol (step 1).

1H-NMR (CDCl3) δ 7,13-7,07 (4H, m), 6,60 (1H, s), 6,21 (1H, Sirs), was 4.02-3,91 (1H, m), 3,26 (2H, Sirs), 2.77-to to 2.57 (2H, m), is 2.37 (3H, s), measuring 2.20 (3H, s)of 1.24 (3H, d, J=6,1 Hz).

Stage 3. (1S)-2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethylamine

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from (2S)-1-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}-2-propanol (stage 2).

MS (EI) m/z: 365 (M+).

Stage 4. (2S)-1-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-2-propanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from (1S)-2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethylacetate (stage 3).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,4 Hz), 7,35 (2H, d, J=8,4 Hz)6,91 (1H, s), 4,18-of 4.05 (1H, m), 2,92 is 2.75 (4H, m)to 2.66 (3H, s), 2,52 (3H, s), 1,34-1,25 (6H, m).

Stage 5. (1S)-2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3, on the basis of (2S)-1-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-2-propanol (stage 4).

1H-NMR (CDCl3) δ a 7.92 (2H, d, J=8,2 Hz), 7,33 (2H, d, J=8,2 Hz), 7,30-7,26 (4H, m), 5,14-5,02 (1H, m), 2,99-2,77 (4H, m)to 2.66 (3H, s), of 2.51 (3H, s), 2,42 (3H, s), 1,29 is 1.23 (6H, m).

MS (ESI) m/z: 507 (MH+), 505 ([M-H]-).

Stage 6. Monohydrochloride 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethyl(4-were)sulfonylamino

The connection specified in the header received in accordance with the method described in example 240, on the basis of (1S)-2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethyl(4-were)sulfanilamide (stage 5).

1H-NMR (DMSO-d6) δ 11,92 (1H, Sirs), 7,76 (2H, d, J=7.9 Hz), 7,49-7,39 (6H, m), 7,26 (1H, Sirs), 4,98-4,88 (1H, m), 2,94-and 2.83 (4H, m), 2.63 in (3H, s)to 2.46 (3H, s), 2,34 (2H, s)of 1.23 (3H, t, J=7.5 Hz), of 1.12 (3H, d, J=6,1 Hz).

MS (ESI) m/z: 507 [(MH)+], 505 [(M-H)-].

[α]24D-12,49° (c 1,014 registered, methanol).

Example 259

2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethyl (4-were) sulfonylurea the

Stage 1. 1-[6-({4-[2-hydroxypropyl]phenyl}amino)-5-nitro-3-pyridinyl]alanon

The connection specified in the header received in accordance with the method described for stage 1 of example 162, on the basis of 1-(6-chloro-5-nitro-3-pyridinyl)ethanone (Paul, B. et al.J. Med. Chem., 1990, 33, 2231-2239) and 1-(4-AMINOPHENYL)-2-propanol (step 1 of example 6).

1H-NMR (CDCl3) δ 10,37 (1H, Sirs), 9,06-9,03 (2H, m), 7,60 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), 4,10-4,00 (1H, m), 2,86-2,69 (2H, m)2,60 (3H, s), 1,53 (1H, d, J=4.0 Hz), of 1.28 (3H, d, J=6.2 Hz).

MS (EI) m/z: 315(M+).

Stage 2. 1-[5-amino-6-({4-[(2-hydroxypropyl]phenyl}amino)-2-pyridinyl]alanon

To a solution of 1-[6-({4-[2-hydroxypropyl]phenyl}amino)-5-nitro-3-pyridinyl]ethanone (stage 1, 1.54 g, 4,88 mmol) in tetrahydrofuran (10 ml) and ethanol (30 ml) was added 10% palladium on coal (150 mg). The resulting mixture was stirred for 19 hours in a hydrogen atmosphere. The mixture was filtered through a thick layer of celite and the filtrate was concentrated to obtain 1,74 g (100%) of the compound indicated in the title, in the form of green syrup.

1H-NMR (CDCl3) δ 8,46 (1H, d, J=1,8 Hz), 7,56 (1H, d, J=1,8 Hz), to 7.50 (2H, d, J=8,3 Hz), 7,20 (2H, d, J=8,3 Hz), 6,85 (1H, Sirs), 3,76-to 3.67 (1H, m)to 3.38 (2H, Sirs), 2,81-2,62 (2H, m), of 2.53 (3H, s)of 1.26 (3H, d, J=6,1 Hz).

Stage 3. 2-[4-(6-Acetyl-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethylamine

The connection specified in the header received in accordance with the method described for article the Hai 5 of example 1, on the basis of 1-[5-amino-6-({4-[(2-hydroxypropyl]phenyl}amino)-3-pyridinyl]ethanone (stage 2).

MS (EI) m/z: 379(M+).

Stage 4. 1-(2-Ethyl-3-{4-[2-hydroxypropyl]phenyl}-3H-imidazo[4,5-b]pyridine-6-metano

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethylacetate (stage 3).

1H-NMR (CDCl3) δ 8,93 (1H, d, J=1,8 Hz), 8,59 (1H, d, J=1,8 Hz), of 7.48 (2H, d, J=8,3 Hz), was 7.36 (2H, d, J=8,3 Hz), 4,18-4,08 (1H, m), 2,94 is 2.80 (2H, m), 2,68 (3H, s)of 1.39 (3H, t, J=7.5 Hz), of 1.33 (3H, d, J=6.2 Hz).

Stage 5. 2-[4-(6-Acetyl-2-ethyl-3H-imidazo[4,5-B]pyridine-3-yl)phenyl]-1-methylethyl (4-were) sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 1-(2-ethyl-3-{4-[2-hydroxypropyl]phenyl}-3H-imidazo[4,5-b]pyridine-6-yl)ethanone (stage 4).

1H-NMR (CDCl3) δ 8,93 (1H, d, J=1,8 Hz), at 8.60 (1H, d, J=1,8 Hz), 7,92 (2H, d, J=8,4 Hz), 7,38-7,29 (6H, m), 5,12-to 5.03 (1H, m)5 3,03-2,82 (4H, m), 2,69 (3H, s), 2,43 (3H, s), 1,28-of 1.24 (6H,m).

MS (ESI) m/z: 521 ([MH)+], 519 [(M-H)-].

Example 260

(1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-B]pyridine-3-yl)phenyl]-1-methylethyl(4-were)sulfonylureas

Stage 1. 1-[6-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-5-nitro-3-pyridinyl]alanon

The connection specified in the header received in accordance with the method described for cattle and 1 of example 162, on the basis of 1-(6-chloro-5-nitro-3-pyridinyl)ethanone (Paul, B. et al.J. Med. Chem., 1990, 33, 2231-2239.) and (2S)-1-(4-AMINOPHENYL)-2-propanol (step 2 of example 248).

1H-NMR (CDCl3) δ 10,37 (1H, Sirs), 9,06-9,03 (2H, m), 7,60 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), 4,10-4,00 (1H, m), 2,86-2,69 (2H, m)2,60 (3H, s), 1,53 (1H, d, J=4.0 Hz), of 1.28 (3H, d, J=6.2 Hz).

Stage 2. 1-[5-amino-6-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-3-pyridinyl]alanon

The connection specified in the header received in accordance with the method described for stage 2 of example 259, on the basis of 1-[6-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-5-nitro-3-pyridinyl]ethanone (stage 1).

1H-NMR (CDCl3) δ 8,46 (1H, d, J=1,8 Hz), 7,56 (1H, d, J=1,8 Hz), to 7.50 (2H, d, J=8,3 Hz), 7,20 (2H, d, J=8,3 Hz), 6,85 (1H, Sirs), 3,76-to 3.67 (1H, m)to 3.38 (2H, Sirs), 2,81-2,62 (2H, m), of 2.53 (3H, s)of 1.26 (3H, d, J=6,1 Hz).

Stage 3. (1S)-2-[4-(6-acetyl-2-ethyl-2H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethylamine

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 1-[5-amino-6-({4-[(2S)-2-hydroxypropyl]phenyl}amino)-3-pyridinyl]ethanone (stage 2).

MS (EI)m/z: 379 (M+).

Stage 4. 1-(2-ethyl-3-{4-[(2S)-2-hydroxypropyl]phenyl}-3H-imidazo[4,5-b]pyridine-6-yl)alanon

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from (1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethylacetate (stage 3).

H-NMR (CDCl3) δ 8,93 (1H, d, J=1,8 Hz), 8,59 (1H, d, J=1,8 Hz), of 7.48 (2H, d, J=8,3 Hz), was 7.36 (2H, d, J=8,3 Hz), 4,18-4,08 (1H, m), 2,94 is 2.80 (2H, m), 2,68 (3H, s)of 1.39 (3H, t, J=7.5 Hz), of 1.33 (3H, d, J=6.2 Hz).

Stage 5. (1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 1-(2-ethyl-3-{4-[(2S)-2-hydroxypropyl]phenyl}-3H-imidazo[4,5-b]pyridine-6-yl)ethanone (stage 4).

1H-NMR (CDCl3) δ 8,93 (1H, d, J=1,8 Hz), at 8.60 (1H, d, J=1,8 Hz), 7,92 (2H, d, J=8,4 Hz), 7,38-7,29 (6H, m), 5,12-to 5.03 (1H, m), 3,03-2,82 (4H, m), 2,69 (3H, s), 2,43 (3H, s), 1,28-of 1.24 (6H, m).

MS (ESI) m/z: 521 [(MH)+], 519 [(M-H)-].

Example 261

Mono-p-toluensulfonate (1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-B]pyridine-3-yl)phenyl]-1-methylethyl 4-were)sulfonylamino

The connection specified in the header received in accordance with the method described in example 231, on the basis of (1S)-2-[4-(6-acetyl-2-ethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-methylethyl(4-were)sulfanilamide (stage 5 of example 260).

1H-NMR (DMSO-d6) δ 11,93 (1H, Sirs), of 8.90 (1H, d, J=1,8 Hz), 8,63 (1H, d, J=1,8 Hz), 7,76 (2H, d, J=8,4 Hz), 7,38-7,29 (8H, m), 7,11 (2H, d, J=8,4 Hz), 4,96-to 4.87 (1H, m), 2,90-and 2.79 (4H, m), 2,32 (3H, s), and 2.27 (3H, s), of 1.26 (3H, t, J=7.5 Hz), of 1.12 (3H, d, J=6.2 Hz).

MS (ESI) m/z: 521[(MH)+], 519 [(M-H)-].

[α]24D-8,17° (c 1,020, methanol).

Example 262

Mono-p-toluensulfonate 2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylamino

Stage 1. 2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol (1,83 g, 5,54 mmol), 2-pyridinecarboxamide (of 0.53 ml, 5,54 mmol) and EtOH (40 ml) was boiled under reflux for 1 hour. After cooling to room temperature the solvent was removed. The residue was dissolved benzene (50 ml) and was treated with Pb(OAc)4(3,38 g, 6,10 mmol) at room temperature for 1 hour. The mixture was diluted in EtOAc and the solution washed with saturated aqueous NaHCO3and saturated salt solution. The organic fraction was dried over MgSO4, then filtered. After evaporation in vacuo the residue was purified by chromatography on a column of silica gel, elwira hexane/EtOAc = 5/2, obtain 1.20 g (52%) of the connection specified in the header.

1H-NMR (CDCl3) δ 8,42-8,39 (1H, m), 8,23 (1H, s), 8,10-8,07 (1H, m), 7,79 to 7.75 (1H, m), 7,40-of 7.23 (6H, m), of 3.97 (2H, t, J=6.6 Hz), 2,99 (2H, t, J=6.6 Hz).

MS (ESI) m/z: 418 ([M+H]+), 476 ([M+CF3CO2]-).

Stage 2. 2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described is shown in example 3, on the basis of 2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol.

1H-NMR (CDCl3) δ 8,39-of 8.37 (1H, m), 8,23 (1H, s), 8,10-of 8.06 (1H, m), 7,92-7,87 (2H, m), 7,81-7,76 (1H, m), 7,33-to 7.18 (8H, m), 4,35 (2H, t, J=6.8 Hz), 2,98 (2H, t, J=6.8 Hz), is 2.41 (3H, s).

MS (ESI) m/z: 615 ([M+H]+), 613 ([M-H]-).

Example 263

Mono-p-toluensulfonate 2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylamino

The connection specified in the header received in accordance with the method described in example 231, on the basis of 2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylamino.

MS (ESI) m/z: 615 ([M+H]+).

Example 264

Mono-p-toluensulfonate N-{[(2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-l}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 1 of example 262).

1H-NMR (CDCl3) δ to 8.41-8,39 (1H, m), 8,24 (1H, s), 8,11 (1H, d, J=8,8 Hz), 7,82-7,76 (1H, m), 7,38 (2H, d, J=8,4 Hz), 7,35 (1H, s), 7,30-of 7.25 (3H, m), and 3.31 (2H, t, J=7.2 Hz), 3,19 (2H, t, J=7.2 Hz).

Stage 2. 1-[4-(2-Azi is oethyl)phenyl]-6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1 H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole (step 1).

1H-NMR (CDCl3) δ 8,40-8,39 (1H, m), 8,24 (1H, s), 8,10 (1H, d, J=7.9 Hz), 7,81 to 7.75 (1H, m), 7,39 (2H, d, J=8,4 Hz), 7,34 (1H, s), 7,29-of 7.25 (3H, m), 3,61 (2H, t, J=6.8 Hz), a 3.01 (2H, t, J=6,8 Hz).

Stage 3. 2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl ethylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl)phenyl]-6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole (stage 2).

1H-NMR (CDCl3) δ of 8.37-at 8.36 (1H, m), 8,19 (1H, s), 8,03-8,00 (1H, m), 7,78-7,71 (1H, m), 7,32-to 7.18 (6H, m), to 3.02 (2H, t, J=6.8 Hz), 2,82 (2H, t, J=6.8 Hz), 2,17 (2H, Sirs).

Stage 4. N-{[(2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethylamine (stage 3).

1H-NMR (CDCl3) δ 8,42-8,39 (1H, m), 8,24 (1H, s), 8,10 (1H, d, J=8.1 Hz), 7,81 to 7.75 (1H, m), of 7.69 (2H, d, J=8,3 Hz), 7,33-7,24 (8H, m), 6,72-6,69 (1H, m), 3,63 of 3.56 (2H, m), with 2.93 (2H, t, J=6.8 Hz), of 2.38 (3H, s).

MS (ESI) m/z: 614 [(MH)+], 612[(M-H) -].

Stage 5. Mono-p-toluensulfonate N-{[(2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-l}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described in example 231, on the basis of N-[(2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (stage 4).

1H-NMR (DMSO-d6) δ 10,63 (1H, Sirs), to 8.41-8,39 (1H, m), 8,35 (1H, s), 8,08-of 7.95 (2H, m), of 7.75 (2H, d, J=8,3 Hz), 7,49 (2H, d, J=8,3 Hz), 7,44-7,27 (8H, m), 7,10 (2H, d, J=7,7 Hz), 6,61-to 6.57 (1H, m), 3,30 is 3.23 (2H, m), to 2.74 (2H, t, J=7.0 Hz), 2,31 (3H, s), and 2.27 (3H, s).

MS (ESI) m/z: 614 [(MH)+], 612[(M-H)-].

Example 265

Mono-p-toluensulfonate N-{[(2-{4-[6-chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-{4-[6-chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 1, example 255).

1H-NMR (DMSO-d6) δ to 13.29 (1H, s), of 8.25 (1H, s), 7,83-7,81 (1H, m), 7,52-the 7.43 (4H, m), 7.23 percent (1H, s), 6,67-of 6.65 (1H, m), of 3.95 (2H, t, J=7,0 Hz), and 3.16 (2H, t, J=7,0 Hz).

Stage 2. 1-[4-(2-azidoethyl)phenyl-6-chloro-2-(1H-pyrazole-3-yl)-5-(triptime who yl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole (step 1).

1H-NMR (DMSO-d6) δ of 13.27 (1H, s), of 8.25 (1H, s), 7,82 (1H, s), 7,52-the 7.43 (4H, m), 7,21 (1H, s), of 6.65 (1H, s)to 3.67 (2H, t, J=7,0 Hz)to 2.99 (2H, t, J=7,0 Hz).

Stage 3. 2-(4-[6-Chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl)phenyl-6-chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole (stage 2).

MS (EI) m/z: 405 (M+).

Stage 4. N-{[2-{4-[6-chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-{4-[6-chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethylamine (stage 3).

1H-NMR (CDCl3) δ 8,17 (1H, s), of 7.69 (2H, d, J=8,4 Hz), EUR 7.57 (1H, d, J=2.2 Hz), 7,30-to 7.18 (8H, m), 6,82-6,77 (1H, m), 6,60 (1H, d, J=2.2 Hz), 3,64-to 3.58 (2H, m), only 2.91 (2H, t, J=6.4 Hz), 2,39 (3H, s).

Stage 5. Mono-p-toluensulfonate N-{[(2-{4-[6-chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the head, received in accordance with the method described in example 231 from N-{[(2-{4-[6-chloro-2-(1H-pyrazole-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (stage 4).

1H-NMR (DMSO-d6) δ at 10.64 (1H, Sirs), 8,24 (1H, s), 8,35 (1H, s), 7,78 to 7.75 (3H, m), 7,49-7,80 (8H, m), 7,11 (2H, d, JK7,9 Hz), 6,60-to 6.57 (1H, m), 6,38-6,37 (1H, m), 3.33 and-3,26 (2H, m), 2,78 (2H, t, J=7.2 Hz), 2,32 (3H, ), of 2.28 (3H, s).

MS (ESI)m/z: 603[(MH)+], 601 [(M-H)-].

Example 266

3-(3-Chloro-4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Stage 1. Diethyl 2-(2-chloro-4-nitrophenyl)malonate

Diethylmalonate (5,2 ml of 34.2 mmol) was added to a suspension of NaH (1.4 g, 34,2 mmol) in 80 ml of 1,4-dioxane, then was added CuBr (4.9 g, 34,2 mmol) and 3-chloro-4-ftorirovannom (5.0 g, 28.5 mmol). The mixture was stirred at room temperature for 0.5 hours and at the boiling point under reflux for 12 hours. The mixture was poured into water and the precipitate was filtered through a thick layer of celite. The filtrate was extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with saturated saline solution, dried (MgSO4) and concentrated to obtain a green oil. This mixture was purified by chromatography on a column with SiO2, elwira hexane/ethyl acetate (10/1), to obtain 7.6 g (85%) of the connection specified in the agolove, in the form of a yellow oil.

1H-NMR (CDCl3) δ 8,30 (1H, d, J=2.4 Hz), 8,16 (1H, DD, J=2,2, 8.6 Hz), 7,74 (1H, d, J=8.6 Hz), 5,27 (1H, s), 4,28 (2H, q, J=7.2 Hz), 4,27 (2H, q, J=7.2 Hz), of 1.29 (6H, t, J=7.2 Hz).

Stage 2. 2-(2-Chloro-4-nitrophenyl)acetic acid

To a solution of diethyl 2-(2-chloro-4-nitrophenyl)malonate (stage 1, 7.6 g, and 24.2 mmol) in methanol (18 ml) was added 6M NaOH (12 ml) and was stirred for 1 hour at 50°C. the Reaction was suppressed by the addition of saturated aqueous solution of citric acid (16 ml) and water. The organic layer was extracted with ethyl acetate (2 x 50 ml), washed with saturated salt solution, dried (MgSO4) and concentrated to obtain 4.52 g (87%) indicated in the title compound as a pale yellow solid.

1H-NMR (CDCl3) δ 12,6 (1H, Sirs), 8,30 (1H, d, J=2.6 Hz), 8,18 (1H, DD, J=2,4, and 8.4 Hz), 7,73 (1H, d, J=8.6 Hz), 3,90 (2H, s).

Stage 3. Methyl 2-(2-chloro-4-nitrophenyl)acetate

To a solution of 2-(2-chloro-4-nitrophenyl)acetic acid (stage 2, 4.5 g, 21 mmol) in dimethylacetate/methanol (4/1) was added trimethylsilylmethyl (0.3 ml) and was stirred for 7 hours at room temperature. The solvent was removed and the residue was purified by chromatography on a column with SiO2, elwira hexane/ethyl acetate (10/1), to obtain 3.6 g (74%) indicated in the title compound as a yellow oil.

1H-NMR (CDCl3) δ of 8.28 (1H, d, J=2.3 Hz), 8,11 (1H, DD, J=2,3, 8.6 G is), to 7.50 (1H, d, J=8.6 Hz), 3,88 (2H, s), 3,74 (3H, s).

Stage 4. Methyl 2-(4-amino-2-chlorophenyl)acetate

To a solution of methyl 2-(2-chloro-4-nitrophenyl)acetate (stage 3, 3.6 g, 15.6 mmol) in ethanol/water (4/1) was added Fe (4.4 g, 78,0 mmol) and NH4Cl (409 mg, 7.8 mmol). The mixture was stirred for 1 hour at boiling temperature under reflux. The solvent was removed and the residue was diluted with CH2Cl2. The mixture was washed with saturated saline solution, dried (MgSO4) and concentrated to obtain 2,59 g (83%) indicated in the title compound as an orange oil. The connection specified in the header received in accordance with the method described for step 2 of example 28, from methyl 2-(2-chloro-4-nitrophenyl)acetate (stage 3).

1H-NMR (CDCl3) δ? 7.04 baby mortality (1H, d, J=8,2 Hz), 6,72 (1H, d, J=2.3 Hz), is 6.54 (1H, DD, J=2,5, and 8.2 Hz), 3,70 (3H, s), 3,66 (2H, s).

Stage 5. Methyl {2-chloro-4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}acetate

To a mixture of methyl 2-(4-amino-2-chlorophenyl)acetate (stage 4, 2.6 g, 13,0 mmol) and 4,6-dimethyl-3-nitro-2-pyridine (stage 2 of example 1, 2.4 g, 13,0 mmol) in DMSO was added diisopropylethylamine. The resulting mixture was stirred for 9 hours at 50°C. the Mixture was poured into water and was extracted with ethyl acetate (3 x 30 ml). The organic layer was washed with saturated saline solution, dried (MgSO4) and concentrated to obtain a brown oil. The oil was purified is using chromatography on a column with SiO 2, elwira hexane/ethyl acetate (10/1), to obtain 1.4 g (29%) indicated in the title compound as a yellow solid.

1H-NMR (CDCl3) δ of 9.55 (1H, Sirs), of 7.90 (1H, d, J=2.2 Hz), the 7.43 (1H, DD, J 2.2, while for 8.3 Hz), 7,24 (1H, d, J=8,3 Hz), 6,59 (1H, s), 3,76 (2H, s), and 3.72 (3H, s), of 2.56 (3H, s)to 2.46 (3H, s).

MS (EI) m/z: 349 (M+).

Stage 6. Methyl 2-chloro-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}acetate

The connection specified in the header received in accordance with the method described for step 2 of example 28, from methyl {2-chloro-4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}acetate (stage 5).

1H-NMR (CDCl3) δ 7,26 (1H, d, J=2.2 Hz), 7,20 (1H, d, J=8,3 Hz), 7,00 (1H, DD, J=2,2, 8,3 Hz), only 6.64 (1H, s), 6,37 (1H, Sirs), 3,70 (3H, s), with 3.27 (1H, Sirs), 2,68 (3H, s), of 2.38 (3H, s), measuring 2.20 (3H, s).

Stage 7. Methyl 2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenylethyl acetate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from methyl 2-chloro-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}acetate (step 6).

1H-NMR (CDCl3) δ to 7.50 (1H, d, 8,3 Hz), 7,47 (1H, d, J=2.2 Hz), 7,31 (1H, DD, J=2,2, 8,3 Hz), 6,92 (1H, s), a 3.87 (2H, s), of 3.77 (3H, s), 2,85 (2H, q, J=7.5 Hz), 2,65 (3H, s), of 2.53 (3H, s)is 1.31 (3H, t, J=7.5 Hz).

MS (EI)m/z: 357 (M+).

Stage 8. 2-[2-Chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenylethanol

To a solution of methyl 2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[,5-b]pyridine-3-yl)phenylacetate (stage 7, 1.13 g, a 3.15 mmol) was carefully added LAH and was stirred for 1 hour at room temperature. The reaction extinguished with water and the mixture was diluted with ethyl acetate (50 ml). To this mixture was added a saturated aqueous solution of potassium sodium tartrate (50 ml) and was stirred for 2.5 hours. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 20 ml). The combined organic layer was washed with saturated saline solution, dried (Mg2SO4) and concentrated to obtain 1.0 g specified in the title compound as a white solid.

1H-NMR (CDCl3) δ 7,41-7,53 (2H, m), 7,25-7,29 (1H, m), 6,92 (1H, s), of 3.96 (2H, m), 3,11 (3H, t, J=7.4 Hz), 2,82 (2H, m), 2,65 (3H, s), of 2.53 (3H, s)of 1.30 (3H, t, J=7,4 Hz).

MS (EI) m/z: 329 (M+).

Stage 9. 3-[3-Chloro-4-(2-chloroethyl)phenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from methyl 2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenylethanol (stage 8).

1H-NMR (CDCl3) δ 7,45-7,52 (2H, m), 7.23 percent-7,31 (1H, m), 6,92 (1H, s), 3,82 (2H, t, J=7,3 Hz), 3,29 (2H, t, J=7,3 Hz), and 2.83 (2H, q, J=7,6 Hz), 2,65 (3H, s), of 2.53 (3H, s)of 1.30 (3H, t, J=7,6 Hz).

Stage 10. 3-[4-(2-Azidoethyl-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 8 when the EPA 1, on the basis of 3-[3-chloro-4-(2-chloroethyl)phenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 9).

1H-NMR (CDCl3) δ 7,45-of 7.48 (2H, m), 7,29 (1H, DD, J=2,1, 7.9 Hz), 6,92 (1H, s), 3,62 (1H, t, J=7,1 Hz), 3,12 (1H, t, J=7,3 Hz), and 2.83 (2H, q, J=7.4 Hz), 2,65 (3H, s), of 2.53 (3H, s)of 1.30 (3H, t, J=7,4 Hz).

Stage 11. 2-[2-Chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanamine

To a solution of methyl 3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-6]pyridine (stage 10, 430 mg, 1.2 mmol) in ethanol/water (4/1) was added Fe (335 mg, 6.0 mmol) and NH4Cl (409 mg, 7.8 mmol). The mixture was stirred and boiled under reflux for 1 hour. The solvent was removed and the residue was diluted in CH2Cl2. The mixture was washed with saturated saline solution, dried (MgSO4) and concentrated to obtain 390 mg of the compound indicated in the title, in the form of an orange oil.

1H-NMR (CDCl3) δ 7,44 (2H, d, J=7,4 Hz), 7,25 (1H, m), 6,92 (1H, s), 2,92 is 3.15 (6H, m), and 2.83 (2H, q, J=7.4 Hz), 2,65 (3H, s), of 2.53 (3H, s)of 1.30 (3H, t, J=7,4 Hz).

Stage 12. 2-[2-Chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl]phenyl]ethanamine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanamine (stage 11).

1H-NMR (CDCl3) δ 7,83 (2H, d, J=8,4 Hz), 7,28 and 7.36 (4H, m), 7,14 (1H, d, J=7,7 Hz), 6,92 (1H, s), 6,28 (1H, Sirs), to 3.58 (2H, dt, J=6 Hz), to 3.02 (2H, t, J=6.4 Hz), is 2.74 (2H, q, J=7,6 Hz)to 2.66 (3H, s), a 2.45 (3H, s)to 2.41 (3H, s), 1,25 (3H, t, J=7,6 Hz).

MS (ESI) m/z: 526 (M+).

EXAMPLE 267

3-(2-Chloro-4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-B]pyridine

Stage 1. 2-{3-Chloro-4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 4,6-dimethyl-3-nitro-2-pyridine (0.66 g, 3.8 mmol, step 2 of example 1) and 4-amino-2-chlorophenylalanine (to 0.72 g, 3.8 mmol,Eur. J. Med. Chem.,1996, 31, 133).

1H-NMR (CDCl3) δ 9,85 (1H, s)of 8.37 (1H, d, J=8,4 Hz), 7,31 (1H, d, J=2.0 Hz), 7,14 (1H, DD, J=2.0 a, 8,3 Hz), 6,60 (1H, s), a 3.87 (2H, dt, J=6,2, 6.4 Hz), 2,84 (2H, t, J=6,4 Hz), of 2.56 (3H, s)to 2.46 (3H, s), 1,40 (1H, t, J=6.2 Hz).

MS (EI) m/z: 321 (M+).

Stage 2. Methyl 3-chloro-(4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-{3-chloro-4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1).

1H-NMR (CDCl3) δ 7,26 (1H, d, J=2.2 Hz), 7,20 (1H, d, J=8,3 Hz), 7,00 (1H, DD, J=2,2, 8,3 Hz), only 6.64 (1H, s), 6,37 (1H, Sirs), 3,70 (3H, s), with 3.27 (1H, Sirs), 2,68 (3H, s), of 2.38 (3H, s), measuring 2.20 (3H, s).

Stage 3. 2-[2-Chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenylethylamine

The connection specified in the header received in accordance with the act shall obom, described for stage 5 of example 1 from 3-chloro-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethylpropylamine (stage 2).

1H-NMR (CDCl3) δ to 7.50 (1H, d, 8,3 Hz), 7,47 (1H, d, J=2.2 Hz), 7,31 (1H, DD, J=2,2, 8,3 Hz), 6,92 (1H, s), a 3.87 (2H, s), of 3.77 (3H, s), 2,85 (2H, q, J=7.5 Hz), 2,65 (3H, s), of 2.53 (3H, s)is 1.31 (3H, t, J=7.5 Hz).

MS (EI) m/z: 357 (M+).

Stage 4. 2-[3-Chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenylethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from methyl 2-[2-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenylethylamine (stage 3).

1H-NMR (CDCl3) δ 7,51 (1H, s), 7,34 (2H, s)6,91 (1H, s), of 3.96 (2H, DD, J=6,2,12,0 Hz), 2,96 (2H, t, J=7.4 Hz), 2,70 (2H, m)to 2.66 (3H, s), of 2.51 (3H, s), 1,67 (1H, shirt, J=6.2 Hz), of 1.28 (3H, t, J=7,4 Hz).

MS (ESI)m/z: 329 (M+).

Stage 5. 3-[2-Chloro-4-(2-chloroethyl)phenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[3-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenylethanol (stage 4).

1H-NMR (CDCl3) δ 7,49 (1H, d, J=1.3 Hz), 7,34-7,49 (2H, m)6,91 (1H, s), 3,80 (2H, t, J=7.2 Hz), 3,17 (2H, t, J=7.0 Hz), 2,60-to 2.85 (2H, m)to 2.66 (3H, s), of 2.51 (3H, s)of 1.28 (3H, t, J=7.5 Hz).

MS (EI) m/z:347(M-H)-].

Stage 6. 3-[4-(2-Azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the zag is lowke, received in accordance with the method described for stage 8 of example 1 from 3-[2-chloro-4-(2-chloroethyl)phenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 5).

1H-NMR (CDCl3) δ 7,49 (1H, m, J=1,8 Hz), 7,31-7,38 (2H, m)6,91 (1H, s), 3,62 (2H, t, J=7.0 Hz), 2,98 (2H, t, J=7,3 Hz), 2,60 is 2.80 (2H, m)to 2.66 (3H, s), of 2.51 (3H, s)of 1.27 (3H, t, J=7.5 Hz).

MS (EI) m/z: 354 (M+).

Stage 7. 2-[3-Chloro-4-(-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-ylphenyl]ethanamine

To a stirred solution of 3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 6, 149 mg, 0.4 mmol) in THF (4ml) was added triphenylphosphine (116 mg, 0.4 mmol) at room temperature. When you are finished adding continued stirring for an additional 2.5 hours at the same temperature for 3.5 hours at boiling temperature under reflux. To the mixture was added H2O (1.0 ml) at room temperature and the solvent was removed. The mixture was dissolved in CH2Cl2(100 ml), washed with saturated salt solution. The organic layer was dried (MgSO4) and concentrated to a yellow oil.

MS (EI) m/z: 328 (M+).

Stage 8. 2-[3-Chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanamine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[3-chloro-4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)fenilalanina (stage 7).

1H-NMR (CDCl3) δ 7,88 (1H, s), a 7.85 (1H, s), 7,19-7,34 (5H, m), 6,92 (1H, s)6,94 (1H, s), 6,13 (1H, Sirs), of 3.54 (2H, m), 2,78 (2H, t, J=6.4 Hz), to 2.67 (3H, s), 2.63 in (3H, m), 2,42 (3H, s), is 2.40 (3H, s), 1,25 (3H, t, J=7.5 Hz).

MS (EI) m/z: 526 (M+).

Example 268

2-Ethyl-3-(3-methoxy-4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Stage 1. Diethyl 2-(2-methoxy-4-nitrophenyl)malonate

The connection specified in the header received in accordance with the method described for stage 1 of example 266, on the basis of 4-bromo-3-methoxyethanol.

1H-NMR (CDCl3) δ for 7.78 (1H, DD, J=2,2, 8,4 Hz), of 7.75 (1H, d, J=2.2 Hz), 7,54 (1H, d, J=8,4 Hz), 5,15 (1H, s), 4,25 (2H, q, J=7.2 Hz), 4,25 (2H, q, J=7.2 Hz), of 3.94 (3H, s)of 1.28 (6H, t, J=7.2 Hz).

Stage 2. 2-(2-Methoxy-4-nitrophenyl)acetic acid

The connection specified in the header received in accordance with the method described for stage 2 of example 266, from diethyl 2-(2-methoxy-4-nitrophenyl)malonate (stage 1).

1H-NMR (CDCl3) δ and 12.4 (1H, Sirs), of 7.82 (1H, DD, J=2,2, 8,4 Hz), of 7.75 (1H, DD, J=2.2 Hz), to 7.50 (1H, d, J=8,4 Hz), 3,90 (3H, s), 3,66 (2H, s).

Stage 3. Methyl 2-(2-methoxy-4-nitrophenyl)acetate

To a solution of 2-(2-methoxy-4-nitrophenyl)acetic acid (step 2, 1.2 g, 5.5 mmol) in methanol/dichloromethane (11 ml, 1/1) was added trimethylsilyldiazomethane (2 M, 5.6 ml, of 11.8 mmol) and was stirred for 10 minutes at room temperature. The mixture was suppressed us is placed in an aqueous solution of citric acid and was extracted with ethyl acetate (3 x 20 ml). The organic layer was washed with saturated saline solution, dried (MgSO4) and concentrated, to obtain 1.2 g specified in the title compound as an orange solid.

1H-NMR (CDCl3) δ 7,83 (1H, DD, J=2,2, 8,3 Hz), 7,73 (1H, DD, J=2.2 Hz), 7,34 (1H, d, J=8.1 Hz), 3,93 (3H, s), 3,71 (2H, s), 3,71 (3H, s).

Stage 4. Methyl 2-(4-amino-2-methoxyphenyl)acetate

To a solution of methyl 2-(2-methoxy-4-nitrophenyl)acetate (stage 3, 1.2 g, 5.5 mmol) in methanol (10 ml) was added 10% Pd/C (130 mg, 0.12 mmol) and was stirred in an atmosphere of hydrogen for 3 hours at room temperature. The catalyst was filtered through a thick layer of celite and thoroughly washed with ethanol and ethyl acetate. The filtrate was concentrated, to obtain 1.1 g specified in the title compound as a pink oil.

1H-NMR (CDCl3) δ 6,94 (1H, d, J=7,7 Hz), of 6.26 (1H, d, J=2.0 Hz), 6,23 (1H, s), 3,70 (3H, s), 3,76 (3H, s)to 3.67 (3H, s), 3,52 (2H, s).

Stage 5. Methyl {4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]-2-methoxyphenyl}acetate

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from methyl 2-(4-amino-2-methoxyphenyl)acetate (stage 4).

1H-NMR (CDCl3) δ a 9.60 (1H, s), 7,47 (1H, d, J=1.7 Hz), 7,06-to 7.15 (2H, m), 6,55 (1H, s), of 3.84 (3H, s), of 3.69 (3H, s), 3,62 (2H, s), of 2.56 (3H, s), is 2.44 (3H, s).

MS (EI) m/z: 345 (M+).

Stage 6. Methyl {4-[(3-amino-4,6-dimethyl-2-pyridinyl)and the Ino]-2-methoxyphenyl}acetate

The connection specified in the header received in accordance with the method described for step 2 of example 28, from methyl {4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]-2-methoxyphenyl}acetate (stage 5).

1H-NMR (CDCl3) δ 7,03 (1H, d, J=5,1 Hz), 7,02 (1H, s), 6,60 (1H, s), to 6.57 (1H, DD, J=2,2, 8,3 Hz), with 3.79 (3H, s), 3,68 (3H, s), of 3.56 (2H, s), of 3.25 to 3.35(Sirs, 2H), of 2.38 (3H, s), measuring 2.20 (3H, s).

MS (EI) m/z: 315(M+).

Stage 7. Methyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)-2-methoxyphenyl]acetate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from methyl {4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]-2-methoxyphenyl}acetate (step 6).

1H-NMR (CDCl3) δ of 7.36 (1H, d, J=7.9 Hz), 6.89 in-6,99 (3H, m), a-3.84 (2H, s), 3,74 (3H, s), 3,71 (2H, s), 2,85 (2H, q, J=7.5 Hz), to 2.66 (3H, s), of 2.53 (3H, s)of 1.30 (3H, t, J=7.5 Hz).

MS (EI) m/z: 353 (M+).

Stage 8. 2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)-2-methoxyphenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 8 of example 266, on the basis of methyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)-2-methoxyphenylacetate (stage 7).

1H-NMR (CDCl3) δ 7,33 (1H, d, J=7,7 Hz), 6.87 in-to 6.95 (3H, m), 3,90 (2H, dt, J=6,0, 6.2 Hz), of 3.84 (3H, s), 2,98(2H, t, J=6.4 Hz), 2,84(2H, q, J=7.5 Hz), to 2.66 (3H, s), of 2.53 (3H, s)of 1.76 (1H, shirt), of 1.30 (3H, t, J=7.5 Hz).

MS (EI) m/z: 324(M-H)-].

Stage 9. 3-[4-(2-Chloroethyl)-3-m is toxigenic]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)-2-methoxyphenyl]ethanol (step 8).

1H-NMR (CDCl3) δ 7,33 (1H, d, J=7,7 Hz), 6.87 in-6,94 (3H, m), of 3.84 (3H, s), of 3.77 (3H, t, J=7,6 Hz), and 3.16 (2H, t, J=7,3 Hz), 2,84 (2H, q, J=7,6 Hz)to 2.66 (3H, s), of 2.53 (3H, s)of 1.30 (3H, t, J=7,6 Hz).

Stage 10. 3-[4-(2-Azidoethyl)-3-methoxyphenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the procedure described in stage 8 of example 1 from 3-[4-(2-chloroethyl)-3-methoxyphenyl]-2-ethyl-5,7-dimethyl-3,7-imidazo[4,5-6]pyridine (stage 9).

1H-NMR (CDCl3) δ 7,45-of 7.48 (2H, m), 7,29 (1H, DD, J=2,1, 7.9 Hz), 6,92 (1H, s), 3,62 (1H, t, J=7,1 Hz), 3,12 (1H, t, J=7,3 Hz), and 2.83 (2H, q, J=7.4 Hz), 2,65 (3H, s), of 2.53 (3H, s)of 1.30 (3H, t, J=7,4 Hz).

Stage 11. 2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl-2-methoxy)phenyl]ethanamine

The connection specified in the header received in accordance with the procedure described in stage 9 of example 1 from 3-[4-(2-azidoethyl)-3-methoxyphenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 10).

1H-NMR (CDCl3) δ 7,30 (1H, d, J=7,7 Hz), 6,92 (1H, DD, J=2,0, 7.9 Hz), 6,91 (1H, Sirs), 6,86 (1H, d, J=2.0 Hz), 3,83 (3H, s)to 2.65 (3H, s), 2,99 (211, shirt, J=4.5 Hz), 2,85 (2H, q, J and 8.3 Hz), 2,84 (2H, q, J=7,7 Hz), of 2.66 (3H, s), of 2.53 (3H, s)of 1.29 (3H, t, J=7,7 Hz).

Stage 12. 2-Ethyl-(3-methoxy-4-{2-[({[(4-were)sulfon the l]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl-2-methoxy)phenyl]ethanamine (stage 11).

1H-NMR (CDCl3) δ 7,86 (2H, d, J=8,3 Hz), 7,30 (4H, m), 7,14 (1H, d, J=8.1 Hz), 7,01 (1H, d, J=7.9 Hz), 6,92 (1H, s), 6,79 (1H, d, J=2.0 Hz), 6,63 (1H, DD, J=1,8, 7,7 Hz), 6,04 (1H, shirt, J=5,1 Hz), 3,74 (3H, s), 3,51 (2H, dt, J 6.0 Hz), 2,85 (2H, t, J=6.2 Hz), 2,70 (2H, q, J=7.5 Hz), to 2.66 (3H, s), is 2.44 (3H, s)to 2.41 (3H, s)of 1.23 (3H, t, J=7.5 Hz).

MS (ESI) m/z: 522 [(M+H)+], 520 [(M-H)-].

Example 269

2-Ethyl-3-(3-methyl-4-(2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Stage 1. Diethyl 2-(2-methyl-4-nitrophenyl)malonate

The connection specified in the header received by the method described in stage 1 of example 268, on the basis of 4-bromo-3-methylnitrobenzene.

1H-NMR (CDCl3) δ 8,10 (1H, s), 8,05-8,10 (1H, m), a 7.62 (1H, d, J=9,2 Hz), is 4.93 (1H, s), 4.26 deaths (2H, q, J=7,3 Hz), 4,25 (2H, q, J=7,3 Hz), the 2.46 (3H, s)of 1.28 (6H, t, J=7,3 Hz).

Stage 2. 2-(2-methyl-4-nitrophenyl)acetic acid

The connection specified in the header received in accordance with the method described for stage 2 of example 266, from diethyl 2-(2-methyl-4-nitrophenyl)malonate (stage 1)

1H-NMR (CDCl3) δ 8,08 (1H, Sirs), 8,02 (1H, DD, J=8.6 Hz), 7,49 (1H, d, J=8,4 Hz), of 3.77 (211, C)to 2.35 (3H, s).

Stage 3. Methyl 2-(2-methyl-4-nitrophenyl)acetate

Connect the out, specified in the header received in accordance with the method described for stage 3 of example 266, based on 2-(2-methyl-4-nitrophenyl)acetic acid (stage 2)

1H-NMR (CDCl3) δ 8,07 (1H, d, J=2.1 Hz), 8,02 (1H, DD, J=2,3, 5,9 Hz), was 7.36 (1H, d, J=8,4 Hz), 3,74 (2H, s), 3,71 (3H, s), 2,42 (3H, s)

Stage 4. Methyl 2-(4-amino-2-were)acetate

The connection specified in the header received in accordance with the method described for stage 4 of example 268, based on methyl-2-(2-methyl-4-nitrophenyl)acetate (stage 3).

1H-NMR (CDCl3) δ 6,97 (1H, d, J=7.9 Hz), 6.48 in-of 6.52 (2H, m)to 3.67 (3H, s), of 3.57 (2H, Sirs), 3,53 (3H, s), 2,22 (3H, s).

Stage 5. Methyl {4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]-2-were}acetate

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from methyl 2-(4-amino-2-were)acetate (stage 4).

1H-NMR (CDCl3) δ 7,54 (1H, sird, J=8,3 Hz), 7,38 (1H, Sirs), 7,17 (1H, d, J=8,39 Hz), of 6.52 (1H, s), of 3.69 (3H, s), 3,63 (2H, s)to 2.55 (3H, s), 2,43 (3H, s), 2,32 (3H, s).

MS (EI) m/z: 345 (M+).

Stage 6. Methyl {4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]-2-were}acetate

The connection specified in the header received in accordance with the method described for step 2 of example 28, from methyl {4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]-2-were}acetate (stage 5).

1H-NMR (CDCl3) δ 7,07 (1H, d, J=9.0 Hz), 6,91-6,93 (2H, m), 6,62 (1, C)6,36 (1H, Sirs), with 3.79 (3H, s)to 3.67 (3H, s), of 3.57 (2H, s), 3,30 (Sirs, 2H), is 2.37 (3H, s), and 2.26 (3H, s), 2,2 (3H, s).

Stage 7. Methyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)-2-were]acetate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from methyl {4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]-2-were}acetate (step 6).

1H-NMR (CDCl3) δ 7,39 (1H, d, J=7,6 Hz), 7,17-of 7.25 (2H, m), 6.90 to (1H, s), 3,74 (3H, s), and 3.72 (2H, s), 2,82 (2H, q, J=7.4 Hz), 2,65 (3H, s), 2,52 (3H, s), is 2.40 (3H, s)of 1.28 (3H, t, J=7,6 Hz).

MS (EI) m/z: 337 (M+).

Stage 8. 2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)-2-were]ethanol

The connection specified in the header received in accordance with the method described for stage 8 of example 266, on the basis of methyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)-2-were]acetic acid ethyl ester (stage 7).

1H-NMR (CDCl3) δ to 7.35 (1H, d, J=7.9 Hz), 7,17 (1H, s), 7,16 (1H, d, J=7.9 Hz), make 6.90 (1H, s), a-3.84 (2H, dt, J=6.8 Hz), 2,96 (2H, t, J=7.0 Hz), of 2.81 (2H, q, J=7.5 Hz), to 2.66 (3H, s), 2,52 (3H, s), 2.40 a (s, 3H), at 1.91 (1H, shirt), of 1.28 (3H, t, J=7.5 Hz).

MS (EI) m/z: 324(M-H)-].

Stage 9. 3-[4-(2-Chloroethyl)-3-were]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)-2-methyl]phenylethanol (stage 8).

1NAMR (CDCl 3) δ to 7.35 (1H, d, J=8,4 Hz), 7,17-7,19 (2H, m), 6.90 to (1H, in), 3.75 (2H, t, J=7,6 Hz), 3,17 (2H, t, J=7,6 Hz), of 2.81 (2H, q, J=7.5 Hz), 2,65 (3H, s)to 2.41 (3H, s), a 2.36 (3H, s)of 1.28 (3H, t, J=7.5 Hz,).

Stage 10. 3-[4-(2-Azidoethyl)-3-were]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 3-[4-(2-chloroethyl)-3-were]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 9).

1H-NMR (CDCl3) δ 7,34 (1H, d, J=8.7 Hz), 7,19-7,26 (2H, m), 6.90 to (1H, s), 3,62 (1H, t, J=7,1 Hz), of 3.56 (2H, t, J=7,6 Hz)to 2.99 (2H, t, J=7,6 Hz), of 2.81 (2H, q, J=7,6 Hz), 2,65 (3H, s), 2,52 (3H, s)to 2.41 (3H, ), of 1.27 (3H, t, J=7,6 Hz).

Stage 11. 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl-2-methyl)phenyl]ethanamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 3-[4-(2-azidoethyl)-3-were]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 10).

1H-NMR (CDCl3) δ to 7.32 (1H, d, J=7,7 Hz), 7,14-7,16 (2H, m)6,91 (1H, Sirs), of 6.90 (1H, s), to 3.02 (2H, shirt, J=7,3 Hz), 2.77-to 2,87 (4H, m), 2,65 (3H, s), of 2.53 (3H, s), is 2.40 (3H, s)of 1.28 (3H, t, J=7.5 Hz).

Stage 12. 2-Ethyl-(3-methyl-4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl-2-methyl)fenilalanina (stage 11).

1H-NMR (CDCl3) δ 7,86 (1H, d, J=8.0 Hz), 7,31 (1H, d, J=8.0 Hz), 7,03 (1H, d, J=7.9 Hz), 6,91 (1H, s), 6,85 (1H, d, J=8,4 Hz), 6,07-6,11 (1H, m), 3,51 (2H, q, J=6.4 Hz), 2,85 (2H, t, J=6.4 Hz), 261-2,69 (2H, m,), 2,69 (3H, s), is 2.44 (3H, s), of 2.28 (3H, s)of 1.23 (3H, t, J=7.5 Hz).

MS (ESI) m/z: 506(M+H)+], 504 [(M-H)-].

Example 270

6-Chloro-2-ethyl-1-(6-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}-3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole

Stage 1. (4-Amino-2-pyridinyl)acetonitrile

The connection specified in the header received in accordance with the method described for step 2 of example 28, on the basis of (4-nitro-2-pyridinyl)acetonitrile (8.6 g, to 52.9 mmol, Katz; R. B.; Voyle, M., Synthesis., 1989, 4, 314).

1H-NMR (CDCl3) δ of 8.04 (1H, d, J=2,8 Hz), 7,17 (1H, d, J=8,2 Hz), of 6.99 (1H, DD, J=2,8, and 8.4 Hz), 3,81 (2H, s), 3,76 (2H, Sirs).

Stage 2. {5-[5-Chloro-2-nitro-(trifluoromethyl)aniline]-2-pyridinyl}acetonitrile

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from (5-aminopyridine-2-yl)acetonitrile (stage 1).

1H-NMR (CDCl3) δ to 9.66 (1H, s), at 8.60 (2H, m), 7,71 (1H, DD, J=2,6, and 8.4 Hz), 7,60 (1H, d, J=8,3 Hz), 7,13 (1H, s), a 4.03 (2H, s).

MS (EI) m/z: 356 (M+).

Stage 3. {5-[2-amino-5-chloro-4-(trifluoromethyl)aniline]-2-pyridinyl}acetonitrile

The connection specified in the header received in accordance with the method described for step 2 of example 28, on the basis of {5-[5-chloro-2-nitro-4-(trifter ethyl)aniline]-2-pyridinyl}acetonitrile (stage 2).

1H-NMR (CDCl3) δ of 8.25 (1H, d, J=2.1 Hz), 7,12-7,34 (3H, m), vs. 5.47 (1H, Sirs), the 3.89 (2H, s), of 3.78 (2H, Sirs).

Stage 4. {5-[6-{Chloro-2-ethyl-5-(trifluoromethyl-1H-benzimidazole-1-yl]-2-pyridinyl}acetonitrile

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from {5-[2-amino-5-chloro-4-(trifluoromethyl)aniline]-2-pyridinyl}acetonitrile (stage 3).

1H-NMR (CDCl3) δ 8,66 (1H, s), 8,15 (1H, s), 7,73-7,83 (2H, m), 7,12(1H, s), of 4.12 (2H, s), and 2.79 (2H, q, J=7,6 Hz)of 1.40 (3H, t, J=7,6 Hz).

Stage 5. 2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}ethanamine

To a solution of {5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}acetonitrile (stage 4, 1.0 g, 2.8 mmol) in ammonia-ethanol (30 ml) was added Raney Ni and was stirred for 8 hours in hydrogen atmosphere (3.0 kgf/cm2). The catalyst was filtered and the solvent was removed. The residue was diluted with ethyl acetate, washed with saturated salt solution, dried (MgSO4) and concentrated, obtaining 813 mg specified in the title compound as a black solid.

MS (EI) m/z: 368 (M+).

Stage 6. 6-Chloro-2-ethyl-1-(6-{2-[({[(methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 0 of example 1, on the basis of 2-[5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}of ethanamine (stage 5).

1H-NMR (CDCl3) δ 8,63 (1H, d, J=2.2 Hz), 8,14 (1H, s), to 7.77 (2H, d, J=8,3 Hz), 7,66 (1H, DD, J=2,6, 8,3 Hz), was 7.45 (1H, d, J=8,3 Hz), 7,30 (2H, d, J=8,4 Hz), 7,21 (1H, s), of 3.73-of 3.80 (2H, m), 3,17 (2H, t, J=6.2 Hz), and 2.79 (2H, q, J=7.5 Hz), 2,42 (3H, s)to 1.38 (3H, t, J=7.5 Hz).

MS (ESI) m/z: 566 [(M+H)+], 564 [(M-H)-].

Example 271

Sodium salt of 6-chloro-2-ethyl-1-(6-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}-3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 6-chloro-2-ethyl-1-(6-{2-[({[(methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole (example 270).

1H-NMR (DMSO-d6) δ 8,71 (1H, Sirs), to 8.20 (1H, Sirs) to 7.95 (1H, m), 7,43-to 7.64 (4H, m), 7,12 (2H, Sirs), 6,09 (1H, Sirs), 3,39 (2H, Sirs), of 2.92 (2H, Sirs), 2,73 (2H, Sirs), 2,28 (3H, Sirs), of 1.27 (3H, Sirs).

MS (ESI) m/z: 566 [(M+H)+], 564 [(M-H)-].

Example 272

2-{5-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}ethyl(4-were)sulfonylureas

Stage 1. Ethyl (5-amino-2-pyridinyl)acetate

To a solution of (5-amino-2-pyridinyl)acetic acid (1,46 g, 9.6 mmol, Daisley; R.W.; Hanbali, J.R.,Synthetic Communications.,1981, 11(9), 743) in ethanol was added conc. H2SO4and was stirred for 16.5 hours in the atmosphere the sphere of hydrogen at room temperature. The mixture was neutralized with a saturated aqueous solution of NaHCO3and the solvent was removed. The mixture was diluted with water and extracted with ethyl acetate (5 x 20 ml). The organic layer was washed with saturated saline solution, dried (MgSO4) and concentrated to obtain 1.2 g specified in the title compound as a brown oil.

1H-NMR (CDCl3) δ of 8.04 (1H, d, J=2,8 Hz), 7,07 (1H, d, J=8,2 Hz), of 6.96 (1H, DD, J=2,6, 8,2 Hz), 4,71(2H, q, J=7,1 Hz), and 3.72 (2H, s), 3,66 (2H, Sirs), 1,25 (3H, t, J=7,1 Hz).

Stage 2. Ethyl {5-[5-chloro-2-nitro-4-(trifluoromethyl)aniline]-2-pyridinyl}acetate

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from ethyl(5-amino-2-pyridinyl)acetate (stage 1).

1H-NMR (CDCl3) δ to 9.66 (1H, s), at 8.60 (2H, m), 7,71 (1H, DD, J=2,6, and 8.4 Hz), 7,60 (1H, d, J=8,3 Hz), 7,13 (1H, s), a 4.03 (2H, s).

MS (EI) m/z: 356 (M+).

Stage 3. Ethyl 5-[2-amino-5-chloro-4-(trifluoromethyl)aniline]-2-pyridinyl}acetate

The connection specified in the header received in accordance with the method described for step 2 of example 28, from ethyl{5-[5-chloro-2-nitro-(trifluoromethyl)aniline]-2-pyridinyl}acetate (step 2).

1H-NMR (CDCl3) δ to 7.25 (1H, d, J=1.5 Hz), 7,21 (1H, m), 7,16 (1H, s), to 7.09 (1H, s), 7,47 (1H, d, J=8,2 Hz), vs. 5.47 (1H, s), 4,20 (2H, q, J=7.2 Hz), 3,80 (2H, s), of 3.77 (2H, Sirs), of 1.28 (3H, t, J=7.2 Hz).

Stage 4. Ethyl 5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazo the l-1-yl]-2-pyridinyl}acetate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from ethyl {5-[2-amino-5-chloro-4-(trifluoromethyl)aniline]-2-pyridinyl}acetate (step 3).

1H-NMR (CDCl3) δ 8,61 (1H, d, J=2.0 Hz), 8,14 (1H, s), 7,71 (1H, DD, J=2.0 a, 8,2 Hz), a 7.62 (1H, d, J=8,2 Hz), 7,21 (1H, s), 4,27 (1H, q, J=7,3 Hz)to 4.01 (2H, s), and 2.79 (2H, q, J=7,6 Hz)to 1.38 (3H, t, J=7.4 Hz), of 1.33 (3H, t, J=7,1 Hz).

Stage 5. 2-{5-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}ethanol

The connection specified in the header received in accordance with the method described for stage 8 of example 266, proceeding from ethyl {5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}acetate (stage 4).

1H-NMR (CDCl3) δ to 8.57 (1H, d, J=2,50 Hz), 8,13 (1H, s), to 7.67 (1H, DD, J=2,6, 8,2 Hz), 7,49 (1H, d, J=8,2 Hz), 7,20 (1H, s)to 4.15 (1H, q, J=5.6 Hz), 3,20 (2H, t, J=5.4 Hz), and 2.79 (2H, q, J=7,4 Hz)of 1.39 (3H, t, J=7,6 Hz).

Stage 6. 2-{5-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}ethanol (stage 5).

1H-NMR (CDCl3) δ 8,59 (1H, d, J=2.3 Hz), 8,13 (1H, s), 7,88 (2H, d, J=8,4 Hz), the 7.65 (1H, DD, J=2,5, and 8.2 Hz), 7,44 (1H, d, J=8.1 Hz), 7,32 (2H, d, J=8.1 Hz), 7,20 (1H, s), of 4.57 (2H, t, J=6,4 Hz)at 3.25 (2H, t, J=6,6 Hz), and 2.79 (2H, q, J=7,4 Hz) to 2.42 (3H, C)to 1.38 (3H, t, J=7,4 Hz).

MS (ESI) m/z: 567 [(M+H)+].

Example 273

Hydrochloride of 2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}ethyl(4-were)sulfonylamino

The connection specified in the header received in accordance with the method described in example 240, on the basis of 2-[5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}ethyl(4-were)sulfanilamide (example 273).

1H-NMR (DMSO-d6) δ 11,9 (1H, Sirs), 8,72 (1H, Sirs), 8,18 (1H, s), 8,03-8,07 (1H, m), 7,74 (1H, d, J=7,6 Hz), 7,58 (1H, d, J=8,2 Hz), the 7.43 (2H, d, J=5,1 Hz), 7,39 (1H, s), of 4.45 (2H, t, J=6.2 Hz), 3,17 (2H, t, J=6.2 Hz), was 2.76 (2H, q, J=7,6 Hz)to 2.35 (3H, s)of 1.27 (3H, t, J=7,3 Hz).

MS (ESI) m/z: 567 [(M+H)+], 565 [(M-H)-].

Example 274

2-Ethyl-3-(4-{2-[({[4-pyridylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for step 2 of example 18, from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 of example 18) and pyridinyl-4-sulfonamida (Chern, Ji-Wang; Leu, Yu-Ling; et al.,J. Med. Chem., 1997, 40, 2276.; Graham, Samuel L.; Shepard, Kenneth L.; et al.,J. Med. Chem., 1989, 32, 2548).

TPL: 227,9-to 228.7°C.

1H-NMR (CDCl3) δ 8,63 (2H, d, J=5,9 Hz), the 7.65 (2H, d, J=5,9 Hz), was 7.36 (4H, s), of 6.96 (1H, s), 3,20 (2H, Sirs), 2,75 (Sirs, 2H), 2,70 (2H, q, J=7,6 Hz), 2,53 (2H, s), is 2.40 (3H, s)of 1.20 (3H, t, J=7,6 Hz).

MS (ESI) m/z: 479(M+H+], 477 [(MH) -].

Example 275

2-ethyl-3-(4-{2-[({[2-pyridylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for step 2 of example 18, from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 of example 18) and pyridinyl-2-sulfonamida (Chern, Ji-Wang; Leu, Yu-Ling; et al., J. Med. Chem., 1997, 40, 2276.; Graham, Samuel L.; Shepard, Kenneth L.; et al., J. Med. Chem., 1989, 32, 2548).

1H-NMR (CDCl3) δ 8,51 (1H, Sirs), 8,08 (1H, Sirs), 7,94 (1H, Sirs), 7,29 (2H, s), 7,19 (1H, Sirs), 6,91 (1H, s), of 2.81 (2H, Sirs), by 2.73 (2H, q, J=7,6 Hz)to 2.66 (3H, s), 2,78 (3H, s), 2.49 USD(m, 2H), of 1.26 (3H, t, J=7,3 Hz).

MS (ESI) m/z: 479(M+H)+], 477 [(M-H)-].

Example 276

2-Ethyl-3-(4-{2-[({[3-pyridylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5,7-dimethyl-3H-imidazo [4,5-b]pyridine

The connection specified in the header received in accordance with the method described for step 2 of example 18, from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylcarbamate (stage 1 of example 18) and pyridinyl-3-sulfonamida (Chern, Ji-Wang; Leu, Yu-Ling; et al.,J. Med. Chem., 1997, 40, 2276.; Graham, Samuel L.; Shepard, Kenneth L.; et al.,J. Med. Chem., 1989, 32, 2548).

1H-NMR (CDCl3) δ to 9.15 (1H, d, J=1.9 Hz), 8,83 (1H, DD, J=1,9, 5,1 Hz), a 8.34 (1H, DD, J=6.5 Hz), to 7.50 (1H, DD, J=4,9, 8.1 Hz), 7,12-of 7.23 (4H, m), 6,93 (1H, s), of 5.92 (1H, Sirs), 3,51 (2H, q, J=5,9 Hz), of 2.86 (2H, m), 2,69 (3H, m)to 2.66 (3H, s), 2,43(3H, s)of 1.27 (3H, t, J=7,6 Hz)./p>

MS (ESI) m/z: 479(M+H)+].

Example 277

2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-phenyl}ethyl-(2-chlorophenyl)sulfonylureas

The connection specified in the header received in accordance with the method described for step 2 of example 243, on the basis of 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl phenyl carbonate and 2-chlorophenylsulfonyl.

1H-NMR (CDCl3) δ 8,18 (1H, s), 8,07 (1H, d, J=7.8 Hz), 7,69 (1H, d, J=3.8 Hz), to 7.59 (1H, DD, J=4,3, 8.1 Hz), 7,51 (2H, d, J=8,4 Hz), 7,44 (2H, d, J=8,4 Hz), 7,31 (1H, s), the 4.29 (2H, t, J=6.2 Hz), 2,94 (211, t, J=6.5 Hz), was 2.76 (2H, q, J=7,6 Hz)of 1.26 (3H, t, J=7,3 Hz).

TPL 202,4-202,8°C.

MS (ESI) m/z: 586(M+H)+], 584 [(M-H)-].

Example 278

2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl-1,1-dimethylethyl(4-were)sulfonylureas

Stage 1. 2-Methyl-1-(4-nitrophenyl)-2-propanol

To a solution of 1,1-dimethyl-2-(4-nitrophenyl)acetic acid ethyl ester (52 mmol) in MeOH (50 ml) was added 4 N. LiOH (40 ml) and the mixture was stirred at 50°C for 2 hours. Then the solvent was removed, the mixture was diluted with water and was extracted with EtOAc (4 x 50 ml). The organic layer was washed with saturated saline solution, dried (MgSO4) and concentrated. This crude product was purified by chromatography on a column with SiO2, elwira hexane/ethyl acetate (5/1), to obtain specified in the title compound as a yellow oil 3,3 g, 33%).

1H-NMR (CDCl3) δ 8,17 (2H, d, J=8,9 Hz), 7,40 (2H, d, J=8.6 Hz), is 2.88 (2H, s), and 1.63 (1H, Sirs), 1,25 (6H,s).

Stage 2. 1-(4-AMINOPHENYL)-2-methyl-2-propanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-methyl-1-(4-nitrophenyl)-2-propanol (stage l).

1H-NMR (CDCl3) δ 7,00 (2H, d, J=8,4 Hz), of 6.65 (2H, d, J=8,4 Hz), 3,61 (2H, Sirs), 2,65 (2H, s)of 1.39 (1H, Sirs), of 1.20 (6H, s).

Stage 3. 1-{4-[(4,6-Dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-methyl-2-propanol

The connection specified in the header received in accordance with the method described for stage 5 of example 266, on the basis of 1-(4-AMINOPHENYL)-2-methyl-2-propanol (stage 2).

1H-NMR (CDCl3) δ a 9.60 (1H, s), to 7.59 (2H, d, J=8.7 Hz), 7,19 (2H, d, J=8,4 Hz), of 6.52 (1H, s)of 2.75 (2H, s)to 2.54 (3H, s), 2,43 (3H, s)of 1.24 (6H, s).

Stage 4. 1-{4-[(3-Amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}-2-methyl-2-propanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 1-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}-2-methyl-2-propanol (stage 3).

1H-NMR (CDCl3) δ 7,10 (4H, s), is 6.61 (1H, s), 6,33 (2H, s), or 3.28 (1H:Sirs), 2,70 (2H, s), is 2.37 (3H, s), measuring 2.20 (3H, s)to 1.22 (6H, s).

Stage 5. 2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-2-methyl-2-propanol

The connection specified in the header received in accordance with the act shall obom, described for stage 5 of example 1 from 1-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}-2-methyl-2-propanol (stage 4).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8.1 Hz), 7,33 (2H, d, J=of 8.47 Hz), 6,91 (1H, s), 2,87 (2H, s)2,84 (2H, q, J=7,6 Hz)to 2.66 (3H, s), 2,52 (3H, s)is 1.31 (6H, s)of 1.28 (2H, d, J=7,6 Hz).

Stage 6. 2-[4-(2-Ethyl-5,7-dimethyl-3H-l[4,5-b]pyridine-3-yl)phenyl]-1,1-dimethylethyl-(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-2-methyl-2-propanol (stage 5).

1H-NMR (CDCl3) δ 7,94 (2H, t, J=8.6 Hz), 7,33 (2H, d, J=8.6 Hz), 7,16 (4H, m), 6,93 (1H, s), 3,10 (2H, s), of 2.81 (2H, q, J=7,6 Hz)to 2.67 (3H, s)to 2.54 (3H, s), is 2.40 (3H, s), 2,42 (3H, s)to 1.48 (6H, s), 1.28 (in 3H, t, J=7,6 Hz).

TPL 173.5 metric-174,0°C.

MS (ESI) m/z: 521(M+H)+], 519 [(M-H)-].

Example 279

6-Chloro-2-ethyl-1-(6-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}-3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole

Stage 1. (6-{[5-Chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}-3-pyridinyl)methanol

The connection specified in the header received in accordance with the method described for stage 5 of example 266, on the basis of 1-(6-amino-3-pyridinyl)methanol.

1H-NMR (CDCl3) δ 10,51 (1H, Sirs), 9,26 (1H, s), at 8.60 (1H, s), 8,42 (1H, s), 7,79 (1H, d, J=8.1 Hz), 7,01 (1H, d, J=8.1 Hz), and 4.75 (2H, s).

Stage 2. (6-{[2-Amino-5-chloro-4-(trifluoromethyl)the dryer is l]amino}-3-pyridinyl}methanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, on the basis of {5-[5-chloro-2-nitro-4-(trifluoromethyl)aniline]-3-pyridinyl}methanol (stage 1).

MS (EI) m/z: 317(M+).

Stage 3. {6-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-3-pyridinyl}methylpropionate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from (6-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}-3-pyridinyl}methanol (stage 2).

MS (EI) m/z: 411 (M+).

Stage 4. {6-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-3-pyridinyl}methanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from {5-[5-chloro-2-nitro-(trifluoromethyl)aniline]-3-pyridinyl}methyl propionate (step 3).

1H-NMR (CDCl3) δ 8,67 (1H, s), 8,19 (1H, s), of 8.09 (1H, d, J=8.6 Hz), 7,79 (1H, d, J=8,4 Hz), the 7.65 (1H, s)5,54 (1H, t, J=5.6 Hz), 4,69 (2H, d, J=5.6 Hz), 2,95 (2H, q, J=7,3 Hz)of 1.27 (3H, t, J=7.2 Hz).

Stage 5. 6-Chloro-1-[5-(chloromethyl)-2-pyridinyl]-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from {5-[5-chloro-2-nitro-4-(trifluoromethyl)aniline]-3-pyridinyl}methanol (stage 4).

1H-NMR (CDCl3) δ 8,72 (1H, d, J=2.2 Hz), to 8.12 (1H, s), 8,07 (1H, DD, J=2,2, 8.1 Hz), 7,5-of 7.48 (2H, m), 4,72 (2H, s), a 3.01 (2H, q, J=7,6 Hz)of 1.39 (3H, t, J=7,6 Hz).

Stage 6. {6-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-yl]-3-pyridinyl}acetonitrile

To a solution of 6-chloro-1-[5-(chloromethyl)-2-pyridinyl]-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole (from stage 5, 550 mg, 1.5 mmol) in DMF (5 ml) and water (1 ml) was added KCN (470 g, 7.2 mmol) at room temperature and then the reaction mixture was stirred for 2 hours. The mixture was diluted with water and was extracted with a solution of ethyl acetate/toluene (4/1) (3 x 30 ml). The organic layer was washed with water, dried (MgSO4) and concentrated. This substance was purified by chromatography on a column with SiO2, elwira hexane/ethyl acetate to obtain 198 mg (37%) indicated in the title compound as an orange oil.

1H-NMR (CDCl3) δ to 8.70 (1H, d, J=2.6 Hz), 8,13 (1H, s), of 8.06 (1H, DD, J=2,6, 8.0 Hz), 7,52 (1H, d, J=8,20 Hz), 7,47 (1H, s), of 3.94 (2H, s), a 3.01 (2H, q, J=7.5 Hz), of 1.40 (3H, t, J=7.5 Hz).

Stage 7. 2-{6-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-3-pyridinyl}ethanamine

The connection specified in the header received in accordance with the method described for stage 5 of example 270, on the basis of {6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-yl]-3-pyridinyl}acetonitrile (stage 6).

MS (EI) m/z: 368 (M+).

Stage 8. 6-Chloro-2-ethyl-1-(6-{2-[({[(methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}-2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-3-pyridinyl}of ethanamine (stage 7).

1H-NMR (CDCl3) δ and 8.50 (1H, s)to 8.12 (1H, s)7,817 (1H, d, J=6.0 Hz), 7,72 (2H, d, J=8,4 Hz), 7,42 (1H, s), 7.24 to 7,37 (3H, t), 7,2 (1H, s), 6,77 1, Sirs), of 3.60 (2H, dt, J=6.2 Hz), 2,94-a 3.01 (4H, m), is 2.37 (3H, s), of 1.37 (3H, t, J=7.5 Hz).

MS (ESI) m/z: 566 [(M+H)+], 564 [(M-H)-].

Example 280

2-{4-(5-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1,1-dimethylethyl (4-were)sulfonylureas

Stage 1. 1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-methyl-2-propanol

The connection specified in the header received in accordance with the method described for stage 5 of example 266, on the basis of 1-(4-AMINOPHENYL)-2-methyl-2-propanol

1H-NMR (CDCl3) δ to 9.70 (1H, Sirs), 8,58 (1H, s), of 7.36 (2H, d, J=8,4 Hz), 7,21-of 7.25 (3H, m), and 2.83 (2H, s)of 1.28 (6H, s).

MS (EI) m/z: 388(M+).

Stage 2. 1-(4-{[2-Amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-methyl-2-propanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 1-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-methyl-2-propanol (stage 1)

1H-NMR (CDCl3) δ 7,10 (4H, s), is 6.61 (1H, s), 6,33 (2H, s), or 3.28 (1H, Sirs), 2,70 (2H, s), is 2.37 (3H, s), measuring 2.20 (3H, s)to 1.22 (6H, s).

MS (EI) 88 (M +).

Stage 3. 1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-2-methyl-2-propanol

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 1-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-2-methyl-2-propanol (stage 2).

1H-NMR (CDCl3) δ to 8.12 (1H, s)of 7.48 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), 7,22 (1H, s), 2,90 (2H, s), 2,80 (2H, q, J=7,3 Hz)of 1.36 (3H, t, J=7,3 Hz) of 1.32 (6H, s).

MS (EI) m/z: 396 (M+).

Stage 4. 2-{4-[5-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1,1-dimethylethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-2-methyl-2-propanol (stage 3).

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,94 (2H, d, J=8.7 Hz), was 7.36 (2H, d, J=8.1 Hz), 7,15-7,27 (5H, m), and 3.16 (2H, s), 2,78 (2H, q, J=7,6 Hz), 2,43 (3H, s)of 1.47 (6H, s)to 1.37 (3H, t, J=7,6 Hz).

TPL 174,6-175,3°C.

MS (ESI) m/z: 594 [(M+H)+], 592 [(M-H)-].

Example 281

2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (2,4-dimethyl-1,3-thiazol-5-yl)sulfonylurea

The connection specified in the header received in accordance with the method described for step 2 of example 243, on the basis of 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethylvinylacetate and 2,4-dimethyl,3-thiazole-5-ralfinamide.

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,41 (2H, d, J=7.9 Hz), 7,27 (2H, d, J=7.9 Hz), 7,20 (1H, s), of 4.45 (2H, t, J=6.9 Hz), is 3.08 (2H, t, J=6.6 Hz), and 2.79 (2H, q, J=7,7 Hz), 2,71 (3H, s), 2,68 (3H, s)of 1.36 (3H, t, J=7,7 Hz).

TPL 168,3-169,0°C.

MS (ESI) m/z: 587(M+H)+], 585 [(M-H)-].

Example 282

2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonylurea

The connection specified in the header received in accordance with the method described for step 2 of example 243, on the basis of 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethylvinylacetate and 5-chloro-1,3-dimethyl-1H-pyrazole-4-ralfinamide.

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,41 (2H, d, J=7.9 Hz), 7,27 (2H, d, J=7.9 Hz), 7,20 (1H, s), of 4.45 (2H, t, J=6.9 Hz), is 3.08 (2H, t, J=6.6 Hz), and 2.79 (2H, q, J=7,7 Hz), 2,71 (3H, s), 2,68 (3H, s)of 1.36 (3H, t, J=7,7 Hz).

TPL 192,0-192,7°C.

MS (ESI) m/z: 604(M+H)+], 602[(M-H)-].

Example 283

2-{4-[5-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}propyl(4-were)sulfonylureas

Stage 1. 2-(4-AMINOPHENYL) 1-propanol

To a stirred solution of ethyl ester of 2-(4-amino-phenyl)-propionic acid (5.0 g, of 25.9 mmol, Takahashi,I. et al., Heterocycles 1996, 43, 2343-2346) in tetrahydrofuran (200 ml) was slowly added alumoweld lithium (1,96 g, to 51.8 mmol) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was extinguished 25% of what astora ammonia (50 ml) while cooling in an ice bath. The precipitate was filtered, and the filtrate was concentrated under reduced pressure, to obtain 3.88 g (99%) of the compound indicated in the title, in the form of a light brown syrup.

1H-NMR (CDCl3) δ 7,03 (2H, d, J=8.5 Hz), of 6.66 (2H, d, J=8.5 Hz), 3,70 is 3.57 (4H, m), 2,90-2,78 (1H, m), 1,34-of 1.30 (1H, m)to 1.22 (3H, d, J=7,1 Hz).

MS (EI) m/z 151 (M+).

Stage 2. 2-(4-{[5-Chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-1-propanol

The connection specified in the header received in accordance with the method described for stage 5 of example 266, based on 2-(4-AMINOPHENYL)-1-propanol (stage 1).

1H-NMR (CDCl3) δ RS 9.69 (1H, Sirs), 8,58 (1H, s), 7,38 (2H, d, J=8,3 Hz), 7,21-7,26 (3H, m), of 3.77 (2H, m), 3,03 (1H, m), 1,41 (1H, t, J=5.7 Hz), of 1.33 (3H, d, J=7,1 Hz).

Stage 3. 2-(4-{[2-Amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)-1-propanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)-1-propanol (stage 2).

1H-NMR (CDCl3) δ 7,21-7,26 (3H, m), 7,07 (1H, s), 6,93 (2H, d, J=8,4 Hz), 5,41 (1H, Sirs), 3,68 at 3.69 (2H, Sirs), with 2.93 (1H, m)to 1.38 (1H, Sirs), of 1.28 (3H, d, J=7,1 Hz).

Stage 4. 2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}-1-propanol

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-(4-{[2-amino-5-chloro-4-(tripto is methyl)phenyl]amino}phenyl)-1-propanol (stage 3).

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,49 (2H, d, J=2.3 Hz), 7,30 (2H, d, J=8,4 Hz), 7,22 (1H, s), 3,83 (2H, m), 3,11 (1H, m), 2,80 (2H, q, J=7,6 Hz) of 1.57 (1H, m), 1,33-of 1.40 (6H, m).

Stage 5. 2-{4-[5-Chloro-2-ethyl-5-(trifloromethyl)-1H-benzimidazole-1-yl]phenyl}-1,1-dimethylethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]-1-propanol (stage 4).

1H-NMR (CDCl3) δ 8,11 (1H, s)7,904 (2H, d, J=8,4 Hz), 7,40 (2H, d, J=8,4 Hz), 7,34 (2H, d, J=8,4 Hz), 7,27 (1H, s), 7,24 (1H, s), 7,20 (1H, s), 4,19-4,30 (2H, m), 3,20 (1H, m), 2,78 (2H, q, J=7.5 Hz), 2,43 (3H, C)of 1.53 (3H, t, J=7,56 Hz)of 1.34 (3H, t, J=6.9 Hz).

TPL 179,9-of 180.5°C.

MS (ESI) m/z: 581(M+H)+], 579 [(M-H)-].

Example 284

2-[4-(5-Acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1,1-dimethylethyl(4-were)sulfonylureas

Stage 1. 1-(4-{[4-Hydroxy-2-methylpropyl " phenyl]amino}-3-nitrophenyl)alanon

The connection specified in the header received in accordance with the method described for stage 5 of example 266, on the basis of 1-(4-AMINOPHENYL)-2-methyl-2-propanol.

1H-NMR (CDCl3) δ 9,85 (1H, Sirs), 8,83 (1H, s), of 7.97 (1H, d, J=9.0 Hz), 7,10-7,40 (4H, m), 2,82 (2H, s), 2,58 (3H, s)of 1.28 (6H, s).

Stage 2. 1-(3-Amino-4-{[4-(2-hydroxy-2-methylpropyl " phenyl]amino}phenyl)alanon

The connection specified in the header received in accordance with the method described is for stage 2 of example 28, on the basis of 1-(4-{[4-hydroxy-2-methylpropyl " phenyl]amino}-3-nitrophenyl)ethanone (stage 1).

1H-NMR (CDCl3) δ 7,38-7,46 (2H, m), 7,16 (2H, DD, J= 8,4 Hz), of 6.96 (2H, d, J=8,4 Hz), 5,62 (2H, Sirs), 3,60 (1H, Sirs), 2,73 (2H, s)to 2.54 (3H, s)of 1.39 (1H, Sirs), 1,24 (6H, s).

Stage 3. 1-{2-Ethyl-1-[4-(2-hydroxy-2-methylpropyl " phenyl]-1H-benzimidazole-5-yl}alanon

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 1-(3-amino-4-{[4-(2-hydroxy-2-methylpropyl " phenyl]amino}phenyl)ethanone (stage 2).

1H-NMR (CDCl3) δ to 8.40 (1H, s), of 7.90 (1H, d, J=8.6 Hz), 7,46 (2H, d, J=8.1 Hz), 7,30 (2H, d, J=8.1 Hz), 7,14 (1H, d, J=8.6 Hz), 2,96 (2H, s), 2,82 (2H, q, J=7,6 Hz), 2,68 (3H, s), and 1.63 (1H, Sirs), to 1.38 (3H, t, J=7,6 Hz), 1,32 (6H, s).

Stage 4. 2-[4-(5-Acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]-1,1-dimethylethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 1-{2-ethyl-1-[4-(2-hydroxy-2-methylpropyl " phenyl]-1H-benzimidazole-5-yl}ethanone (stage 3).

1H-NMR (CDCl3) δ to 8.41 (1H, s), 7,88-of 7.95 (3H, m), 7,09-to 7.35 (7H, m), 3,14 (2H, s), 2,80 (2H, q, J=7,6 Hz), 2,68 (3H, s), is 2.40 (3H, s)of 1.45 (6H, s)to 1.38 (3H, t, J=7,6 Hz).

TPL 103,4-104,2°C.

MS (ESI) m/z:534(M+H)+], 532 [(M-H)-].

Example 285

Mono-hydrochloride, 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(5-methyl-2-pyridinyl)sulfonylamino/u>

The connection specified in the header received in accordance with the method described for step 2 of example 243, on the basis of 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethylvinylacetate.

1H-NMR (CDCl3) δ to 8.57 (1H, s), 8,15 (1H, s)to 8.12 (1H, d, J=8.0 Hz), to 7.77 (1H, d, J=7.9 Hz), 7,37 (1H, d, J=7.9 Hz), 7,17-of 7.25 (4H, m), 4,36 (2H, t, J=6,6 Hz)of 3.00 (2H, t, J=6.6 Hz), 2,77 (2H, q, J=7.5 Hz), the 2.46 (3H, s)of 1.36 (3H, t, J=7,3 Hz).

TPL 205,8°C.

MS (ESI) m/z: 567 [(M+H)+], 565 [(M-H)-].

Example 286

Monohydrochloride 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(5-methyl-2-pyridinyl)sulfonylamino

The connection specified in the header received in accordance with the method described in example 240, on the basis of 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (5-methyl-2-pyridinyl)sulfanilamide (example 285).

1H-NMR (CDCl3) δ 8,53 (1H, s), 8,49 (1H, s), 8,08 (1H, d, J=7,6 Hz), 7,78 (1H, d, J=6.8 Hz), 7,53 (2H, Sirs), 7,41 (3H, Sirs), to 4.38 (2H, t, J=5,9 Hz), 3,21 (2H, Sirs), of 3.07 (2H, t, J=5,9 Hz), 2,47 (3H, s)and 1.51 (3H, Sirs).

TPL 200,2 C.

MS (ESI) m/z: 567 [(M+N)+], 565 [(M - H)-].

Example 287

2-{5-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-3-pyridinyl}ethyl (4-were)sulfonylureas

Stage 1. Benzyl ether of 2-(6-nitro-3-pyridinyl)malonate

To a mixture of 5-bromo-2-nitropyridine (8,66 g, and 42.7 mmol) and benzilate of malonate (9,50 g, and 42.7 mmol) in t is traditionale (160 ml) and dimethylformamide (40 ml) was added To a 2CO3(5,90 g, and 42.7 mmol). The organic layer was washed with saturated saline solution, dried (MgSO4) and stirred at the boil under reflux for 20 hours the Mixture is diluted with water (1 l), extracted with ethyl acetate (3 X 200 ml) and concentrated to obtain 5,26 g specified in the title compound as an orange oil.

1H-NMR (CDCl3) δ 8,61 (1H, d, J=2.2 Hz), compared to 8.26 (1H, d, J=8,4 Hz), 8,19 (1H, DD, J=2,1, 8.6 Hz), 7,29-7,38 (5H, m), with 5.22 (2H, d, J=3.6 Hz), 4,84 (1H, s), 4,22 (2H, m)of 1.23 (3H, t, J=7,1 Hz).

Stage 2. Ethyl(6-nitro-3-pyridinyl)acetate

To a solution of benzyl ethyl 2-(6-nitro-3-pyridinyl)malonate (5,26 g of 15.3 mmol) in ethanol was added palladium on coal (530 mg) and was stirred for 6 hours in an atmosphere of hydrogen at room temperature. The catalyst was filtered through a thick layer of celite and the filtrate was concentrated to obtain specified in the title compound as a yellow-brown oil.

1H-NMR (CDCl3) δ to 7.95 (1H, d, J=l,8 Hz), 7,40 (1H, DD, J=2,4, and 8.4 Hz), 6.48 in (1H, d, J=8,4 Hz), 4,42 (2H, Sirs), 4,14 (2H, q, J=7,1 Hz), of 3.46 (2H, s)of 1.26 (3H, t, J=7,1 Hz).

Stage 3. 2-(6-Amino-3-pyridinyl)ethanol

To a solution of ethyl(6-nitro-3-pyridinyl)acetate (468 mg, 2,60 mmol) in tetrahydrofuran was added LiAlH4and was stirred for 2 hours at room temperature. The reaction extinguished 25% saturated aqueous NH3and the precipitate was removed. The filter is centered with obtaining specified in the title compound as a yellow oil.

1H-NMR (CDCl3) δ 7,73 (1H, d, J=2,8 Hz), 7.23 percent (1H, DD, J=8.6 Hz), 6,37 (1H, d, J=2,6, 8.1 Hz), 5,63 (2H, Sirs), 3,49 (2H, t, J=7,3 Hz), of 2.51 (2H, t, J=7,3 Hz).

MS (EI) m/z: 138 (M+).

Stage 4. (6-{[5-Chloro-2-nitro-4-trifluoromethyl)phenyl]amino}-3-pyridinyl}ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 2-(6-amino-3-pyridinyl)ethanol (stage 3).

1H-NMR (CDCl3) δ 8,49 (1H, s), 8,32 (1H, d, J=2.2 Hz), to 7.64 (1H, DD, J=2,4, and 8.4 Hz), was 7.36 (1H, s), 6,97 (1H, d, J=8,4 Hz), 3,91 (2H, t, J=6.5 Hz), 2,89 (2H, t, J=6.5 Hz).

MS (EI) m/z 138(M+).

Stage 5. (6-{[2-Amino-5-chloro-4-(trifluoromethyl)phenyl]amino}-3-pyridinyl)ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, on the basis of (6-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}-3-pyridinyl}ethanol (step 4).

MS (EI) m/z: 331 (M+).

Stage 6. 2-{6-[6-Chloro-2-ethyl(trifluoromethyl)-1H-benzimidazole-1-yl]-3-pyridinyl}ethylpropane

To (6-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}-3-pyridinyl)ethanol (787 mg, is 2.37 mmol, from stage 5) was added propionic acid and propionic anhydride and stirred at 120°C for 15 hours. The mixture was suppressed NaOH and was extracted with dichloromethane (3 x 30 ml). The organic layer was washed with saturated saline solution, dried (MgSO4) and concentrated to obtain 5,26 g specified in the agolove compound as an orange oil.

1H-NMR (CDCl3) δ 8,58 (1H, d, J=1.9 Hz), to 8.12 (1H, s), 7,83 (1H, DD, J=2,2, 8.1 Hz), 7,45 (1H, s), 7,39 (1H, d, J=8.1 Hz), and 4.40 (2H, t, J=6.8 Hz), of 4.12 (2H, q, J=7,3 Hz), 3,10 (2H, t, J=6.5 Hz), 2,99 (2H, q, J=7,6 Hz), 2,29 is 2.44 (2H, m)to 1.38 (3H, t, J=7,4 Hz)and 1.15 (3H, t, J=7,6 Hz).

Stage 5. 2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-3-pyridinyl}ethanol

The connection specified in the header received in accordance with the method described for stage 8 of example 266, on the basis of 2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}ethylpropylamine (stage 4).

1H-NMR (CDCl3) δ at 8.60 (1H, d, J=2.3 Hz), 8,11 (1H, s), to $ 7.91 (1H, DD, J=2.5 and 8.0 Hz), 7,45 (1H, s), 7,38 (1H, d, J=8.1 Hz), 4,01 (1H, t, J=6.2 Hz), 3.72 points-of 3.77 (2H, m), 2,94 totaling 3.04 (2H, m)to 1.38 (3H, t, J=7,4 Hz).

Stage 6. 2-{6-[6-Chloro-2-ethyl-5-(trifluoromethyl-1H-benzimidazole-1-yl]-3-pyridinyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-2-pyridinyl}ethanol (stage 5).

1H-NMR (CDCl3) δ with 8.33 (1H, d, J=1.9 Hz), 8,08 (1H, s), to $ 7.91 (2H, d, J=8,4 Hz), of 7.70 (1H, DD, J=2,4, 8.1 Hz), 7,29-7,42 (4H, m), 7,2O(1H, s), 4,39 (2H, t, J=6.2 Hz), of 3.00 (2H, t, J=6.2 Hz), with 2.93 (2H, t, J=a 7.6 Hz), 2,43 (3H, s)of 1.32 (3H, t, J=7,4 Hz).

MS (ESI) m/z: 567 [(M+H)+], 565 [(M-H)-].

Example 288

Monohydrochloride 2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-3-pyridinyl}ethyl(4-methylphe the Il)sulfonylamino

Stage 1

The connection specified in the header received in accordance with the method described in example 240, on the basis of 2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]-3-pyridinyl}ethyl(4-were)sulfanilamide (example 287).

1H-NMR (CDCl3) δ to 8.40 (1H, Sirs), 8,49 (1H, Sirs), to 8.12 (1H, Sirs), 7,82 (2H, Sirs), the 7.65 (1H, Sirs), 7,25-7,28 (2H, m), and 4.40 (2H,Sirs), the 3.35 (1H, s), of 3.12 (2H, Sirs), is 2.41 (3H, s), 2,43 (3H, s)of 1.53 (3H, Sirs).

MS (ESI) m/z: 567 [(M+H)+], 565 [(M-H)-].

Example 289

2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-5-ethanallanfurniture

The connection specified in the header received in accordance with the method described for step 2 of example 243, on the basis of 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-phenylcarbamate and 5-ethanolamide.

1H-NMR (CDCl3) δ 9,39 (1H, s), to 8.70 (2H, t, J=6.3 Hz), 8,43 (1H, d, J=6.2 Hz), 8,29 (1H, d, J=8.1 Hz), to 8.12 (1H, s), 7,78 (1H, t, J=7,6 Hz), 7,16-7,33 (5H, m), 4,32 (2H, t, J=6.9 Hz), of 2.97 (2H, t, J=6.8 Hz), 2,77 (2H, q, J=7.4 Hz), 1,346 (3H, t, J=7,4 Hz).

MS (ESI) m/z: 603(M+H)+], 601 [(M-H)-].

Example 290

2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-5-chinainternational

The connection specified in the header received in accordance with the method described for step 2 of example 243, on the basis of 4-(6-chloro-2-ethyl-5-trifluoromethyl-1-Ben is imidazol-1-yl)phenethyl-(4-were)sulfonylamino and 5-hinolincarbonova.

1H-NMR (CDCl3) δ 8,43 (1H, d, J=8.6 Hz), 8,20 is 8.25 (2H, m), 8,13 (1H, s)to 8.12 (1H, s,), 7,81-to $ 7.91 (2H, m), 7.68 per-7,72 (1H, m), 7,30-7,34 (2H, m), 7,12-7,16 (3H, m), 4,37 (2H, t, J=6.6 Hz), 2,98 (2H, t, J=6.3 Hz)that is 2.74 (2H, q, J=7.4 Hz), of 1.35 (3H, t, J=7,4 Hz).

MS (ESI) m/z: 567 [(M+H)+], 565 [(M-H)-].

Example 291

2-{4-[6-Chloro-2-ethyl-5-(trifloromethyl-1H-benzimidazole-1-yl]phenyl}ethyl-[5-(dimethylamino)-1-naphthenyl]sulfonylurea

The connection specified in the header received in accordance with the method described for step 2 of example 243, on the basis of 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-phenylcarbamate and 5-(dimethylamino)-1-natinalfred.

1H-NMR (CDCl3) δ 8,61 (1H, d, J=8,4 Hz), 8,46 (1H, DD, J=1,2, 7.5 Hz), to 8.12 (1H, s), 87,58 (2H, t, J=8,3 Hz), 7,12-7,24 (6H, m), 4,30 (2H, t, J=6.8 Hz), with 2.93 (2H, t, J=6.8 Hz), a 2.75 (2H, q, J=7.5 Hz), of 1.35 (3H, t, J=7.5 Hz).

TPL 203,4°C.

MS (ESI) m/z 645(M+H)+], 643 [(M-H)-].

Example 292

2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-(1-methyl-1H-imidazol-4-yl)sulfonylurea

The connection specified in the header received in accordance with the method described for step 2 of example 243, on the basis of 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-phenylcarbamate and 1-methyl-1H-imidazol-4-ralfinamide.

1H-NMR (CDCl3) δ 8,13 (1H, s), 7,72 (1H, d, J=1.5 Hz), 7,55 (1H, d, J=1.3 Hz), 7,41 (2H, d, J=8,2 Hz), 7,26 (2H, d, J=8,2 G is), then 7.20 (1H, s), to 4.38 (2H, t, J=6.6 Hz), of 3.78 (3H, s), 3.04 from (2H, d, J=6,8 Hz), and 2.79 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

TPL 204,3°C.

MS (ESI) m/z: 556 [(M+H)+], 554 [(M-H)-].

Example 293

Monohydrochloride 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-(1-methyl-1H-imidazol-4-yl)sulfonylamino

The connection specified in the header received in accordance with the method described in example 240, on the basis of 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-(1-methyl-1H-imidazol-4-yl)sulfonylamino (example 292).

MS (ESI) m/z: 556 [(M+H)+], 554 [(M-H)-].

Example 294

2-{4-[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-(1,2-dimethyl-1H-imidazol-4-yl)sulfonylurea

The connection specified in the header received in accordance with the method described for step 2 of example 243, on the basis of 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-phenylcarbamate and 1,2-dimethyl-1H-imidazol-4-ralfinamide.

1H-NMR (CDCl3) δ to 8.12 (1H, s), 7,63 (1H, s), 7,41 (2H, d, J=8,2 Hz), 7,25 (2H, d, J=8,2 Hz), 7,19 (1H, s), 4,37 (2H, t, J=6.8 Hz), to 3.64 (3H, s), 3.04 from (2H, d, J=6.6 Hz), and 2.79 (2H, q, J=7,6 Hz), 2,42 (3H, s), of 1.36 (3H, t, J=7,6 Hz).

TPL 221,2°C.

MS (ESI)m/z: 570(M+H)+], 568 [(M-H)-].

Example 295

The dihydrochloride of 2-{[6-Chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-(1,2-dimethyl-1H-imidazol-4-yl)Sul is phenylcarbamate

The connection specified in the header received in accordance with the method described in example 240, on the basis of 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-(1,2-dimethyl-1H-l-4-yl)sulfonylamino (example 294).

MS (ESI) m/z: 570(M+H)+], 568 [(M-H)-].

Example 296

2-{4-[5,7-Dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl-]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[5,7-Dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 236, on the basis of 4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenylethanol.

1H-NMR (DMSO-d6) δ 13,15 (1H, Sirs), to 7.77 (3H, s), 7,35 (2H, d, J=7,7 Hz), 7,25 (2H, d, J=7,7 Hz), 7,02 (1H, s), 6,53 (1H, s), and 4.75 (2H, t, J=4,8 Hz), 3,71 (2H, q, J=6.8 Hz), of 2.81 (1H, t, J=6.6 Hz), 2,58 (3H, s), to 2.42 (3H, s).

Stage 2. 2-{4-[5,7-Dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-3-]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[5,7-dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethanol (step 1).

1H-NMR (DMSO-d6) δ 13,14 (1H, Sirs), 7,69 for 7.78 (3H, m), 7,21-the 7.43 (6H, m), 7,02 (1H, s), of 6.52 (1H, s), 4,18 (2H, t, J=6.4 Hz), 2,89 (2H, t, J=6.4 Hz), 2,58 (2H, s)to 2.41 (3H, s), 2,32 (3H, s).

MS (ESI) m/z: 531(M+H)+], 529 [(M-H)-]./p>

Example 297

Sodium salt of 2-{4-[5,7-dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl-]phenyl}ethyl(4-were)sulfonylamino

Stage 1. 2-{4-[5,7-dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described in example 2 from 2-{4-[5,7-dimethyl-2-(1H-pyrazole-3-yl)3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl(4-were)sulfanilamide (example 296).

1H-NMR (CDCl3) δ 9,85 (1H, s)of 8.37 (1H, d, J=8,4 Hz), 7,31 (1H, d, J=2.0 Hz), 7,14 (1H, DD, J=2.0 a, 8,3 Hz), 6,60 (1H, s), a 3.87 (2H, dt, J=6,2,6,4 Hz), 2,84 (2H, t, J=6.4 Hz), of 2.56 (3H, s)to 2.46 (3H, s), 1,40 (1H, t, J=6.2 Hz).

MS (ESI) m/z: 531 (MH+), 529 ([M-H]-).

Example 298

N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5 - B]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. 3-[4-(2-chloroethyl)phenyl]5,7-dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-{4-[5,7-dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethanol (example 297, stage 1).

1H-NMR (CDCl3) δ 13,15 (1H, s), to 7.77 (2H, Sirs), the 7.43 (2H, Sirs), 7,20 (2H, Sirs),? 7.04 baby mortality (1H, s), is 6.54 (1H, Sirs), of 3.96 (2H, t, J=6,8 Hz)and 3.15 (2H, TM, J=6,8 Hz), 2,60 (3H, s), is 2.30 (3H, s).

Stage 2. 3-[4-(2-Azidoethyl)phenyl]-5,7-dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine (stage 1).

1H-NMR (DMSO-d6) δ 13,15 (1H, Sirs), 9,85 (1H, Sirs), 7,76 (1H, Sirs), 7,41 (2H, d, J=8.1 Hz), 7,31 (2H, d, J=8.1 Hz),? 7.04 baby mortality (1H, s), 6,53 (1H, s), of 3.69 (2H, t, J=6.6 Hz), 2,95 (2H, t, J=6.8 Hz), 2,58 (3H, s), 2,42 (3H, ).

MS (EI) m/z: 358 (M+).

Stage 3. 2-{4-[5,7-Dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethanamine

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 3-[4-(2-azidoethyl)phenyl]-5,7-dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine (stage 2).

1H-NMR (DMSO-d6) δ 9,83 (1H, Sirs), to 7.68 (2H, Sirs), 7.23 percent-the 7.43 (5H, m),? 7.04 baby mortality (1H, s), of 5.75 (1H, s), 2,68-2,90 (4H, m), 2,59 (3H, s), 2,42 (3H, s).

MS (EI) m/z: 332 (M+).

Stage 4. N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-{4-[5,7-dimethyl-2-(1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}of ethanamine (stage 3).

1H-NMR (CD3OD) δ 7,80 (2H, d, J=8,2 Hz), 7,58 (1H, Sirs), 7,20-to 7.35 (6H, m), was 7.08 (1H, s), of 6.20 (1H, Sirs), 3,42 (2H, t, J=6.8 Hz), 2,84 (2H, t, J=6.9 Hz), 2,68 (2H, s)of 2.50 (3H, s), of 2.34 (3H, s).

MS (ESI) m/z: 530 (MH+), 28 ([M-H] -).

Example 299

2-[4-(5-Cyano-2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfonylureas

Stage 1. 4-Chloro-2-methyl-5-nitrobenzonitrile

To a solution of 4-chloro-2-methyl-5-nitrobenzonitrile (10 g, 66 mmol) in conc. H2SO4added KNO3(7.0 g, or 69.3 mmol) at 0°C in small portions and then the reaction mixture was stirred over night at room temperature. Then the substance was poured on ice and was extracted with AcOEt. The combined extracts were washed a feast upon. aqueous NaHCO3, dried over MgSO4and concentrated. The obtained precipitates were collected by filtration, washed with ether and dried under reduced pressure to obtain 5.5 g (42%) specified in the connection header.

1H-NMR (CDCl3) δ 8,19 (1H, s), EUR 7.57 (1H, s)of 2.64 (3H, s).

Stage 2. 4-{[4-(2-Hydroxyethyl)phenyl]amino}-2-methyl-5-nitrobenzonitrile

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 3-bromo-6-chloro-2,4-dimethyl-5-nitropyridine (stage 2).

1H-NMR (CDCl3) δ 9,76 (1H, Sirs), 8,51 (1H, s), of 7.36 (1H, d, J=8,4 Hz), 7,22 (1H, d, J=8,3 Hz), of 6.96 (1H, s), of 3.94 (2H, DD, J=11,7, 6.2 Hz), to 2.94 (2H, t, J=6.4 Hz), 2,42 (3H, s).

Stage 3. 5-Amino-4-{[4-(2-hydroxyethyl)phenyl]amino}-2-methylbenzonitrile

The connection specified in the header received in accordance with the method, sunnym for stage 4 of example 1, on the basis of 2-{4-[(5-bromo-4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 3).

1H-NMR (CDCl3) δ 7,19 (1H, d, J=8,4 Hz), 6,94-to 7.00 (4H, m), 5,59 (1H, Sirs), 3,84-are 3.90 (2H, m), 3,50 (2H, Sirs), 2,85 (2H, t, J=6.4 Hz), is 2.37 (3H, s).

Stage 5. 2-[4-(5-Cyano-2-ethyl-6-methyl-1H-benzimidazo-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(3-amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4).

MS (EI) m/z: 361 (M+).

Stage 6. 2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-6-methyl-1H-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(6-bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl-2-methylpropanoate (stage 5).

1H-NMR (CDCl3) δ 8,00 (1H, s)to 7.50 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 6,98(1H, s)to 4.01 (2H, t, J=6.4 Hz), 3,03 (2H, t, J=6.6 Hz), and 2.79 (2H, q, J=7.5 Hz), of 2.56 (3H, s)of 1.35 (3H, t, J=7.5 Hz).

Stage 7. 2-[4-(5-cyano-2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-6-methyl-1H-benzimidazole-5-carbonitrile (stage 6).

1H-NMR (CDCl3) δ 8,03 (1H, s), 7,92 (2H, d, J=8,4 Hz), 7,39 (2H, d, J=8,4 Hz), to 7.35 (2H, d, J=8.1 Hz), 7,26 (2H, d, J=8.1 Hz), of 6.96 (1H, s), 4,39 (2H, t, J=6.8 Hz), totaling 3.04 (2H, t, J=6.6 Hz), 2,77 (2H, q, J=7,7 Hz), to 2.57 (3H, s), is 2.44 (3H, s)of 1.35 (3H, t, J=7.5 Hz).

Example 300

N-[({2-[4-(5-Cyano-2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethyl}amino)carbonyl](4-methylbenzenesulfonamide

Stage 1. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(6-bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethanol (step 6).

1H-NMR (CDCl3) δ 8,02 (1H, s)of 7.48 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), of 6.96-6,98 (1H, m), 3,83 (2H, t, J=7,1 Hz), 3,21 (2H, t, J=7.0 Hz), 2,78 (2H, q, J=7.5 Hz), 2,58 (3H, s)of 1.35 (3H, t, J=7.5 Hz).

Stage 2. 1-[4-(2-Azidoethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-bromo-3-[4-(2-chloroethyl)phenyl]-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (stage 7).

MS (EI) m/z: 412 (M+).

1H-NMR (CDCl3) δ 8,02 (1H, s)of 7.48 (2H, d, J=8.0 Hz), 7,30 (2H, d, J=8,2 Hz), to 6.95 (1H, s), 3,63 (2H, t, J=6.8 Hz), 3,03 (2H, t, J=7.0 Hz), 2,78 (2H, q, J 7.5 Hz), to 2.57 (3H, s)of 1.35(3H,t,J=7,3 Hz).

Stage 3. 1-[4-(2-amino-ethyl)phenyl]-2-ethyl-6-methyl-1H-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described on the I stage 9 of example 1, on the basis of 2-[4-(6-bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]utilised (stage 8).

1H-NMR (CDCl3) δ 7,49 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), 6,93 (1H, s), 6,60 (2H, Sirs), 3,32 is 3.00 (5H, m), 2,65 (3H, s), 2,48 (3H, s)is 1.31 (6H, d, J=6,8 Hz).

Stage 4. N-[({2-[4-(5-cyano-2-ethyl-6-methyl-1H-benzimidazole-1-yl)phenyl]ethyl}amino)carbonyl](4-methyl)benzosulfimide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from [4-(2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethylamine (step 9).

1H-NMR (CDCl3) δ 8,00 (1H, s), 7,72 (2H, d, J=8,4 Hz), 7,42 (2H, d, J=8,4 Hz), 7,28-to 7.32 (4H, m), to 6.95(1H, m), 3,56-3,63 (2H, m), 2,96 (2H, t, J=7,1 Hz), 2,78 (2H, q, J=7,7 Hz)to 2.54 (3H, s)to 2.41 (3H, s), 1,34 (3H, t, J=7.5 Hz).

Example 301

Di-hydrochloride 2-amino-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

Stage 1. 2-Amino-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl-3H-imidazo[4,5-b]pyridine

To a stirred solution of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (300 mg, 0.66 mmol) in THF (6 ml) solution was added Enrichment (175 mg, of 1.65 mmol) in water (2 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2and washed with saturated salt rastv the rum. The organic layer was dried over MgSO4and filtered. After concentration in vacuo the residue was purified using preparative TLC (CH2Cl2/MeOH = 10/1), to obtain 224 mg (71%) of the connection specified in the header.

1H-NMR (DMSO-d6) δ was 10.82 (1H, s), 8,54 (2H, s), 7,79 (2H, d, J=8,3 Hz), 7,51-7,40 (6H, m), 7,06 (1H, s)6,91 (1H, t, J=5.5 Hz), 3,29-3,24 (2H, m), 2,80 was 2.76 (2H, m), 2,48 (3H, s), of 2.38 (3H, s), a 2.36 (3H, s).

MS (ESI) m/z: 479 ([M+H]+), 477 ([M-H]-).

Stage 2. Di-hydrochloride 2-amino-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described in example 240, based on 2-amino-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine.

MS (ESI) m/z: 479 ([M+H]+), 477([M-H]-).

Example 302

5,7-Dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine

A mixture of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (110 mg, 0.24 mmol), di-2-pyridylketone (68 mg, 0.29 mmol) and THF (5 ml) was stirred at room temperature for 3 days. The mixture was diluted with CH2Cl2and washed with 0,1M HCl and saturated salt solution. The organic fraction was dried over MgSO4and filtered. R is storytell removed to obtain N-[({2-[4-[(5,7-dimethyl-2-effect-free remedy 3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl}-4-methylbenzenesulfonamide [MS (ESI) m/z: 496 ([M+H] +), 494 ([M-H]-)]. This substance was dissolved THF (2 ml), then 1M NaOMe in MeOH (0,49 ml) and MeI (45 μl, 0.73 mmol) was added to the mixture at room temperature. After 1 hour the mixture was evaporated in vacuum and the residue was purified using preparative TLC (CH2Cl2/MeOH = 10/1), to obtain 31 mg (25%) of the compounds listed in the header.

1H-NMR (CDCl3) δ 7,86 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8.1 Hz), 7,22-7,16 (4H, m), to 6.88 (1H, s), of 6.02 (1H, t, J=5.6 Hz), 3,51 is-3.45 (2H, m), and 2.83 (2H, t, J=6.2 Hz), to 2.67 (3H, s), 2,62 (3H, s), 2,42 (3H, s), 2,417 (3H, s).

MS (ESI) m/z: 510 ([M+H]+), 508 ([M-H]-).

Example 303

5,7-Dimethyl-2-(methylamino)-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

A mixture of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (300 mg, 0.66 mmol), methylisothiocyanate (56 μl, 0.86 mmol) and THF (6 ml) was stirred at room temperature for 3 days. The solvent was removed to obtain N-{[(2-{4-[(4,6-dimethyl-{[(methylamino)carbonothioyl]amino}-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide [MS (ESm/z: 527 ([M+H]+), 525 ([M-H]-)]. This substance was dissolved MeCN (4 ml) and was treated with MeI (54 μl) at 0°C for 20 hours. After concentration under reduced pressure the residue was purified using preparative TLC (EtOAc/EtOH = 20/1), to obtain 170 mg (52%) of the compounds specified in the header is.

1H-NMR (CD3OD) δ 7,72 (2H, d, J=8,3 Hz), 7,24 (4H, d, J=7.9 Hz), to 7.15 (2H, d, J=8,4 Hz), 6,70 (1H, s), or 3.28 (2H, t, J=7.0 Hz), 2,90 (3H, s), of 2.72 (2H, t, J=7,0 Hz)to 2.41 (3H, s), and 2.26 (3H, s), 2,24 (3H, s).

MS (ESI) m/z: 493 ([M+H]+), 491 ([M-H]-).

Example 304

Mono-hydrochloride 5,7-dimethyl-2-(methylamino)-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

The connection specified in the header received in accordance with the method described in example 240, on the basis of the hydrochloride 5,7-dimethyl-2-(methylamino)-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine.

MS (ESI) m/z: 493 ([M+H]+, 491 ([M-H]-.

Example 305

N-[5,7-Dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine-2-yl]ndimethylacetamide

2-Amino-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (73 mg) was treated with pyridine (1 ml) and Ac2O (0.2 ml) at room temperature for 3 hours. After evaporation in vacuo the residue was purified using preparative TLC (hexane/acetone = 1/1), to obtain 4 mg (5%) of the compounds listed in the header.

1H-NMR (CDCl3) δ 7,79 (2H, d, J=8,4 Hz), 7,34-7,22 (7H, m),? 7.04 baby mortality (1H, s), 6,30 (1H, Sirs), 3,51-of 3.48 (2H, m), 2,87-and 2.83 (2H, m)to 2.66 (3H, s), of 2.53 (3H, s), 2,42 (3H, s), and 2.26 (3H, s).

MS (ESI) m/z: 521 ([M+H]+), 519 ([M-H]-).

Example 306

5,7-dime the Il-2-(dimethylamino)-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of 2-amino-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (70 mg) in THF (1 ml) was added NaH (21 mg, 0.88 mmol) at room temperature. After 10 minutes, to the mixture was added MeI (27 μl) and stirred at room temperature for 2 days. The mixture was poured into ice water and was extracted with CH2Cl2and the organic fraction was dried over MgSO4, then filtered. After removal of the solvent by evaporation, the residue was purified using preparative TLC (CH2Cl2/MeOH =10/1), to obtain 27 mg (36%) of the compounds listed in the header.

1H-NMR (CDCl3) δ 7,86 (2H, d, J=8,4 Hz), 7,32-7,24 (4H, m), 7,16 (2H, d, J=8,4 Hz), 6,77 (1H, s), 6,04 (1H, t, J=5.7 Hz), 3,50-3,44 (2H, m), 2,78 (2H, t, J=6.3 Hz), 2,71 (6H, s)to 2.55 (3H, s)to 2.41 (3H, s), 2,34 (3H, s).

MS (ESI) m/z: 507 ([M+H]+), 505 ([M-H]-).

Example 307

2-[4-(2-Amino-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl (4-were)sulfonylureas

Stage 1. 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol.

1H-NMR (CDCl3) δ of 9.55 (1H, s), 7,89 (2H, d, J=8,3 Hz), 7,54 (2H, d, J=8.6 Hz), 7,32 (2H, d, J=8.6 Hz), 7,11 (2H, d, J=8,4 Hz), is 6.54 (1H, s), 4,28 (2H, t, J=7.0 Hz), is 2.88(2H, t, J=7.0 Hz), to 2.55 (3H, s), 2,43 (6H, s).

MS (ESI) m/z: 485 ([M+H]+), 483 ([M-H]-)

Stage 2. 2-{4-[(3-Amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethyl(4-were)sulfonylamino.

1H-NMR (CDCl3) δ of 7.82 (2H, d, J=8,3 Hz), 7,25 (2H, d, J=8,3 Hz), 6,93 (2H, d, J=8,4 Hz), at 6.84 (2H, d, J=8,4 Hz), of 6.66 (1H, s), 4,22 (2H, t, J=6.6 Hz), 2,77 (2H, t, J=6.6 Hz), 2,39 (3H, s), is 2.37 (3H, s), 2,22 (3H, s).

MS (ESI) m/z: 455 ([M+H]+), 453 ([M-H]-).

Stage 3. 2-[4-(2-Amino-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl)phenyl]ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 127, on the basis of 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl(4-were)sulfonylamino.

1H-NMR (DMSO-d6) δ 7,76 (2H, d, J=8,3 Hz), 7,42-to 7.35 (6H, m), 6,78 (1H, s), is 6.61 (1H, Sirs), 4,22 (2H, t, J=6.6 Hz), 2,92 (2H, d, J=6.6 Hz), 2,373 (3H, s)2,365 (3H, s), 2,32 (3H, s).

MS (ESI) m/z: 480 ([M+H]+) 478 ([M-H]-).

Example 308

2-{4-[5,7-Dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 129, on the basis of 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)and the eno]phenyl}ethyl(4-were)sulfonylamino.

1H-NMR (DMSO-d6) δ for 7.78 (2H, d, J=8.1 Hz), 7,43-7,33 (7H, m), 6,77 (1H, s), to 6.43 (1H, Sirs), 4,25 (2H, t, J=6.6 Hz), with 2.93 (2H, t, J=6.6 Hz), is 2.88 (3H, s)to 2.41 (3H, s), is 2.37 (3H,s), 2,31 (3H, s).

MS (ESI) m/z: 494 ([M+H]+), 492 ([M-H]-).

Example 309

2-{4-[5,7-Dimethyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 128, on the basis of 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl(4-were)sulfonylamino.

1H-NMR (CDCl3) δ a 7.92 (2H, d, J=8,4 Hz), of 7.36-7,22 (6H, m), to 6.88 (1H, s), 4,32 (2H, t, J=6.6 Hz), with 2.93 (2H, t, J=6.6 Hz), of 2.72 (3H, s), 2,62 (3H, s), 2,48 (3H, s)to 2.41 (3H, s).

MS (ESI) m/z: 511 ([M+H]+), 509 ([M-H]-).

Example 310

2-{4-[5,7-Dimethyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl(4-were)sulfonylureas

To a stirred solution of 2-{4-[5,7-dimethyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine-3-yl]phenyl}ethyl(4-were)sulfanilamide (100 mg, 0.20 mmol) in AcOH (1 ml) was added a solution of KMnO4(62 mg, 0,39 mmol) in water (2 ml) at room temperature. After 1 hour the mixture was poured into ice-cold saturated aqueous solution of NaHCO3and was extracted with CH2Cl2. The organic layer was dried over MgSO4and filtered. After concentration in vacuo the residue was purified using preparative TLC CH2Cl2/MeOH = 10/1 to obtain 70 mg (66%) of compounds specified in the header.

1H-NMR (CDCl3) δ to $ 7.91 (2H, d, J=8,4 Hz), 7,47 (2H, d, J=8,2 Hz), 7,34-7,26 (4H, m), was 7.08 (1H, s), 4,35 (2H, t, J=6,7 Hz), of 3.45 (3H,s), 2,96 (2H, t, J=6,7 Hz), 2,68 (3H, in), 2,55 (ZN, C), 2,42 (3H, s).

MS (ESI) m/z: 543 ([M+H]+), 541 ([M-H]-).

Example 311

5-Acetyl-2-(methylamino)-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 129, on the basis of N-{[(2-{4-[(4-acetyl-2-AMINOPHENYL)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide.

1H-NMR (CDCl3) δ of 8.06 (1H, s), 7,75-7,66 (3H, m), 7,38-7,26 (6H, m), 6.89 in (1H, d, J=8,3 Hz), 6,60 (1H, Sirs), 3,55 (2H, DD, J=12,5 and 6.6 Hz), is 3.08 (3H, s), only 2.91 (2H, t, J=6.6 Hz), 2,61 (3H, s), of 2.38 (3H, s).

MS (ESI)m/z: 506 ([M+H]+), 504 ([M-H]-).

Example 312

2-{4-[6-Chloro-2-(3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[6-Chloro-2-(3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described in example 138, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol.

1H-NMR (CDCl3) δ to 8.70 (1H, DD, J=2.2 and 0.7 Hz), to 8.62 (1H, DD, J=4.5 and 1.7 Hz), 8,23 (1H, s), 8,01-of 7.97 (1H, m), 7,45 (2H, DD, J=6.5 and 2.2 Hz), 7,37-7,24 (7H, m), of 3.97 (2H, t, J=6.6 Hz), 2,99 (2H, t, 3=6,6 Hz).

MS (ESI) m/z: 418 ([M+H]+), 476 ([+CF 3CO2]).

Stage 2. 2-{4-[6-chloro-2-(3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[6-chloro-2-(3-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl)phenyl}ethanol.

1H-NMR (CDCl3) δ 8,73 (1H, DD, J=4.9 and 1.8 Hz), 8,40-at 8.36 (1H, m), 8,23 (1H, s), to $ 7.91 (1H, DD, J=2.2 and 0.7 Hz), 7,84-7,80 (2H, m), 7,49-the 7.43 (2H, m), 7,31-7,17 (6H, m), of 4.44 (2H, t, J=6.2 Hz), to 3.02 (2H, t, J=6.2 Hz), to 2.41 (3H, s).

MS (ESI) m/z: 615 ([M+H]+), 613 ([M-H]-).

Example 313

2-{4-[6-Chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[6-Chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described in example 138, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol.

1H-NMR (CDCl3) δ at 8.60 (2H, DD, J=4.6 and 1.7 Hz), of 8.25 (1H, s), 7,49-7,44 (4H, m), 7,37 (1H, s), 7,27-of 7.23 (2H, m)4,00 (2H, t, J=6.4 Hz), to 3.02 (2H, t, J=6.4 Hz).

MS (ESI) m/z: 418 ([M+H]+), 476 ([M+CF3CO2]-).

Stage 2. 2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described is applied in example 3, on the basis of 2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol.

1H-NMR (CDCl3) δ at 8.60 (2H, DD, J=4.8 and 1.5 Hz), of 8.27 (1H, s), 7,89 (2H, d, J=8,3 Hz), 7,44-to 7.18 (9H, m), 4,39 (2H, t, J=6.4 Hz), 3,03 (2H, t, J=6.4 Hz), is 2.40 (3H, s).

MS (ESI) m/z: 615 ([M+H]+), 613 ([M-H]-).

Example 314

2-{4-[6-Chloro-2-(2-were)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[6-Chloro-2-(2-were)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described in example 138, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol.

1H-NMR (CDCl3) δ by 8.22 (1H, s), 7,47 (1H, s), 7,33-7,10 (8H, m)to 3.89 (2H, t, J=6.4 Hz), 2,89 (2H, t, J=6.4 Hz), measuring 2.20 (3H, s).

MS (ESI) m/z: 431 ([M+H]+).

Stage 2. 2-{4-[6-Chloro-2-(2-were)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[6-chloro-2-(2-were)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol.

1H-NMR (CDCl3) δ 8,24 (1H, s), 7,78 (2H, d, J=8,2 Hz), 7,46 (1H, s), 7,35-to 7.09 (8H, m), 7,00 (2H, d, J=8,4 Hz), 4,27 (2H, t, J=6.8 Hz), is 2.88 (2H, t, J=6.8 Hz), is 2.41 (3H, s), 2,11 (3H,s).

MS (ESI) m/z: 628([M+H]+), 489 ([M+CH3CO2]-).

Example 315

2{4-[6-Chloro-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1 H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[6-chloro-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described in example 138, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol.

1H-NMR (CDCl3) δ 8,23 (1H, s), of 7.75 (1H, d, J=3.1 Hz), 7,47 was 7.45 (3H, m), of 7.36-7,27 (3H, m)to 3.99 (2H, t, J=6.4 Hz), 3,03 (2H, t, J=6.4 Hz).

MS (ESI) m/z: 424 ([M+H]+), 482 ([M+CH3CO2]-).

Stage 2. 2-{4-[6-Chloro-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[6-chloro-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol.

1H-NMR (CDCl3) δ 8,23 (1H, s), to $ 7.91 (2H, d, J=8,4 Hz), 7,74 (1H, d, J=3.1 Hz), 7,46 (1H, d, J=3.1 Hz), 7,38-7,26 (7H, m), and 4.40 (2H, t, J=6.8 Hz), totaling 3.04 (2H, t, J=6.8 Hz), 2,42 (3H, s).

MS (ESI) m/z: 621 ([M+H]+), 619 ([M-H]-).

Example 316

2-{4-[6-Chloro-2-(1H-imidazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[6-chloro-2-(1H-imidazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described in example 138 from 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol.

1H-NMR (CDCl3/CD3OD=4/1) δ of 8.09 (1H, s), the 7.65 (1H, s)to 7.50 (2H, d, J=8.7 Hz), 7,33 (2H, d, J=8,2 Hz), 7,25 (1H, s)6,91 (1H, s), 3,93 (2H, t, J=6,4 Hz)of 3.00 (2H, t, J=6.4 Hz).

MS (ESI)m/z: 407 ([M+H]+), 405 ([M-H-]).

Stage 2. 2-4-[6-Chloro-2-(1H-imidazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[6-chloro-2-(1H-imidazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol.

MS (ESI) m/z: 604([M+H]+), 602 ([M-H]-).

Example 317

2-[4-(5,6-Dimethyl-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfonylureas

Stage 1. 4-(2-hydroxyethyl)phenylboronic acid

To a stirred solution of 4-bromophenethylamine alcohol (5,00 g, 24,9 mmol) in THF (80 ml) was added a solution of 1,5M n-BuLi in hexane (39,8 ml, 59,7 mmol) at -78°C for 30 minutes. After 1 hour, a solution of B(OiPr)3 (8,61 ml of 37.3 mmol) in THF (20 ml) was slowly added to the mixture at -78°C. the resulting mixture was heated to room temperature and was treated with 2M HCl (100 ml) for 1 hour. This substance was extracted with CH2Cl2and was dried over MgSO4, then filtered. After evaporation in vacuo the residue was purified by chromatography on a column of silica gel, elwira CH2Cl2/MeOH=20/1, obtaining 2,61 g (63%) of the connection specified in the head.

1H-NMR (CD3OD) δ to 7.64-of 7.48 (2H, m), 7,19-7,13 (2H, m), 3,70 (2H, t, J=7.2 Hz), 2,77 (2H, t, J=7.2 Hz).

MS (ESI) m/z: 165 ([M-H]-).

Stage 2. 4-{2-[({[(4-Methylphenylsulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid

4-(2-Hydroxyethyl)phenylboronic acid (1,00 g of 6.02 mmol) was treated pTsNCO (1,01 ml, 6,63 mmol) and pyridine (90 ml) at room temperature for 2 hours. The mixture was poured into ice-cold 2M HCl and was extracted with EtOAc. The organic layer was dried over MgSO4and filtered. After removal of solvent the residue was purified by chromatography on a column of silica gel, elwira CH2Cl2/MeOH = 20/1, to obtain 2.20 g (amounts.) the connection specified in the header.

1H-NMR (DMSO-d6) δ 11,95 (1H, Sirs), of 7.97 (1H, s), 7,75-to 7.67 (2H, m), 7,40 (2H, d, J=8.6 Hz), 7,13 (2H, d, J=7,7 Hz), 4,18 (2H, t, J=6.6 Hz), of 2.81 (2H, t, J=6.6 Hz), is 2.40 (3H, s).

MS (ESI) m/z: 381 ([M+NH4]+), 362 ([M-H]-).

Stage 3. 2-[4-(5,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfonylureas

A mixture of 4-{2-[({[(4-were)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid (100 mg, 0.28 mmol), 5,6-dimethylbenzimidazole (40 mg, 0.28 mmol), Cu(OAc)2(60 mg, 0.33 mmol), triethylamine (115 μl, 0.83 mmol), MS4A (100 mg) and CH2Cl2(4 ml) was stirred at room temperature for 1 week. After filtration through a layer of celite the filtrate was diluted with CH2Cl2and so mawali water. The organic fraction was dried over MgSO4and filtered. After concentration under reduced pressure the residue was purified using preparative TLC (CH2Cl2/MeOH = 10/1), to obtain 28 mg (22%) of the connection specified in the header.

1H-NMR (CDCl3) δ of 7.82 (2H, d, J=8,4 Hz), 7,72 (1H, s), EUR 7.57 (1H, s), 7,33 (2H, d, J=8.1 Hz), 7,12 (2H, d, J=8,4 Hz), 7,07 (1H, s), 7,01 (2H, d, J=8,4 Hz), 4,39 (2H, t, J=6,1 Hz)to 2.94 (2H, t, J=6,1 Hz), 2,42 (3H, s), 2,39 (3H, s), and 2.26 (3H, s).

MS (ESI) m/z: 464 ([M+H]+), 462 ([M-H]-).

Example 318

6-Chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile (example 111, step 4).

1H-NMR (CDCl3) δ 8,07 (1H, s)to 7.50 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), 7,19 (1H, s), 3,83 (2H, t, J=7,1 Hz), up 3.22 (2H, t, J=7,1 Hz), and 2.79 (2H, q, J=7.5 Hz), of 1.37 (3H, t, J=7.5 Hz).

Stage 2. 1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carbonitrile (stage 1).

1H-NMR (CDCl3) ; 8,07 (1H, s), 7,49 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 7,18 (1H, s)to 3.64 (2H, t, J=7.0 Hz), totaling 3.04 (2H, t, J=7,0 Hz), and 2.79 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

Stage 3. 1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile (stage 2).

1H-NMR (CDCl3) δ of 8.06 (1H, s), 7,46 (2H, d, J=8.1 Hz), 7,26 (2H, d, J=8.1 Hz), 7,19 (1H, s)to 3.09 (2H, t, J=7,1 Hz), 2,89 (2H, t, J=7,1 Hz), and 2.79 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

Stage 4. 6-Chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile (stage 3).

TPL 219-224°C; IR (KBr) v: 3388, 2229, 1708, 1618, 1514, 1466, 1344, 1161, 1089 cm-1.

MS (ESI) m/z 522 (M+H)+, 520(M-H)-;1H-NMR (DMSO-d6) δ scored 8.38 (1H, s), to 7.77 (2H, d, J=8,2 Hz), 7,31-7,49 (6H, m), 7,32 (1H, s), 6,53 (1H, Sirs), 3,26 of 3.28 (2H, m), 2,69-of 2.81 (4H, m)to 2.35 (3H, s), 1,25 (3H, t, J=7,6 Hz).

Example 319

6-Chloro-5-(dimethylamino)-2-ethyl-1-[4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1.N{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}-N,N-dimethylamine

A mixture of 6-CHL is R-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-ylamine (example 110, stage 6, 100 mg, 0.3 mmol) and NaBHU (153 mg, 4 mmol) in THF (5 ml) was added to a mixture of 38% formaldehyde (0.5 ml, 5.6 mmol) and 3M aqueous solution of H2SO4(0.4 ml, 0.12 mmol) at 0°C. the Mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate (100 ml). The organic layer was washed with a saturated aqueous solution (50 ml), then dried (Na2SO4). After removal of solvent the crude product was purified flash chromatography on a column elwira hexane/ethyl acetate (1:2), to obtain 48 mg (46%) of the compound indicated in the title, in the form of a white solid product.

MS (EI) m/z: 361 (M+).

1H-NMR (CDCl3) δ 7,54 (1H, s), 7,44 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), 7,13 (1H, s), 3,82 (2H, t, J=7.0 Hz), 3,19 (2H, t, J=7.0 Hz), 2,82 (6H, s)of 2.75 (2H, q, J=7,6 Hz)of 1.35 (3H, t, J=7,6 Hz).

Stage 2. N-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}-N,N-dimethylamine

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from N-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}-N,N-dimethylamine (stage 1).

1H-NMR (CDCl3) δ 7,54 (1H, s), the 7.43 (2H, d, J=8,2 Hz), 7,29 (2H, d, J=8,2 Hz), 7,12 (1H, s), 3,62 (2H, t, J=7.0 Hz), a 3.01 (2H, t, J=7.0 Hz), 2,82 (6H, s)of 2.75 (2H, q, J=7,6 Hz)of 1.34 (2H, t, J=7,6 Hz).

Stage 3. N-{1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}-N,N-dimethylamine

With the Association, specified in the header received in accordance with the method described for stage 7 of example 37, on the basis of N-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}-N,N-dimethylamine (stage 2).

1H-NMR (CDCl3) δ 7,54 (1H, s), 7,41 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8.1 Hz), 7,13 (1H, s), is 3.08 (2H, t, J=6.9 Hz), 2,87 (2H, t, J=6.9 Hz), 2,82 (6H, s)of 2.75 (2H, q, J=7,6 Hz)of 1.35 (3H, t, J=7,6 Hz).

Stage 4. 6-Chloro-5-(dimethylamino)-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from N-{1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}-N,N-dimethylamine (stage 3).

TPL: p.108-114°C.

MS (ESI)m/z: 540 (MH+), 538 ([M-H]-).

1H-NMR (CDCl3) δ 7,73 (2H, d, J=8.0 Hz), 7,54 (1H, s), 7,25-7,39 (6H, m), 7,11 (1H, s), of 6.73 (1H, Sirs), to 3.58 (2H, q, J=6.9 Hz), to 2.94 (2H, t, J=6.9 Hz), 2.71 to 2,82 (8H, m), is 2.40 (3H, s)of 1.33 (3H, t, J=7,6 Hz).

Example 320

6-chloro-2-ethyl-5-(methylamino)-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 6-Chloro-1-[4-(2-chloroethyl)phenyl)-2-ethyl-1H-benzimidazole-5-informaed

To a solution of acetic anhydride (0,14 ml) in THF (5 ml) was added formic acid (0.06 ml, of 1.65 mmol) at 0°C in nitrogen atmosphere and the mixture was stirred at 60°C for 2 hours. Then the mixture was again cooled to° C was added 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-ylamine (example 110, step 6, 100 mg, 0.3 mmol) in THF (2 ml). The mixture was stirred at room temperature for 2 hours. The volatile component was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 ml). The organic layer was washed 2 N. aqueous solution of NaOH (50 ml), saturated brine (50 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (1:10), to obtain 68 mg (67%) of the compound indicated in the title, in the form of a light yellow solid.

MS (EI) m/z: 361 (M+).

1H-NMR (CDCl3) δ 8,53-8,76 (1H, Sirs), 7,66 (1H, s), 7,44-of 7.48 (2H, m), 7,26-7,31 (2H, m), 7,18 (1H, s), 3,83 (2H, t, J=6.9 Hz), 3,20 (2H, t, J=6.9 Hz), 2,78 (2H, q, J=7.4 Hz), 1.32 to 1.39 in (3H, m).

Stage 2. N-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}-N-methylamine

A solution of 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-Informatica (stage 1, 112 mg, 0.3 mmol) in THF (15 ml) was added to Me2S BH3(0,07 ml, 0.77 mmol) under nitrogen atmosphere at room temperature. The mixture was boiled under reflux for 1 hour. Then the mixture was cooled to room temperature and was added methanol (3 ml) and 2 N. aqueous HCl (12 ml). The mixture was stirred at 70°C for 30 minutes. The volatile component was removed PR is the reduced pressure and the residue was dissolved with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous NaHCO3(50 ml), saturated brine (50 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (1:4), with 93 mg (87%) of the compound indicated in the title, in the form of a white solid.

MS (EI) m/z: 347 (M+).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,2 Hz), 7,29 (2H, d, J=8,2 Hz),? 7.04 baby mortality (1H, s), 7,03 (1H, s), 3,81 (2H, t, J=6.9 Hz), 3,18 (2H, t, J=6.9 Hz), 2,95 (3H, s)of 2.75 (2H, q, J=7,6 Hz)of 1.34 (3H, t, J=7,6 Hz).

Stage 3. N-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}-N-methylamine

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from N-{6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}-N-methylamine (stage 2).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz),? 7.04 baby mortality-7,03 (2H, m), 4,19 (1H, Sirs), 3,61 (2H, t, J=7,0 Hz)of 3.00 (2H, t, J=7.0 Hz), 2,95 (3H, s)of 2.75 (2H, q, J=1,6 Hz)of 1.33 (3H, t, J=7,6 Hz).

Stage 4. N-{1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}-N-methylamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, on the basis of N-{1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}-N-methylamine (stage 3).

1H-NMR (CDCl3) δ 7,39 (2H, d, J=8,4 Hz), 7,25 (2H, d, J=8,4 Hz) 7,06 (1H, C), 7,03 (1H, s)to 3.64 (2H, Sirs)and 3.15 (2H, t, J=7.2 Hz), 2,94-2,99 (5H, m), by 2.73 (2H, q, J=7.5 Hz), 1,32 (3H, t, J=7.5 Hz).

Stage 5. 6-Chloro-2-ethyl-5-(methylamino)-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from N-{1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl}-N-methylamine (stage 4).

TPL: 95-100°C.

MS (ESI) m/z: 526(MH+), 524([M-H]-).

1H-NMR (CDCl3) δ 7,73 (2H, d, J=8,4 Hz), 7.23 percent and 7.36 (7H, m), 7,03 (1H, s), of 3.57 (2H, t, J=6.6 Hz), 2,89-to 2.94 (5H, m), by 2.73 (2H, q, J=7.4 Hz), 1,32 (3H, t, J=7,4 Hz).

Example 321

4-cyano-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 3-Chloro-2-nitrobenzamide

A mixture of 3-chloro-2-nitrobenzoic acid (1 g, 4.9 mmol) and thionyl chloride (9 ml) was stirred at 80°C for 1 hour. Thionyl chloride was removed under reduced pressure and the residue was dissolved dichloromethane (15 ml). The mixture was cooled to 0°and was added dropwise a 30% aqueous NH3(2 ml). The mixture was stirred at 0°C for 25 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate (300 ml). The organic layer was washed with saturated aqueous Na2CO3(100 ml) and saturated saline (100 ml). This organic phase was dried (Na2SO4

1H-NMR (CDCl3) δ 7,68-a 7.92 (3H, m).

Stage 2. 3-Chloro-2-nitrobenzonitrile

A solution of 3-chloro-2-nitrobenzamide (stage 1, 1.2 g, 4.9 mmol) in DMF(8 ml) was added to thionyl chloride (2 ml, of 24.8 mmol) in DMF (3 ml) dropwise at room temperature. The mixture was stirred at 120°C for 2.5 hours. The mixture was poured into ice water and was extracted with ethyl acetate (200 ml). The organic layer was washed saturated aqueous NaHCO3(100 ml), saturated brine (100 ml), then dried (MgSO4) and concentrated. The residue was purified flash chromatography, elwira hexane/ethyl acetate (3:1/1:2), with 1 g (amounts.) the connection specified in the header, in the form of a light yellow solid.

1H-NMR (CDCl3) δ to 7.61-to 7.68 (1H, m), 7,74 for 7.78 (2H, m).

Stage 3. 2-[4-(3-Cyano-2-nitroaniline)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 3-chloro-2-nitrobenzonitrile (stage 2) and 4-aminophenylacetamido alcohol.

MS (EI) m/z: 283 (M+)-.

1H-NMR (CDCl3) δ 9,37 (1H, Sirs), 7,15-7,41 (7H, m), 3,91 (2H, t, J=6.4 Hz), only 2.91 (2H, t, J=6.4 Hz).

Stage 4. 2-Amino-3-[4-(2-hydroxyethyl)aniline]benzonitrile

The connection specified in the header received in accordance with the method described on the I stage 2 of example 40, on the basis of 2-[4-(3-cyano-2-nitroaniline)phenyl]ethanol (step 3).

MS (EI) m/z: 253 (M+).

1H-NMR (CDCl3) δ 7,22-7,28 (2H, m), 7,10 (2H, d, J=8,4 Hz), 6,69 to 6.75 (3H, m), 5,13 (1H, Sirs), of 4.54 (2H, Sirs), a-3.84 (2H, t, J=6.4 Hz), 2,80 (2H, t, J=6.4 Hz).

Stage 5. 2-[4-(4-Cyano-2-ethyl-1-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-amino-3-[4-(2-hydroxyethyl)aniline]benzonitrile (stage 4).

TLC, Rf = 0,6, hexane:ethyl acetate (1:1).

Stage 6. 2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-4-carbonitrile

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(4-cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 5).

MS (EI) m/z: 291 (M+).

1H-NMR (CDCl3) δ 7,58 (1H, d, J=6.3 Hz), 7,49 (2H, d, J=8,3 Hz), 7,19-to 7.32 (4H, m)to 4.01 (2H, t, J=6.4 Hz), to 3.02 (2H, t, J=6.4 Hz), of 2.86 (2H, q, J=7,6 Hz)of 1.34 (3H, t, J=7,6 Hz).

Stage 7. 1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-4-carbonitrile (stage 6).

1H-NMR (DMSO-d6) δ 7,72 (1H, DD, J=1.2 Hz, 7.4 Hz), 7,51-of 7.60 (4H, m), 7,30-7,42 (2H, m), of 3.97 (2H, t, J=7.0 Hz), 3,18 (2H, t, J=7.0 Hz), 2,79 (H, kV, J=7,6 Hz)of 1.26 (3H, t, J=7,6 Hz).

Stage 8. 1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile (stage 7).

1H-NMR (CDCl3) δ to 7.59 (1H, DD, J=1.2 Hz, 7,3 Hz), of 7.48 (2H, d, J=8.0 Hz), 7,19-to 7.32 (4H, m), 3,63 (2H, t, J=6.6 Hz), 3,03 (2H, t, J=6.6 Hz), 2,84 (2H, q, J=7,6 Hz)is 1.31 (3H, t, J=7,6 Hz).

Stage 9. 1-[4-(2-amino-ethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile (stage 8).

1H-NMR (CDCl3) δ 7,58 (1H, DD, J=1.3 Hz, 7.4 Hz), 7,44 (2H, d, J=8,2 Hz), 7,19-to 7.32 (4H, m), is 3.08 (2H, t, J=6,7 Hz), 2,81-of 2.93 (4H, m)of 1.33 (3H, t, J=7.5 Hz).

Stage 10. 4-cyano-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-[4-(2-amino-ethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carbonitrile (stage 9).

TPL: 95-103°C.

IR (KBr) v: 2225, 1676, 1516, 1433, 1340, 1161, 1091, 794, 663 cm-1.

MS (ESI) m/z: 488(MH+), 486 ([M-H]-).

1H-NMR (CDCl3) δ 7,72 (2H, d, J=8.1 Hz), to 7.59 (1H, d, J=7,0 Hz), 7,42 (H, d, J=8.1 Hz), 7.18 in-to 7.32 (6H, m), 6,72 (1H, Sirs), of 3.57 (2H, t, J=7,1 Hz), 2,96 (2H, t, J=7,1 Hz), 2,85 (2H, q, J=7,6 Hz)to 2.41 (3H, s)of 1.33 (3H, t, J=7,6 Hz).

Example 322

2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-4-carboxamide

Stage 1. 2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-4-carboxamide

To a stirred suspension of 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (stage 4,820 mg, 3.3 mmol) in toluene (30 ml) was added dropwise propionate (630 mg, 6.8 mmol) at 0°C and the reaction mixture is boiled under reflux for 1.5 hours. After cooling, the mixture was poured into water (50 ml) and was extracted with ethyl acetate (100 ml). The organic layer was washed 2 N. aqueous NaOH (50 ml) and saturated saline (50 ml), then dried (Na2SO4). The solvent was removed under reduced pressure and the residue was dissolved THF (20 ml) and methanol (20 ml). To the mixture was added 4 N. aqueous LiOH (10 ml) and stirred at room temperature for 14 hours. The mixture was evaporated. The residue was dissolved with ethyl acetate (100 ml) and washed with water (50 ml). The organic layer was washed with saturated saline (50 ml) and dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (1:2/1:5/0:1), with Poluchenie mg (26%) compound specified in the header, in the form of a white solid.

MS (EI) m/z: 309 (M+).

1H-NMR (CDCl3) δ 9,81 (1H, Sirs), 8,13 (1H, DD, J=2.0 Hz, 7.0 Hz), 7,47 (2H, d, J=8.0 Hz), 7,25-7,31 (4H, m), of 5.99 (1H, Sirs), of 4.00 (2H, t, J=6.4 Hz), a 3.01 (2H, t, J=6.4 Hz), 2,82 (2H, q, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz).

Stage 2. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-1-benzimidazole-4-carboxamide

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-[4-(6-chloro-2-ethyl-5-nitro-1H-benzimidazole-1-yl)phenyl]ethanol (step 1).

1H-NMR (DMSO-d6) δ 9,29 (1H, Sirs), 7,81-to $ 7.91 (1H, m), 7,79 (1H, Sirs), 7,49-of 7.60 (4H, m), 7.24 to 7,33 (2H, m), of 3.97 (2H, t, J=6.8 Hz), 3,18 (2H, t, J=6.8 Hz), 2,80 (2H, q, J=7.5 Hz), of 1.27 (3H, t, J=7.5 Hz).

Stage 3. 1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carboxamide

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-carboxamide (stage 2).

1H-NMR (DMSO-d6) δ:9,29 (1H, Sirs), 7,89 (1H, d, J=7,3 Hz), 7,79 (1H, Sirs), 7,51-to 7.59 (4H, m), 7,22-7,33 (2H, m), 3,68 (2H, t, J=6.6 Hz), a 3.01 (2H, t, J=6.6 Hz), 2,77 (2H, q, J=7.5 Hz), of 1.27 (3H, t, J=7.5 Hz).

Stage 4. 1-[4-(2-amino-ethyl)phenyl]-2-ethyl-1H-benzimidazole-4-carboxamide

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl]-6-chloro-2-ethyl-1 H-benzimidazole-5-carboxamide (stage 3).

1H-NMR (DMSO-d6) δ of 9.30 (1H, Sirs), 7,89 (1H, d, J=6.5 Hz), 7,81 (1H, Sirs), of 7.48-7,49 (4H, m), 7,26-7,30 (2H, m), 2.77-to 2,89 (6H, m)of 1.28 (3H, t, J=6.4 Hz).

Stage 5. 2-Ethyl-1-[4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-4-carboxamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-carboxamide (stage 4).

TPL: 208-214°C.

IR (KBr) v: 3336, 1664, 1589, 1508, 1406, 1342, 1168, 976 cm-1.

MS (ESI)m/z: 506 (MH+), 504 ([M-H]-).

1H-NMR (DMSO-d6) δ 9,29 (1H, Sirs), 7,89 (1H, DD, J=1.3 Hz, 7.2 Hz), 7,75-7,79 (3H, m), 7,22-7,49 (8H, m), is 6.54 (1H, Sirs), 2,75-and 2.83 (4H, m)to 2.35 (3H, s)of 1.27 (3H, t, J=7,4 Hz).

Example 323

6-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(methylsulphonyl)-1H-benzimidazole

Stage 1. 1,5-dichloro-2-(methylsulfinyl)-4-nitrobenzene

To a mixture of (2,4-dichlorophenyl)methylsulfone (Mitsunori Ono, Nakamura Yoshisada, Sato shingeo, Itoh Isamu,Chem. Lett, 1988, 395-398.; 3.33 g, 16 mmol) and sulfuric acid (conc. 14 ml) was added a mixture of sulfuric acid (4 ml) and nitric acid (fuming, 2 ml) dropwise in an ice bath. The mixture was stirred at 55°C for 1 hour. The mixture was poured into ice water and neutralized 6 N. aqueous NaOH and then was extracted with Dichlorotoluene layer was washed with saturated saline solution and dried (Na 2SO4). The solvent was removed under reduced pressure and the residue was purified flash chromatography, elwira hexane/ethyl acetate (2:1/1:1), to obtain 3 g (74%) of the compound indicated in the title, in the form of a white solid.

1H-NMR (CDCl3) δ to 8.45 (1H, s), the 7.65 (1H, s), 2,89 (3H, s).

Stage 2. 1,5-Dichloro-2-(methylsulphonyl)-4-nitrobenzene

To a solution of 1,5-dichloro-2-(methylsulfinyl)-4-nitrobenzene (1.0 g, 3.9 mmol) in dichloromethane (50 ml) was added 3-chloroperoxybenzoic acid (1.7 g, 9.8 mmol). The mixture was stirred in nitrogen atmosphere at room temperature for 3 hours. To the mixture was added saturated aqueous NaHCO3(20 ml) and was extracted with dichloromethane (50 ml). The organic layer was washed with saturated saline (50 ml), dried (Na2SO4) and concentrated. The residue was purified flash chromatography, elwira hexane/ethyl acetate (2:1), with 1 g (100%) of the compound indicated in the title, in the form of a white solid.

MS (EI) m/z: 269 (M+).

1H-NMR (CDCl3) δ 8,68 (1H, s), 7,81 (1H, s), 3,30 (3H, s).

Stage 3. 2-{4-[5-chloro-4-(methylsulphonyl)-2-nitroaniline]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, on the basis of 1,5-dichloro-2-(methylsulphonyl)-4-nitrobenzene and 4-aminophenylacetamido alcohol (stage 2).

MS (EI)m/z: 370 (M +).

1H-NMR (CDCl3) δ 9,81 (1H, Sirs), 8,99 (1H, s), 7,39 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), 7,18 (1H, s), of 3.94 (2H, t, J=6.2 Hz)at 3.25 (3H, s), 2,95 (2H, t, J=6.2 Hz).

Stage 4. 2-{4-[2-Amino-5-chloro-4-(methylsulphonyl)aniline]phenyl}ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 40, from 2-{4-[5-chloro-4-(methylsulphonyl)-2-nitroaniline]phenyl}ethanol (step 3).

MS (EI) m/z: 340 (M+).

1H-NMR (CDCl3) δ to 7.50 (1H, s), 7,22 (2H, d, J=8,4 Hz), to 7.15 (1H, s)to 7.00 (2H, d, J=8,4 Hz), 5,71 (1H, Sirs), 3,88 (2H, t, J=6.4 Hz), to 3.67 (2H, Sirs), up 3.22 (3H, s), of 2.86 (2H, t, J=6.4 Hz).

Stage 5. 2-{4-[6-Chloro-2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-l}ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[2-amino-5-chloro-4-(methylsulphonyl)aniline]phenyl}ethanol (step 4).

TLC, Rf = 0.7 and hexane:ethyl acetate (1:2).

Stage 6. 2-{4-[6-Chloro-2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-{4-[6-chloro-2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethylpropylamine (stage 5).

MS (EI) m/z: 378(M+).

1H-NMR (CDCl3) δ at 8.60 (1H, s), 7,52 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), 7,10 (1H, s), 3,97-Android 4.04 (2H, m), 3,29 (3H, s), 3,03 (2H, t, J=6.5 Hz),2,80 (2H, kV, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

Stage 7. 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl-methylsulfone

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-{4-[6-chloro-2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 6).

1H-NMR (CDCl3) δ to 8.62 (1H, s)to 7.50 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,4 Hz), 7,24 (1H, s), 3,83 (2H, t, J=7,1 Hz), 3,29 (3H, s), up 3.22 (2H, t, J=7,1 Hz), 2,80 (2H, q, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz).

Stage 8. 1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl-methylsulfone

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl-methyl-sulfone (stage 7).

1H-NMR (CDCl3) δ to 8.62 (1H, s)to 7.50 (2H, d, J=8,4 Hz), 7,25 (2H, d, J=8,4 Hz), 7.23 percent (1H, s)to 3.64 (2H, t, J=6.9 Hz), 3,29 (3H, s), totaling 3.04 (2H, t, J=6.9 Hz), 2,80 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

Stage 9. 2-{4-[6-Chloro-2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethanamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-1H-benzimidazole-5-yl-methyl-sulfone (stage 8).

1H-NMR (CDCl3) δ 8,61 (1H, s), 7,47 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), 7,24 (1H, s), 3,29 (3H, s), 3,10 (2H, t, J=7,1 Hz), 2,90 (2H, t, J=7,1 Hz), 2,8 (2H, kV, J=7.5 Hz), of 1.37 (3H, t, J=7.5 Hz).

Stage 10. 6-{ENT-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(methylsulphonyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-{4-[6-chloro-2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}of ethanamine (stage 9).

TPL: 105-118°C.

IR (KBr) v: 2879, 1676, 1518, 1458, 1309, 1142, 1089, 993 cm-1.

MS (ESI) m/z: 575 (MH+), 573 ([M-H]-).

1H-NMR (CDCl3) δ 8,59 (1H, s), of 7.75 (2H, d, J=8,4 Hz), the 7.43 (2H, d, J=8,4 Hz), 7,29-7,33 (4H, m), 7,21 (1H, s), 6,69 (1H, Sirs), 3,55-3,62 (2H, m), 3,29 (3H, s), 2,96 (2H, t, J=6.9 Hz), 2,80 (3H, q, J=7.5 Hz), 2,41 (3H, s)of 1.34 (3H, t, J=7.5 Hz).

Example 324

Sodium salt of 6-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(methylsulphonyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described in example 2 from 6-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(methylsulphonyl)-1H-benzimidazole (example 323)

TPL: 175-183°C.

IR (KBr) v: 3375, 1604, 1516, 1458, 1139, 1083, 993 cm-1.

Example 325

2-{4-[6-Chloro-2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[6-Chloro-2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethyl(methylphenyl)sulfonylurea

The connection specified in the header received in accordance with the method described in example 3, from 2-4-[6-chloro-2-ethyl-5-(methylsulphonyl)-1H-benzimidazole-1-yl]phenyl}ethanol (example 323, step 6).

TPL: 105-110°C.

IR (KBr) v: 1751, 1517, 1458, 1309,1163, 1141, 1089 cm-1.

MS (ESI) m/z: 576 (MH+), 574 ([M-H]-).

1H-NMR (CDCl3) δ at 8.60 (1H, s), to $ 7.91-7,94 (2H, m), 7,21-the 7.43 (7H, m), and 4.40 (2H, Sirs), and 3.31 (3H, s), 3,05 (2H, Sirs), 2,78-of 2.81 (2H, m), is 2.44 (3H, s)of 1.33 (3H, t, J=7,6 Hz).

Example 326

5-(Aminosulfonyl)-6-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

Stage 1. 2,4-Dichloro-5-nitrobenzenesulfonamide

2,4-Dichloronitrobenzene (10 g, 52 mmol) was added to the CISO3H (8 ml, 120 mmol) dropwise in an ice bath. The mixture was stirred at 130°C for 26 hours. The mixture was cooled to room temperature and poured into ice-cold water. The obtained precipitates were collected by filtration and dried under reduced pressure to obtain 9 g (60%) of the compound indicated in the title, in the form of a brown solid.

MS (EI) m/z: 290 (M+).

1H-NMR (CDCl3) δ to 8.70 (1H, s), of 7.90 (1H, s).

Stage 2. N-(tert-butyl)-2,4-dichloro-5-nitrobenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 1 of example 87, on the basis of 2,4-dichloro-5-nitrobenzoic hanil chloride and tert-butylamine (stage 1).

1H-NMR (CDCl3) δ 8,65 (1H, s), 7,74 (1H, s), free 5.01 (1H, Sirs), of 1.27 (9H, s).

Stage 3. N-(tert-butyl)-2-chloro-4-[4-(2-hydroxyethyl)aniline]-5-nitrobenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 1 of example 162, proceeding from N-(tert-butyl)-2,4-dichloro-5-nitrobenzenesulfonamide and 4-aminophenylacetamido alcohol (stage 2).

1H-NMR (CDCl3) δ 9,72 (1H, Sirs), of 8.95 (1H, s), 7,37 (2H, d, J=8,3 Hz), 7,24 (2H, d, J=8,3 Hz), 7,17 (1H, s), 4,79 (1H, Sirs), 3,90-of 3.96 (2H, m)to 2.94 (2H, t, J=6.4 Hz), 1.26 in (9H, s).

Stage 4. 5-Amino-N-(tert-butyl)-2-chloro-4-[4-(2-hydroxyethyl)aniline]benzosulfimide

The connection specified in the header received in accordance with the method described for step 2 of example 40, proceeding from N-(tert-butyl)-2-chloro-4-[4-(2-hydroxyethyl)aniline]-5-nitrobenzenesulfonamide (stage 3).

MS (EI) m/z: 397 (M+).

1H-NMR (CDCl3) δ 7,51 (1H, s), 7,20 (2H, d, J=8,4 Hz), 7,14 (1H, s), to 6.95 (2H, d, J=8,4 Hz), with 5.22 (1H, Sirs), 4,89 (1H, Sirs), a 3.87 (2H, t, J=6.4 Hz), 2,85 (2H, t, J=6.4 Hz), of 1.23 (9H, s).

Stage 5. 2-[4-(6-Chloro-2-ethyl-5-nitro-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1, starting from 5-amino-N-(tert-butyl)-2-chloro-4-[4-(2-hydroxyethyl)amino]benzosulfimide (stage 4).

TLC, Rf=0,8, hexane:ethyl acetate (1:2).

Stage 6. N-(Tert-is util)-6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-sulfonamide

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(6-chloro-2-ethyl-5-nitro-1H-benzimidazole-1-yl)phenyl]ethyl propionate (step 5).

1H-NMR (CDCl3) δ to 8.57 (1H, s), 7,49 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 7,20 (1H, s), to 4.98 (1H, Sirs), of 4.00 (2H, Sirs), to 3.02 (2H, t, J=6.4 Hz), and 2.79 (2H, q, J=7.5 Hz), of 1.37 (3H, t, J=7.5 Hz), to 1.21 (9H, s).

Stage 7. N-(Tert-butyl)-6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-sulfonamide

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from N-(tert-butyl)-6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-sulfonamida (stage 6).

1H-NMR (CDCl3) δ 8,58 (1H, s), 7,49 (2H, d, J=8,4 Hz), 7,32 (2H, d, J=8,4 Hz), 7,19 (1H, s), 4,96 (1H, Sirs), 3,83 (2H, t, J=7.0 Hz), 3,21 (2H, t, J=7.0 Hz), 2,80 (2H, q, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz), 1,22 (9H, s).

Stage 8. 1-[4-(2-azidoethyl)phenyl]-N-(tert-butyl)-6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from N-(tert-butyl)-6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-sulfonamida (stage 7).

1H-NMR (CDCl3) δ to 8.57 (1H, s)of 7.48 (2H, d, J=8,2 Hz), 7,32 (2H, d, J=8,2 Hz), 7,19 (1H, s), 4,96 (1H, Sirs), 3,63 (2H, t, J=6.9 Hz), 3,03 (2H, t, J=6.9 Hz), and 2.79 (2H, q, J=7.4 Hz), of 1.37 (3H, t, J=7.4 Hz), 1,21 (9H, s).

Stage 9. 1-[4-(2-l The]-N-(tert-butyl)-6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamide

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl)phenyl]-N-(tert-butyl)-6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamida (stage 8).

1H-NMR (CDCl3) δ to 8.57 (1H, s), 7,44 (2H, d, J=8.5 Hz), 7,29 (2H, d, J=8.5 Hz), 7,20 (1H, s)of 5.03 (1H, Sirs), to 3.09 (2H, t, J=6.9 Hz), 2,89 (2H, t, J=6.9 Hz), and 2.79 (2H, q, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz), 1,22 (9H, s).

Stage 10. 5-[(Tert-butylamino)sulfonyl]-6-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-[4-(2-amino-ethyl)phenyl]-N-(tert-butyl)-6-chloro-2-ethyl-1H-benzimidazole-5-sulfonamida (stage 9).

1H-NMR (CDCl3) δ 8,54 (1H, s), 7,78 (2H, d, J=8,3 Hz), 7,41 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,2 Hz), 7.23 percent (2H, d, J=8,2 Hz), 7,16 (1H, s), is 6.61 (1H, Sirs), to 5.21 (1H, Sirs), 3,54-of 3.60 (2H, m), 2,95 (2H, t, J=6,9 Hz), 2,78 (2H, q, J=7.5 Hz), is 2.41 (3H, s)of 1.35 (3H, t, J=7.5 Hz), to 1.21 (9H, s).

Stage 11. 5-(Aminosulfonyl)-6-chloro-2-ethyl-1-4-{2-[({[((4-(were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 1 of example 88, starting from 5-[(tert-butylamino)sulfonyl]-6-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (article is Diya 9).

TPL: 163-170°C.

IR (KBr) v: 1676, 1517, 1400, 1340, 1159, 1089, 995 cm-1.

MS (ESI) m/z:576 (MH+), 574 ([M-H]-).

1H-NMR (DMSO-d6) δ of 8.25 (1H, s), to 7.77 (2H, d, J=8,3 Hz), 7,55 (2H, Sirs), 7,37-of 7.48 (6H, m), 7,20 (1H, s), is 6.54 (1H, Sirs), with 3.27 (2H, Sirs), 2,71-of 2.81 (4H, m), of 2.34 (3H, s)of 1.23 (3H,t, J=7,6 Hz).

Example 327

2-{4-[5-(Aminosulfonyl)-6-chloro-2-ethyl-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-(4-[(Tert-butylamino)sulfonyl]-6-chloro-2-ethyl-1H-benzimidazole-1-yl}phenyl)ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from N-(tert-butyl)-6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-sulfonamida (example 326, stage 6).

1H-NMR (CDCl3) δ 8,58 (1H, s), to 7.93 (2H, d, J=8,2 Hz), 7,33-7,39 (4H, m), 7,20 (2H, d, J=8,2 Hz), 7,16 (1H, s), 5,07 (1H, Sirs), to 4.38 (2H, t, J=6.2 Hz), 3,03 (2H, t, J=6.2 Hz), 2,78 (2H, q, J=7.5 Hz), 2,44 (3H, ), is 1.35 (3H, t, J=7.5 Hz), to 1.21 (9H, s).

Stage 2. 2-{4-[5-(Aminosulfonyl)-6-chloro-2-ethyl-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described for stage 1 of example 88, based on 2-(4-{5-[(tert-butylamino)sulfonyl]-6-chloro-2-ethyl-1H-benzimidazole-1-yl}phenyl)ethyl(4-were)sulfanilamide (stage 1).

TPL-115°C.

IR (KBr) v: 1676, 1517, 1400, 1340, 1159, 1089 995 cm -1.

MS(ESI) m/z: 576 (MH+), 574 ([M-H]-).

1H-NMR (DMSO-d6) δ of 8.25 (1H, s), 7,76 (2H, d, J=8,4 Hz), 7,55 (2H, Sirs), 7,47 (4H, s), 7,41 (2H, d, J=8,4 Hz), 7,20 (1H, s), the 4.29 (2H, t, J=6.6 Hz), 2,96 (2H, t, J=6.6 Hz), a 2.75 (2H, q, J=7.5 Hz), to 2.35 (3H, s), to 1.24 (3H, t, J=7.5 Hz).

Example 328

2-[4-(6-Chloro-5-cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfonylureas

Stage 1. 2-[4-(6-Chloro-5-cyano-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile (example 111, step 4).

TPL: 85-98 °C.

IR (KBr) v: 1747, 1618, 1517, 1465, 1348, 1290, 1163, 1089 cm-1.

MS (ESI) m/z: 523 (MH+), 521 ([M-H]-).

1H-NMR (CDCl3) δ 8,07 (1H, s), 7,92 (2H, d, J=8,4 Hz), 7,40 (2H, d, J=8,4 Hz), 7,35 (2H, d, J=8.1 Hz), 7,25 (2H, d, J=8.1 Hz), 7,17 (1H, s), 4,39 (2H, t, J=6.8 Hz), totaling 3.04 (2H, t, J=6.8 Hz), 2,78 (2H, q, J=7,6 Hz), 2,44 (3H, s)of 1.35 (3H, t, J=7,6 Hz).

Example 329

N-[(2-[4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

Stage 1. 4-Cyano-3,5-dimethyl-2-nitrophenyl-triftorbyenzola

To a solution of 4-hydroxy-2,6-dimethyl-3-nitro-benzonitrile (v. Auwers; Saurwein; Fortsch. Ch. Phys.; 18; Heft 2, S. 23; 2.6 g, a 13.4 mmol) in dichloromethane (150 ml) was added trifter anhydride (3.4 ml, 20 mmol) and pyridine (1 ml, 20 mmol) at 0°C. the Mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated saline (50 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (2:1), to obtain 3 g (69%) of the compound indicated in the title, in the form of a light yellow solid.

MS (EI) m/z: 324 (M+).

1H-NMR (CDCl3) δ 7,34 (1H, s), 2,68 (3H, s), 2,61 (3H, s).

Stage 2. 2-{4-[(4-Cyano-3,5-dimethyl-2-nitrophenyl)amino]phenyl}acetate

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 4-cyano-3,5-dimethyl-2-nitrophenylacetylene (stage 1).

1H-NMR (CDCl3) δ 8,08 (1H, Sirs), 7,27 (2H, d, J=8,4 Hz), to 7.15 (2H, d, J=8,4 Hz), 4,30 (2H, t, J=7.0 Hz), 2,96 (2H, t, J=7.0 Hz), 2,65 (3H, s)to 2.41 (3H, s), is 2.05 (3H, s).

Stage 3. 2-{4-[(4-Cyano-3,5-dimethyl-2-nitrophenyl)amino]phenyl}acetate

The connection specified in the header received in accordance with the method described for stage 3 of example 6, from 2-{4-[(4-cyano-3,5-dimethyl-2-nitrophenyl)amino]phenyl}ethyl acetate (stage 2).

1H-NMR (CDCl3) δ 7,14 (2H, d, J=8,4 Hz), 6,85-6,89 (3H, m), of 5.50 (1H, Sirs), 4.26 deaths (2H, t, J=7,1 Hz), of 3.54 (2H, Sirs), 2,89 (2H, t, J=7,1 Hz), 2,4 (3H, C)is 2.37 (3H, s), is 2.05 (3H, s).

Stage 4. 2-[4-(5-Cyano-2-ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]acetate

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(4-cyano-3,5-dimethyl-2-nitrophenyl)amino]phenyl}ethyl acetate (stage 3).

1H-NMR (CDCl3) δ 7,45-7,47 (2H, m), 7,26-7,29 (2H, m), 6,79 (1H, Sirs), 4,37 (2H, t, J=7.0 Hz), is 3.08 (2H, t, J=7.0 Hz), 2,83-2,89 (5H, m), of 2.56 (3H, s), is 2.09 (3H, s)of 1.28 (3H, Sirs).

Stage 5. 2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-4,6-dimethyl-1H-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]acetic acid ethyl ester (stage 4).

MS (EI) m/z: 319 (M+).

1H-NMR (CDCl3) δ 7,40-7,51 (4H, m), 6,93 (1H, s), 3,68 of 3.75 (2H, m), 2,85 (2H, t, J=6,7 Hz), 2,68 was 2.76 (5H, m)of 2.50 (3H, s)to 1.22 (3H, t, J=7,4 Hz).

Stage 6. 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (stage 5).

1H-NMR (CDCl3) δ was 7.45 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz), 6,79 (1H, s), 3,83 (2H, t, J=7,1 Hz), 3,21 (2H, t, J=7,1 Hz), is 2.88 (3H, s), of 2.81 (2H, q, J=7,6 Hz)to 2.55 (3H, s)of 1.29 (3H, t, J=7,6 Hz).

The study is 7. 1-[4-(2-Azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (stage 6).

MS (EI) m/z:412 (M+).

1H-NMR (CDCl3) δ 7,47 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8.1 Hz), 6,78 (1H, s), 3,63 (2H, t, J=6.8 Hz), 3,03 (2H, t, J=6.8 Hz), 2,87 (3H, s), 2,80 (2H, q, J=7,6 Hz)to 2.55 (3H, s)of 1.29 (3H, t, J=7,6 Hz).

Stage 8. 1-[4-(2-amino-ethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (stage 7).

1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8.6 Hz), 7,25 (2H, d, J=8.6 Hz), 6,79 (1H, s), is 3.08 (2H, t, J=7.0 Hz), 2.63 in-2.91 in (7H, m)to 2.55 (3H, s)of 1.29 (3H, t, J=7,6 Hz).

Stage 9. N-[({2-[4-(5-cyano-2-ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-[4-(2-amino-ethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (stage 8).

TPL: 140-145 °C.

IR (KBr) v: 3340, 2214, 1664, 1517, 1338, 1166, 1091 cm-1;

MS (ESI) m/z: 516(MH+), 514([M-H]-).

1H-NMR (CDCl3) #x003B4; 7,71 (2H, d, J=8,4 Hz), 7,41 (2H, d, J=8,4 Hz), 7,25-7,31 (4H, m), 6,77 (1H, s), of 6.73 (1H, Sirs), 3,55-3,62 (2H, m), 2,95 (2H, t, J=7.0 Hz), 2,87 (3H, s), 2,80 (2H, q, J=7,6 Hz), 2,52 (3H, s)to 2.41 (3H, s), of 1.28 (3H, t, J=7,6 Hz).

Example 330

2-[4-(5-(Aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

Stage 1. 2-{4-[5-(Aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (example 111, step 5).

TPL: 170-175°C.

IR (KBr) v: 3463, 3342, 1747, 1685, 1593, 1161, 1080, 881 cm-1.

MS (ESI) m/z: 541 (MH+), 539([M-H]-).

1H-NMR (CDCl3) δ 8,13 (1H, s), of 7.96 (2H, d, J=8,4 Hz), 7,40 (2H, d, J=8,4 Hz), was 7.36 (2H, d, J=8.1 Hz), 7,01 (2H, d, J=8.1 Hz), 6,94 (1H, s), 6,55 (1H, Sirs), to 4.38 (2H, t, J=6,1 Hz), a 3.01 (2H, t, J=6,1 Hz), 2,70 (2H, q, J=7.5 Hz), a 2.45 (3H, s)of 1.29 (3H, t, J=7.5 Hz).

Example 331

2-[4-(5-Cyano-2-ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfonylureas

Stage 1. 2-[4-(5-Cyano-2-ethyl-4,6-dimethyl-1H-benzimidazole-1-yl)phenyl]ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (example 39, stage 5).

TPL: 208-213°C.

IR (KBr) v: 1747, 1517, 1230, 1161, 1089 cm-1.

MS (ESI) m/z: 517(MH+), 515 ([M-H]-).

1H-NMR (DMSO-d6) δ 7,76 (2H, d, J=8,4 Hz), 7,40-of 7.48 (6H, m)6,91 (1H, s), 4,27 (2H, t, J=6,7 Hz), 2,96 (2H, t, J=6,7 Hz), 2,67-2,73 (511, m), 2,48 (3H, s), a 2.36 (3H, s)to 1.21 (3H, t, J=7,6 Hz).

Example 332

2-[4-(5-Acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl (4-were)sulfonylureas

Stage 1. 2-[4-(5-Acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}ethanone (example 78, step 4).

TPL: 188-190°C.

IR (KBr) v: 1743, 1683, 1606, 1515, 1348, 1163, 1076 cm-1.

MS (ESI) m/z: 506 (MH)+, 504([M-H]-).

1H-NMR (DMSO-d6) δ with 8.33 (1H, d, J=1.4 Hz), 7,82 (1H, DD, J=1,4 Hz and 8.4 Hz), 7,76 (2H, d, J=8,4 Hz), 7,45 (4H, s), 7,40 (2H, d, J=8,4 Hz), 7,14 (1H, d, J=8,4 Hz), 4,28 (2H, t, J=6.5 Hz), of 2.97 (2H, t, J=6.5 Hz), 2,75 (2H, q, J=7,4 Hz)of 2.64 (3H, s)to 2.35 (3H, s), 1,25 (3H, t, J=7,4 Hz).

Example 333

6-Chloro-2-ethyl-N-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

Stage 1. 2,4-Dichloro-N-methyl-5-nitrobenzamide

To a solution of 2,4-dichloro-5-nitrobenzoic acid (8 g, to 33.9 mmol) in toluene (200 ml) was added thionyl chloride (12,4 ml, 169 mmol) at room temperature. The mixture is stirred at 80 C for 5 hours. The solvent was removed and the residue was dissolved with tetrahydrofuran (60 ml). To the mixture was added 40% methylamine (1.4 ml, to 33.9 mmol) at 0°C and the mixture was stirred at room temperature for 2.5 hours. The volatile component was removed under reduced pressure and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (100 ml), saturated brine (100 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (2:1/1:1/1:2), with the receipt of 5.3 g (63%) of the compound indicated in the title, in the form of a light yellow solid.

1H-NMR (CDCl3) δ of 8.27 (1H, s), the 7.65 (1H, s)and 3.15 (3H, s).

Stage 2. 2-Chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N-methyl-5-nitrobenzamide

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 2,4-dichloro-N-methyl-5-nitrobenzamide (stage 1).

1H-NMR (CDCl3) δ 9,62 (1H, s), by 8.22 (1H, s), 7.24 to to 7.35 (4H, m), to 6.95 (1H, s), 3,60-to 3.67 (2H, m), 2,73-and 2.79 (5H, m).

Stage 3. 5-Amino-2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N-methylbenzamide

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N-methyl-5-nitrobenzamide (stage 2).

1H-NMR (CDCl3) 4 7,28 (1H, s), to 7.15 (2H, d, J=8,4 Hz), was 7.08 (1H, s), 6.89 in (2H, d, J=8,4 Hz), 6,53 (1H, Sirs), 5,41 (1H, Sirs), 3,84-3,86 (2H, m), 3,66 (2H, Sirs), of 3.00 (3H, d, J=5.0 Hz), and 2.83 (2H, t, J=6.6 Hz).

Stage 4. 6-Chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-N-methyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 5 of example 1, starting from 5-amino-2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N-methylbenzamide (stage 3).

MS (EI) m/z: 357 (M+).

1H-NMR (CDCl3) δ 7,98 (1H, s), 7,47 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8.1 Hz), to 7.09 (1H, s), 6,23 (1H, Sirs), 3,96-was 4.02 (2H, m), 3,05 (3H, d, J=4,9 Hz)of 3.00 (2H, t, J=6.4 Hz), 2,77 (2H, q, J=7,6 Hz)of 1.34 (3H, t, J=7,6 Hz).

Stage 5. 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-N-methyl-1H-benzimidazole-5-carboxamide (stage 4).

1H-NMR (CDCl3) δ 7,98 (1H, s), 7,47 (2H, d, J=8,3 Hz), 7,31 (2H, d, J=8,3 Hz), 7,10 (1H, s), 6.35mm (1H, Sirs), 3,83 (2H, t, J=6.9 Hz), 3,21 (2H, t, J=6.9 Hz), 3,05 (3H, d, J=4.9 Hz), 2,82 (2H, q, J=7,6 Hz), 1,36 (3H, t, J=7,6 Hz).

Stage 6. 1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-N-mate is -1 H-benzimidazole-5-carboxamide (stage 5).

MS (EI) m/z: 382 (M+).

1H-NMR (CDCl3) δ 7,94 (1H, s), 7,46 (2H, d, J=8.0 Hz), 7,27 (2H, d, J=8.0 Hz), 7,06 (1H, s), 3,63 (2H, t, J=7.0 Hz), 2,98-3,06 (5H, m), 2,77 (2H, q, J=7.5 Hz), of 1.34 (3H, t, J=7,6 Hz).

Stage 7: 1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide (stage 6).

1H-NMR (CDCl3) δ to $ 7.91 (1H, s), 7,42 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz), 7,06 (1H, s), 6,55 (1H, Sirs), 3,03-3,10 (5H, m), 2,72-and 2.83 (2H, m)of 1.33 (3H, t, J=7,6 Hz).

Stage 8: 6-Chloro-2-ethyl-N-methyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-[4-(2-amino-ethyl)phenyl]-6-chloro-2-ethyl-N-methyl-1H-benzimidazole-5-carboxamide (stage 7).

TPL: 122-135°C.

IR (KBr) v: 2877, 1637, 1519, 1400, 1340, 1161, 1091 cm-1.

MS (ESI) m/z: 554 (MH+), 552 ([M-H]-).

1H-NMR (CDCl3) δ 7,79-to 7.84 (3H, m), 7,28-7,33 (4H, m), 7,12 (2H, d, J=8,2 Hz), of 6.96 (1H, s), to 6.80 (1H, Sirs), 6,70 (1H, Sirs), 3,48-of 3.54 (2H, m), is 3.08 (3H, d, J=4,8 Hz), 2,89 (2H, t, J=6.9 Hz), of 2.72 (2H, q, J=7.5 Hz)that is 2.41 (3H, s)of 1.30 (3H, t, J=7.5 Hz).

Example 334

2-[4-{6-Chloro-2-ethyl-5-[(methylamino)carbonyl]-1H

Stage 1. 2-{6-Chloro-2-ethyl-5-[(methylamino)carbonyl]-1H-benzimidazole-1-yl}phenyl)ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-N-methyl-1H-benzimidazole-5-carboxamide (example 333, stage 4).

TPL: 201-204°C.

MS (ESI) m/z: 555 (MH+), 553 ([M-H]-).

1H-NMR (DMSO-d6) δ 8,27-8,29 (1H, m), 7,76 (2H, d, J=8.1 Hz), 7,69 (1H, s), 7,40-of 7.48 (6N, m), 7,06 (1H, s), 4,28 (2H, t, J=6.3 Hz), 2,96 (2H, t, J=6.3 Hz), 2,69-2,78 (5H, m), a 2.36 (3H, s)of 1.23 (3H, t, J=7.5 Hz).

Example 335

2-{4-[6-Chloro-5-[(dimethylamino)carbonyl]-2-(1-methylethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

Stage 1. 2,4-Dichloro-N,N-dimethyl-5-nitrobenzamide

To a solution of 2,4-dichloro-5-nitrobenzoic acid (4 g, 17 mmol) in toluene (50 ml) was added thionyl chloride (6 ml, 84 mmol) at room temperature. The mixture was stirred at 80°C for 2 days. The solvent was removed and the residue was dissolved in tetrahydrofuran (30 ml). To the mixture was added 50% dimethylamine (760 mg) at 0°C and the mixture was stirred at room temperature overnight. The volatile component was removed under reduced pressure and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), saturated brine (50 ml), then dried (Na2SO4). the donkey removal of the solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (1:1), to obtain 3.6 g (82%) of the compound indicated in the title, in the form of a light yellow solid.

1H-NMR (CDCl3) δ of 7.90 (1H, s), the 7.65 (1H, s)and 3.15 (3H, s), 2.91 in (3H, s).

Stage 2. 2-Chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N,N-dimethyl-5-nitrobenzamide

The connection specified in the header received in accordance with the method described for stage 3 of example 1, from 2,4-dichloro-N,N-dimethyl-5-nitrobenzamide (stage 1).

MS (EI) m/z: 363 (M+).

1H-NMR (CDCl3) δ 9,52 (1H, Sirs), to 8.20 (1H, s), 7,34 (2H, d, J=8,2 Hz), 7,22 (2H, d, J=8,2 Hz), 7,16 (1H, s)to 3.92 (2H, m), of 3.13 (3H, s), 2,89-to 2.94 (5H, m).

Stage 3. 5-Amino-2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N,N-dimethylbenzamide

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N,N-dimethyl-5-nitrobenzamide (stage 2).

1H-NMR (CDCl3) δ 7,05-7,11 (3H, m), 6,79 (2H, d, J=8.5 Hz), 6,63 (1H, s)5,59 (1H, s), 3,79-a 3.83 (4H, m), 3,11 (3H, s), of 2.92 (3H, s), and 2.79 (2H, t, J=6.4 Hz).

Stage 4. 2-{4-[6-Chloro-5-[(dimethylamino)carbonyl]-2-(1-methylethyl)-1H-benzimidazole-1-yl]phenyl}ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1, starting from 5-amino-2-chloro-4-{[4-(2-hydroxyethyl)phenyl]amino}-N,N-dimethylbenzamide (stage 3).

Stage 5. 6-Chloro-1-[4(2-hydroxyethyl)phenyl]-N,N-dimethyl-2-(1-methylethyl)-1 H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-{4-[6-chloro-5-[(dimethylamino)carbonyl]-2-(1-methylethyl)-1H-benzimidazole-1-yl]phenyl}of ethylpropane (stage 4).

MS (EI) m/z: 371 (M+).

1H-NMR (CDCl3) δ 7,66 (1H, s), 7,46 (2H, d, J=8.5 Hz), 7,27 (2H, d, J=8.5 Hz), 7,12 (1H, s), 3.95 to 4.00 points (2H, m), 3,17 (3H, s)of 3.00 (2H, d, J=6.6 Hz), 2,87 (3H, s), 2,78 (2H, q, J=7.5 Hz), of 1.34 (3H, t, J=7.5 Hz,).

Stage 6. 2-{4-[6-Chloro-5-[(dimethylamino)carbonyl]-2-(1-methylethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 6-chloro-1-[4-(2-hydroxyethyl)phenyl]-N,N-dimethyl-2-(1-methylethyl)-1H-benzimidazole-5-carboxamide (stage 5).

TPL: 173-176°C.

IR (KBr) v: 1741, 1637, 1519, 1398, 1344, 1159, 1078, 904 cm-1.

MS (ESI) m/z: 569 (MH+), 567 ([M-H]-).

1H-NMR (CDCl3) δ to 7.93 (2H, d, J=8,4 Hz), of 7.70 (1H, s), 7,27-7,34 (4H, m), 7,09 for 7.12 (3H, m), 4,35 (2H, t, J=6.6 Hz), 3,19 (3H, s), 2,98 (2H, t, J=6.6 Hz), is 2.88 (3H, s), is 2.74 (2H, q, J=7.5 Hz), 2,42 (3H, s), 1,29 (3H, t, J=7.5 Hz).

Example 336

2-(4-{6-Chloro-2-ethyl-5-[(metiloksi)methyl]-1H-benzimidazole-1-yl}phenyl)ethyl (4-were)sulfonylureas

Stage 1. 1,5-Dichloro-2-[(metiloksi)methyl]-4-nitrobenzene

To a solution of 1,5-dichloro-2-(chloromethyl)-4-nitrobenzene (Hagmann, William K.; Dorn, Conrad P.; Frnkshun, Robert A.; O'grady, Laura A.; Bailey, Philip J.; et al.; JMCMAR; J. Med. Chem.; EN; 29; 8; 1986; 1436-1441, 10.6 g, 44 mmol) in methanol (30 ml) was added sodium methoxide (44 ml, 66 mmol) at room temperature. The mixture was stirred at 80°C for 21 hours. The volatile component was removed under reduced pressure and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), saturated brine (50 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (6:1/4:1), to obtain 2.8 g (27%) of the compound indicated in the title, in the form of a light yellow oil.

1H-NMR (CDCl3) δ 8,01 (1H, s), to 7.09 (1H, s), of 4.49 (2H, s), of 3.96 (3H, s).

Stage 2. 2-[4-({5-Chloro-4-[(methoxy)methyl]-2-nitrophenyl}amino)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1, on the basis of 1,5-dichloro-2-[(metiloksi)methyl]-4-nitrobenzene (stage 1).

1H-NMR (CDCl3) δ to 9.45 (1H, Sirs), of 8.28 (1H, s), 7,17-7,33 (5H, m), of 4.44 (2H, s), 3,91 (1H, Sirs), of 3.45 (3H, s), only 2.91 (2H, t, J=6.6 Hz).

Stage 3. 2-[4-({2-Amino-5-chloro-4-[(metiloksi)methyl]phenyl}amino)phenyl]ethanol

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-[4-({5-chloro-4-[(metiloksi)methyl]-2-nitrophenyl}amino)phenyl]ethanol (step 2)./p>

1H-NMR (CDCl3) δ 7,07-7,01 (3H, m), to 6.88 (1H, s), 6,74 (2H, d, J=8,4 Hz), 5,16 (1H, Sirs), 4,47 (2H, s), 3,82 (2H, t, J=6.6 Hz), 3,71 (2H, Sirs), of 3.46 (3H, s), and 2.79 (2H, t, J=6.6 Hz).

Stage 4. 2-(4-{6-Chloro-2-ethyl-5-[(metiloksi)methyl]-1H-benzimidazole-1-yl}phenyl)ethanol

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-({2-amino-5-chloro-4-[(metiloksi)methyl]phenyl}amino)phenyl]ethanol (step 3).

MS (EI) m/z: 334 (M+).

1H-NMR (CDCl3) δ of 7.82 (1H, s), 7,46 (2H, d, J=8,2 Hz), 7,28 (2H, d, J=8,2 Hz), 7,12 (1H, s)and 4.65 (1H, s)to 3.99 (2H, Sirs), of 3.45 (3H, s)of 3.00 (3H, t, J=7,6 Hz), 2,78 (2H, q, J=7,6 Hz)of 1.34 (3H, t, J=7,6 Hz).

Stage 5. 2-(4-{6-Chloro-2-ethyl-5-[(metiloksi)methyl]-1H-benzimidazole-1-yl}phenyl)ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-(4-{6-chloro-2-ethyl-5-[(metiloksi)methyl]-1H-benzimidazole-1-yl}phenyl)ethanol (stage 4).

TPL:of 174.5 °C.

IR (KBr) v: 3377, 2813, 1718, 1519, 1398, 1342, 1159, 1093, 1062 cm-1.

MS (ESI) m/z: 542(MH+), 540 ([M-H]-).

1H-NMR (CDCl3) δ 7,94 (2H, d, J=8,2 Hz), 7,83 (1H, s), 7,08-7,33 (7H, m), with 4.64 (s, 2H), 4,37 (2H, t, J=6.4 Hz), of 3.46 (3H, s), of 2.97 (2H, t, J=6.4 Hz), 2,73 (2H, q, J=7.5 Hz), 2,42 (3H, s)of 1.26 (3H, t, J=7.5 Hz,).

Example 337

2-{4-[6-Chloro-2-ethyl-5-(hydroxymethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

Stage 1. 2-{4-[6-X is the PR-5-(chloromethyl)-2-ethyl-1 H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-[4-({2-amino-5-chloro-4-[(metiloksi)methyl]phenyl}amino)phenyl]ethanol (example 336, stage 3).

MS (EI) m/z: 348 (M+).

1H-NMR (CDCl3) δ 7,83 (1H, s), 7,46 (2H, d, J=8,2 Hz), 7,27 (2H, d, J=8,2 Hz), to 7.15 (1H, s), 4,84 (2H, s), 3.96 points-was 4.02 (2H, m)of 3.00 (2H, t, J=6.4 Hz), 2,77 (2H, q, J=7.5 Hz), of 1.34 (2H, t, J=7.5 Hz).

Stage 2. 6-Chloro-5-(chloromethyl)-1-[4-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 2 of example 90, from 2-{4-[6-chloro-5-(chloromethyl)-2-ethyl-1H-benzimidazole-1-yl]phenyl}ethanol (step 1).

MS (EI) m/z: 405(M+).

1H-NMR (CDCl3) δ 7,83 (1H, s), the 7.43 (2H, d, J=8,4 Hz), 7.23 percent (2H, d, JM8,4 Hz), 7,11 (1H, s), is 4.85 (2H, s), 3,91 (2H, t, 3=6,4 Hz)to 2.94 (2H, t, J=6.4 Hz), was 2.76 (2H, q, J=7.5 Hz), of 1.33 (3H, t, J=7.5 Hz), 0,87 (9H, s)0,00 (6H, s).

Stage 3. {6-Chloro-1-[4-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}methylpropanoate

To a solution of 6-chloro-5-(chloromethyl)-1-[4-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazole (stage 2, 403 mg, 0.86 mmol) in N,N-dimethylformamide (10 ml) was added propionic acid (0.06 ml, 0.86 mmol) and NaHCO3(144 mg, 1,72 mmol) at room temperature. The mixture was stirred PR is 60° With over 7 hours. The mixture was added to water (50 ml) and was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated saline (50 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (8:1/4:1), to obtain 235 mg (53%) of the compound indicated in the title, in the form of a light yellow oil.

1H-NMR (CDCl3) δ 7,81 (1H, s), the 7.43 (2H, d, J=8.5 Hz), 7,24 (2H, d, J=8.5 Hz), 7,11 (1H, s)5,33 (2H, s), 3,91 (2H, t, J=6.6 Hz), with 2.93 (2H, t, J=6.6 Hz), 2,77 (2H, q, J=7.5 Hz), 2,42 (2H, q, J=7.5 Hz), 1,33 (3H, t, J=7.5 Hz), of 1.18 (3H, t, J=7.5 Hz), of 0.87 (9H, s)0,00 (6H, s).

Stage 4. {6-Chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}methylpropanoate

The connection specified in the header received in accordance with the method described for stage 6 of example 90, on the basis of {6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}methyl of propanoate (stage 3).

MS (EI) m/z:386 (M+).

1H-NMR (CDCl3) δ of 7.70 (1H, s), 7,37 (2H, d, J=8,3 Hz), 7,17 (2H, d, J=8,3 Hz),? 7.04 baby mortality (1H, s), a total of 5.21 (2H, s), 3,88 (2H, d, J=6.6 Hz), only 2.91 (2H, t, J==6,6 Hz)to 2.67 (2H, q, J=7.5 Hz), 2,32 (2H, q, J=7.5 Hz), 1,24 (3H, t, J=7.5 Hz), a 1.08 (3H, t, J=7.5 Hz).

Stage 5. [6-Chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)oxy]ethyl}phenyl)-1H-benzimidazole-5-yl]methylpropanoate

The connection specified in the header of the received matched the accordance with the method, described in example 3, on the basis of {6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}methylpropanoate (stage 4).

1H-NMR (CDCl3) δ a 7.92 (2H, d, J=8,3 Hz), 7,81 (1H, s), to 7.32 and 7.36 (4H, m), 7,21-of 7.25 (2H, m), 7,10 (1H, s), 5,32 (2H, s), to 4.38 (2H, t, J=6,7 Hz), to 3.02 (2H, t, J=6,7 Hz), was 2.76 (2H, q, J=7,6 Hz), 2,37-2,49 (5H, m), of 1.33 (3H, t, J=7,6 Hz)of 1.18 (3H, t, J=7,6 Hz).

Stage 6. 2-{4-[6-chloro-2-ethyl-5-(hydroxymethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from [6-chloro-2-ethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)oxy]ethyl}phenyl)-1H-benzimidazole-5-yl]methylpropanoate (stage 5).

TPL:172,7 °C.

IR (KBr) v: 1745, 1519, 1240, 1160, 1089, 1058 cm-1.

MS (ESI) m/z: 528 (MH+), 526 ([M-H]-).

1H-NMR (DMSO-d6) δ 7,74-to 7.77 (3H, m), 7,39-7,46 (6H, m), 7,03 (1H, s), 4,63 (2H, s), 4,27 (2H, t, J=6.6 Hz), 2,95 (2H, t, J=6.6 Hz), of 2.72 (2H, q, J=7.5 Hz), was 2.34 (3H, s)of 1.23 (3H, t, J=7.5 Hz).

Example 338. N-({[2-(4-{6-chloro-2-ethyl-5-[(metiloksi)methyl]-1H-benzimidazole-1-yl}phenyl)ethyl]aminocarbonyl)-4-methylbenzenesulfonamide

Stage 1. 1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-5-[(metiloksi)methyl]-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 5 of example 26, from 2-(4-{6-chloro-2-ethyl-5-[(bk)methyl]-1H-benzimidazole-1-yl}phenyl)this is Ola (example 336, stage 4).

MS (EI) m/z: 369 (M+).

1H-NMR (CDCl3) δ of 7.82 (1H, s), was 7.45 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), 7,11 (1H, s)and 4.65 (2H, s), 3,62 (2H, t, J=7.0 Hz), of 3.45 (3H, s), to 3.02 (2H, t, J=7.0 Hz), 2,77 (2H, q, J=7,7 Hz)of 1.34 (3H, t, J=7,7 Hz).

Stage 2. 2-(4-{6-chloro-2-ethyl-5-[(metiloksi)methyl]-1H-benzimidazole-1-yl}phenyl)ethanamine

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 1-[4-(2-azidoethyl)phenyl]-6-chloro-2-ethyl-5-[(metiloksi)methyl]-1H-benzimidazole (step 1).

1H-NMR (CDCl3) δ of 7.82 (1H, s), 7,42 (2H, d, J=8,4 Hz), 7.24 to 7,29 (2H, m), 7,12 (1H, s)and 4.65 (1H, s), of 3.45 (3H, AC), is 3.08 (2H, t, J=6,7 Hz), is 2.88 (2H, t, J=6,7 Hz), 2,77 (2H, q, J=7,6 Hz)of 1.34 (3H, t, J=7,6 Hz).

Stage 3. N-({[2-(4-{6-chloro-2-ethyl-5-[(metiloksi)methyl]-1H-benzimidazole-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-(4-{6-chloro-2-ethyl-5-[(metiloksi)methyl]-1H-benzimidazole-1-yl}phenyl)ethanamine (stage 2).

TPL 134,6°C.

IR (KBr) v: 3377, 2813, 1718, 15,19, 1398, 1342, 1159, 1093, 1062 cm-1.

MS (ESI) m/z: 541 (MH+), 539 ([M-H]-).

1H-NMR (CDCl3) δ of 7.82 (1H, s), 7,72 (2H, d, J=8,4 Hz), 7.24 to 7,39 (4H, m), to 7.09 (1H, s), 6,72 (1H, Sirs)and 4.65 (2H, s), of 3.57 (2H, m), of 3.45 (3H, s), with 2.93 (2H, d, J=6.8 Hz), 2,77 (2H, q, J=7.5 Hz), 2.40 a (3H, s), 1.32 to (3H, t, J=7.5 Hz).

Example 339

2-{4-[6-Chloro-2-[3-(4-pyridinyl)propyl]-5-(trifter ethyl)-1 H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

Stage 1. 2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate

To a mixture of 2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol (example 104, step 1, of 8.1 g of 22.4 mmol) and pyridine (1.8 ml, 22,45 mmol) in dichloromethane (200 ml) was added acetylchloride (1.6 ml, of 22.4 mmol) at 0°C. the Mixture was stirred at 0°C for 45 minutes. The mixture was added to water (50 ml) and was extracted with dichloromethane (300 ml). The organic layer was washed with saturated saline (100 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (2:1), with 8.6 g (95%) of the compound indicated in the title, in the form of a yellow solid.

1H-NMR (CDCl3) δ,9,68 (1H, Sirs), to 8.57 (1H, s), 7,35 (2H, d, J=8,4 Hz), 7,22 (2H, d, J=8,4 Hz), 7,17 (1H, s)to 4.33 (2H, t, J=7,0 Hz)of 3.00 (2H, t, J=7.0 Hz), to 2.06 (3H, s).

Stage 2. 2-{4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (stage 1).

1H-NMR (CDCl3) δ 7,13-7,16 (3H, m), 7,06 (1H, s), 6.89 in (2H, d, J=8,4 Hz), 5,43 (1H, Sirs), 4.26 deaths (2H, t, J=7.2 Hz), of 3.69 (2H, Sirs), 2,89 (2H, d, J=7,2 Hz), 2,04 (3H, s).

tadia 3. 2-(4-{[5-Chloro-2-{[4-(4-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate

A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (stage 2,250 mg, 0.67 mmol), 4-(4-pyridinyl)butane acid (200 mg, 1 mmol) and WSC (191 mg, 1 mmol) in dichloromethane (7 ml) was stirred at room temperature for 1.5 hours. The mixture was added water (5 ml) and was extracted with dichloromethane (30 ml). The organic layer was washed with saturated saline (5 ml), then dried (Na2S04). The solvent was removed under reduced pressure to get the connection specified in the header, in the form of a light brown amorphous substance.

MS (EI) m/z: 519 (M+).

Stage 4. 2-{4-[6-Chloro-2-[3-(4-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

A mixture of 2-(4-{[5-chloro-2-{[4-(4-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (stage 3,220 mg, 0.42 mmol) and 2 N. NaOH (15 ml) in ethanol (20 ml) was stirred at 40°C for 7 hours. The solvent was removed and the residue was added water (50 ml). The mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated saline (50 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira dichloromethane:methanol (20:1), with 105 mg (54%) specified in the header of the is placed in the form of a light brown oil.

1H-NMR (CDCl3) δ 8,40-8,42 (2H, m), 8,10 (1H, s), the 7.43 (2H, d, J=8,3 Hz), 7,16-7,19 (3H, m), 7,02 (2H, d, J=6.0 Hz), of 4.00 (2H, t, J=6.2 Hz), of 3.00 (2H, t, J=6.2 Hz), a 2.75 (2H, t, J=7,3 Hz), 2,68 (2H, t, J=7,3 Hz), 2,11-2,19 (2H, m).

Stage 5. 2-{4-[6-Chloro-2-[3-(4-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[6-chloro-2-[3-(4-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 4).

TPL: 80-87°C.

IR (KBr) v: 1743, 1610, 1517, 1431, 1346, 1161 cm-1.

MS (ESI) m/z: 657 (MH+), 655 ([M-H]-).

1H-NMR (CDCl3) δ 8,32 (2H, d, J=6.0 Hz), of 8.09 (1H, s), to 7.99 (2H, d, J=8,2 Hz), 7,34 (2H, d, J=8,2 Hz), 7,22 (2H, d, J=8,2 Hz), to 7.15 (1H, s), 6,94-7,02 (4H, m), 4,48 (2H, t, J=5.4 Hz), 3,01 (211, t, J=5.4 Hz), to 2.74 (2H, t, J=6.0 Hz), of 2.54 (2H, t, J=7.9 Hz), 2,44 (3H,s), 2,16-of 2.21 (2H, m).

Example 340

2-{4-[6-Chloro-2-[3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

Stage 1. 2-(4-{[5-chloro-2-{[4-(3-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate

The connection specified in the header received in accordance with the method described for stage 3 of example 339, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (example 339, step 2).

1H-NMR (CDCl3) δ 8,43 (2H, Sirs), 7,50-7,71 (2H, m), 7,15-7,28 (6H, m), 96 (2H, d, J=8,3 Hz), to 6.43 (1H, Sirs), 4.26 deaths (2H, t, 1=1.0 Hz), 2,90 (2H, t, J=7.0 Hz), 2,70 (2H, t, J=7,3 Hz)to 2.41 (2H, t, J=7,3 Hz), 2,03-of 2.08 (5H, m).

Stage 2. 2-{4-[6-chloro-2-[3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 4 of example 339, based on 2-(4-{[5-chloro-2-{[4-(3-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (stage 1).

MS (EI) m/z:459 (M).

1H-NMR (CDCl3) δ with 8.33 (1H, d, J=4.4 Hz), of 8.09 (1H, s), a 7.62 (1H, s), 7,43-to 7.50 (3H, m), 7,16-7,22 (4H, m), was 4.02 (2H, t, J=5.6 Hz), 2,99 (2H, t, J=5.6 Hz), is 2.74 (2H, t, J=7.5 Hz), of 2.64 (2H, t, J=6.6 Hz), 2,04-2,13 (2H, m).

Stage 3. 2-{4-[6-chloro-2-[3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[6-chloro-2-[3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 2).

TPL: 90-95°C.

IR (KBr) v: 1743, 1517, 1431, 1346, 1301, 1161, 1130, 1085 cm-1.

MS (ESI) m/z: 657 (MH+), 655 ([M-H]-).

1H-NMR (CDCl3) δ 8,59 (1H, DD, J=1.7 Hz, 5.1 Hz), 8,08 (1H, s), 7,95 (2H, d, J=8,3 Hz), 7,86 (1H, d, J=1.7 Hz), 7,54-7,58 (1H, m), 7,27-7,34 (5H, m), 7,20 (1H, s), 7,12 (2H, d, J=8,4 Hz), to 4.46 (2H, t, J=5,1 Hz), of 3.00 (2H, t, J=5,1 Hz), 2.77-to 2,82 (2H, m), 2,62 (2H, t, J=7.0 Hz), 2,43 (3H, s), 1.85 to 1.91 a (2H, m).

Example 341

2-{4-[6-chloro-2-[3-oxo-3-(3-pyridinyl)propyl]-5-(three is tormentil)-1 H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-(4-{[5-chloro-2-{[4-oxo-4-(3-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)amino}phenyl)ethyl acetate

The connection specified in the header received in accordance with the method described for stage 3 of example 339, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (example 339, step 2).

1H-NMR (CDCl3) δ 9,19 (1H, d, J=2.2 Hz), 8,80 (1H, DD, J=1,8 Hz, 3.9 Hz), to 8.20 (1H, d, J=7.9 Hz), to 7.64 (2H, Sirs), 7,44 (1H, DD, J=5.8 Hz, 7.9 Hz), 7,28 (1H, s), 7,19 (2H, d, J=8,3 Hz), 7,05 (2H, d, J=8,3 Hz), 6,70 (1H, Sirs), 4,27 (2H, t, J=7,1 Hz), 3,49 (2H, t, J=5.5 Hz), of 2.92 (2H, t, J=7,1 Hz), 2,78 (2H, t, J=5.8 Hz), was 2.05 (3H, s).

Stage 2. 3-[6-Chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]-1-(3-pyridinyl)-1-propanone

The connection specified in the header received in accordance with the method described for stage 4 of example 339, based on 2-(4-{[5-chloro-2-{[4-oxo-4-(3-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (stage 1).

1H-NMR (CDCl3) δ 9,05-9,06 (1H, m), 8,77-8,79 (1H, m), 8,24-of 8.28 (1H, m), of 8.06 (1H, s), 7,54 (2H, d, J=8.5 Hz), 7,40-7,46 (3H, m), 3,97-Android 4.04 (2H, m), 3,66 (2H, t, J=7.0 Hz), 3,19 (2H, t, J=7.0 Hz), to 3.02 (2H, t, J=6,4 Hz).

Stage 3. 2-{4-[6-Chloro-2-[3-oxo-3-(3-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-(4-were)sulfonylureas

The connection specified in the header received in accordance with the way the, described in example 3 from 3-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]-1-(3-pyridinyl)-1-propanone (stage 2).

TPL: 89-95°C.

IR (KBr) v: 2972, 1747, 1693, 1517, 1346, 1230, 1161, 1085 cm-1.

MS (ESI) m/z: 671 (MH+), 669 ([M-H]-).

1H-NMR (CDCl3) δ 8,91 (1H, s), 8,83 cent to 8.85 (1H, m), 8,23-of 8.27 (1H, m), with 8.05 (1H, s), 7,92 (2H, d, J=8,2 Hz), 7,33-of 7.48 (7H, m), 7,21 (1H, s), 4,43 (2H, t, J=6.3 Hz), 3,47 (2H, t, J=7,1 Hz)at 3.25 (2H, t, J=7,1 Hz), totaling 3.04 (2H, t, J=6.3 Hz), 2,43 (3H, s).

Example 342

2-{4-[6-Chloro-2-[3-oxo-3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

Stage 1. 2-(4-{[5-Chloro-2-{[4-oxo-4-(2-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate

The connection specified in the header received in accordance with the method described for stage 3 of example 339, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (example 339, step 2).

MS (EI) m/z:533 (M+).

Stage 2. 3-[6-Chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H benzimidazole-2-yl]-1-(2-pyridinyl)-1-propanone

The connection specified in the header received in accordance with the method described for stage 4 of example 339, based on 2-(4-{[5-chloro-2-{[4-oxo-4-(2-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (stage 1).

1H-NMR (CDCl3) δ 8,67-8,69 (1H, m), to 7.84 (1H, s), of 7.96-to 7.99 (1H, m), 7,81-to 7.84 (1H, m, 7,39-7,51 (5H, m), 7.23 percent (1H, s), 3.96 points-was 4.02 (2H, m), 3,91 (2H, t, J=6.9 Hz)and 3.15 (2H, t, J=6.9 Hz), a 3.01 (2H, t, J=6.4 Hz).

Stage 3. 2-{4-[6-chloro-2-[3-oxo-3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 3-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]-1-(2-pyridinyl)-1-propanone (stage 2).

TPL: 233,6°C.

IR (KBr) v: 1743, 1703, 1515, 1481, 1336, 1203, 1120, 1087, 995 cm-1.

MS (ESI) m/z: 671 (MH+), 669 ([M-H]-).

1H-NMR (DMSO-d6) δ a total of 8.74-8,76 (1H, m), 8,13 (1H, S), of 7.90-8,03 (2H, m), to 7.77 (2H, d, J=8.1 Hz), 7,66-of 7.70 (1H, m), 7,49-7,58 (4H, m), 7,42 (2H, d, J=8.1 Hz), 7,34 (1H, s), 4,30 (2H, t, J=6.4 Hz), 3,83 (2H, t, J=6,4 Hz), to 3.09 (2H, t, J=6.4 Hz), 2,98 (2H, t, J=6.4 Hz), 2,50 (3H, s).

Example 343

2-{4-[6-Chloro-2-[3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

Stage 1. 2-(4-{[5-Chloro-2-{[4-(2-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate

The connection specified in the header received in accordance with the method described for stage 3 of example 339, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (example 339, step 2).

1H-NMR (CDCl3) δ 9,26 (1H, Sirs), 8,39-to 8.41 (1H, m), 7,86 (1H, s), 7,69-7,72 (1H, m), 7,49 (1H, s), 7,25-7,28 (1H, m), 7,15-7,21 (3H, m), 7,00 (2H, d, J=8,4 Hz), 4,27 (2H, the, J=7,1 Hz), 2,98 (2H, t, J=6.3 Hz), only 2.91 (2H, t, J=7,1 Hz), 2,33 (2H, t, J=5,9 Hz), was 2.05 (3H, s).

Stage 2. 2-{4-[6-chloro-2-[3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 4 of example 339, based on 2-(4-{[5-chloro-2-{[4-(2-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (stage 1).

1H-NMR (CDCl3) δ 8,43-to 8.45 (1H, m), of 8.09 (1H, s), 7,53-to 7.59 (1H, m), 7,45 (2H, d, J=8,2 Hz), 7,22-of 7.25 (3H, m), 7,05-7,13 (2H, m), 3,98 (2H, t, J=6.3 Hz), of 3.00 (2H, t, J=6.3 Hz), 2,84 (4H, t, J=7.5 Hz), 2,18-2,22 (2H, m), 1,81-1,90 (2H, m).

Stage 3. 2-{4-[6-Chloro-2-[3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylamino

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[6-chloro-2-[3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 2).

TPL: 193°C.

IR (KBr) v: 1747, 1626, 1517, 1433, 1350, 1159, 1120, 1085 cm-1.

MS (ESI) m/z: 657 (MH+), 655 ([M-H]-).

1H-NMR (CDCl3) δ of 8.47-8,49 (1H, m), 8,08 (1H, s), of 7.90 (2H, d, J=8,4 Hz), 7,60-7,66 (1H, m), of 7.36 (2H, d, J=8,4 Hz), 7,11-7,22 (7H, m), of 4.44 (2H, t, J=6.0 Hz), a 3.01 (2H, t, J=6.0 Hz), 2,82-is 2.88 (4H, m), of 2.45 (3H, C)1,84-of 1.94 (2H, m).

Example 344

2-{4-[6-chloro-2-[3-(pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylurea-p-toluensulfonyl the

The connection specified in the header received in accordance with the method described in example 231, on the basis of 2-{4-[6-chloro-2-[3-(2-pyridinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfanilamide (example 343).

TPL: 108-110 °C.

IR (KBr) v: 3062, 1745, 1456, 1232, 1163, 1010 cm-1.

Example 345

N-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. N-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazole-1-yl]phenyl}amino]carbonyl}-4-methylbenzenesulfonamide

A mixture of N-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide (example 78, 238 mg, 0.47 mmol) and 2 N. NaOH (0.1 ml) in ethanol (10 ml) was added a mixture of NaBH4(178 mg, 0.47 mmol) and 2 N. NaOH (0.1 ml) in ethanol (4 ml) at room temperature. The mixture was stirred at room temperature for 4 hours. The mixture was added water (10 ml) and neutralized NH4Cl. The mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated saline (10 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (1:4/1:6)/ CH2Cl2:methanol(10:1), with 198 mg (83%) of the compound indicated in the title, in the form of a white solid.

TPL: 190°C.

IR (KBr) v: 3384, 2979, 1716, 1514, 1404, 1159, 1087 cm-1.

MS (ESI) m/z: 507 (MH+), 505 ([M-H]-).

1H-NMR (CDCl3) δ 7,73-7,76 (3H, m), 7,21-7,34 (7H, m), 7,20 (1H, d, J=8.5 Hz), 6,66 (1H, Sirs), 5,02 (1H, q, J=6.4 Hz), 3,52-3,59 (2H, m), only 2.91 (2H, t, J=7.0 Hz), a 2.75 (2H, q, J=7.5 Hz), 2,39 (3H, s), and 1.54 (3H, d, J=6.4 Hz), of 1.30 (3H, t, J=7.5 Hz).

Example 346

p-Toluensulfonate N-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described in example 231, on the basis of N-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (example 345).

TPL: 110-115°C.

IR (KBr) v: 3062, 1708, 1519, 1340, 1163 cm-1.

Example 347

N-({[2-(4-{2-Ethyl-5-[1-(metiloksi)ethyl]-1H-benzimidazole-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide

Stage 1. N-[2-(4-{2-ethyl-5-[12-(metiloksi)ethyl]-1H-benzimidazole-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide

A solution of N-{[(2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (example 345,151 mg, 0.3 mmol) in CH2Cl2(15 ml) was added thionyl chloride (0.1 ml, 1.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue R which was storyli in methanol (15 ml). The mixture was added triethylamine (of 0.08 ml, 0.6 mmol) and stirred at room temperature for 5 hours. The solvent was removed and the residue was extracted with CH2Cl2(50 ml). The organic layer was washed with water (10 ml), saturated brine (10 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (1:6)/CH2Cl2:methanol (10:1), with 139 mg (89%) of the compound indicated in the title, in the form of a white solid.

MS (ESI) m/z: 521 (MH+), 519([M-H]-).

1H-NMR (CDCl3) δ the 7.65 to 7.75 (3H, m), 7,27-7,37 (6H, m), 7,16-7,20 (1H, m), 7,07 (1H, d, J=8,3 Hz), 6,69 (1H, Sirs), was 4.42 (1H, q, J=6.5 Hz), 3,54-3,62 (2H, m), up 3.22 (3H, s), with 2.93 (2H, t, J-7.0 Hz), with 2.93 (2H, t, J=7,0 Hz), 2,78 (2H, q, J=7,6 Hz), 2,39 (3H, s), for 1.49 (3H, d, J=6.5 Hz), 1,32 (3H, t, J=7,6 Hz).

Example 348

p-Toluensulfonate N-({[2-(4-{2-ethyl-5-[1-(metiloksi)ethyl]-1H-benzimidazole-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described in example 231, proceeding from N-({[2-(4-{2-ethyl-5-[l-(metiloksi)ethyl]-1H-benzimidazole-1-yl}phenyl)ethyl]amino}carbonyl)-4-methylbenzenesulfonamide (example 347).

TPL: 110-115°C.

IR (KBr) v: 3064, 1710, 1519, 1452, 1340, 1163, 1033 cm-1.

Example 349

p-Toluensulfonate N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H -benzimidazole-1-yl]phenyl)ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

A solution of N-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide (example 78, 100 mg, 0,19 mmol) in tetrahydrofuran (15 ml) was added MeMgI (1.2 ml, 0,99 mmol) dropwise under nitrogen atmosphere at 0°C. the Mixture was stirred at 0°C for 1 hour and then stirred at comentou temperature for 30 minutes. The mixture was added to water (10 ml) and was extracted with CH2Cl2(50 ml). The organic layer was washed with saturated saline (10 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira CH2Cl2:methanol (30:1/20:1/10:1), to obtain 100 mg (97%) of the compound indicated in the title, in the form of a white solid.

MS (ESI) m/z: 521 (MH+), 519 ([M-H]-).

1H-NMR (CDCl3) δ 7,87 (1H, s), 7,76 (2H, d, J=7.9 Hz), 7,17-7,38 (7H, m), 7,00 (1H, d, J=8.5 Hz), 6,69 (1H, Sirs), 3,52 (2H, Sirs), is 2.88 (2H, Sirs), 2,73 (2H, Sirs), a 2.36 (3H, s)of 1.62 (6H,s)of 1.27 (3H, m).

Stage 2. p-Toluensulfonate N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header, received and in accordance with the method, described in example 231, on the basis of N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (stage 1).

TPL: 146-150°C.

IR (KBr) v: 2871, 1685, 1519, 1448, 1340, 1124 cm-1.

Example 350

2-Ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

Stage 1. 1-[4-(2-Chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-lH-benzimidazole-5-carboxamide

A solution of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carbonitrile (example 329, stage 6,997 mg, 2,95 mmol) in S. H2SO4(50 ml) was stirred at 80°C for 15 hours. The mixture was poured on ice and neutralized with NaOH. The mixture was extracted with ethyl acetate (600 ml). The organic layer was washed with saturated saline (300 ml), then dried (Na2SO4). The solvent was removed to obtain 871 mg (83%) of the compound indicated in the title, in the form of a white solid.

MS (EI) m/z: 355 (M+).

1H-NMR (CDCl3) δ the 7.43 (2H, d, J=8,4 Hz), 7,28 (2H, d, J=8,4 Hz), was 6.73 (1H, s), 6,56 (1H, Sirs), 5,88 (1H, Sirs), 3,82 (2H, t, J=7.0 Hz), 3,19 (2H, t, J=7.0 Hz), 2,82 (2H, q, J=,6 Hz), of 2.72 (3H, s)to 2.41 (3H, s), of 1.26 (3H, t, J=7,6 Hz).

Stage 2. 1-[4-(2-Azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 8 of the example 1, on the basis of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide (step 1).

1H-NMR (CDCl3) δ 7,44 (2H, d, J=8,4 Hz), 7,27-7,30 (2H, m), of 6.73 (1H, s), 5,97 (1H, Sirs), 5,72 (1H, Sirs), 3,62 (2H, t, J=7,1 Hz), to 3.02 (2H, t, J=7,1 Hz), 2,80 (2H, q, J=7.5 Hz), 2,73 (3H, s), 2,42 (3H, s)of 1.26 (3H, t, J=7.5 Hz).

Stage 3. 1-[4-(2-amino-ethyl)l-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 1-[4-(2-azidoethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide (stage 2).

1H-NMR (CDCl3) δ 7,41 (2H, d, J=8,2 Hz), 7,26 (2H, d, J 8.2 Hz), 6,74 (1H, s), 6,00 (1H, Sirs), USD 5.76 (1H, Sirs), of 3.07 (2H, t, J=7,1 Hz), 2,87 (2H, t, J, and 7.1 Hz), 2,81 (211, kV, J=7.5 Hz), is 2.74 (3H, s), 2,43 (3H, s), of 1.26 (3H, t, J=7.5 Hz).

Stage 4. 2-Ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-[4-(2-amino-ethyl)phenyl]-2-ethyl-4,6-dimethyl-1H-benzimidazole-5-carboxamide (stage 3).

MS (ESI) m/z: 534 (MH+), 532 ([M-H]-).

1H-NMR (CD3OD) δ 7,88 (1H, s), 7,80 (2H, d, J=8,3 Hz), 7,25-7,42 (6H, m), 6,74 (1H, Sirs), 3,42 (2H, t, J=6.8 Hz), of 2.86 (2H, t, J=6.8 Hz), and 2.79 (2H, q, J=7,6 Hz), 2,65 (3H, s), is 2.37 (3H, s), of 2.34 (3H, s), 1,21 (3H, t, J=7,6 Hz).

Stage 5. p-Toluensulfonate 2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-IU is ylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1 H-benzimidazole-5-carboxamide

The connection specified in the header received in accordance with the method described in example 231, based on 2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide (stage 4).

Example 351

p-Toluensulfonate N-{[(2-{4-[2-ethyl-5-(TRIFLUOROACETYL)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. 2,2,2-Cryptor-1-(4-{[4-(2-hydroxyethyl)phenyl]amino}-3-nitrophenyl)alanon

The connection specified in the header received in accordance with the method described for stage 1 of example 45, from 1-(4-amino-3-nitrophenyl)-2,2,2-triptoreline.

1H-NMR (CDCl3) δ for 9.47 (1H, Sirs), 8,10 (1H, d, 1=2,6 Hz), 7,16-7,33 (6H, m), a 3.87-of 3.94 (2H, m), only 2.91 (2H, t, J=6.4 Hz), USD 1.43 (1H, t, J=5.6 Hz).

Stage 2. 1-(3-Amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)-2,2,2-triptoreline

The connection specified in the header received in accordance with the method described for stage 4 of example 1, from 2,2,2-Cryptor-1-(4-{[4-(2-hydroxyethyl)phenyl]amino}-3-nitrophenyl)ethanone (stage 1).

1H-NMR (CDCl3) δ 7,05-to 7.09 (3H, m), 6,57-6,70 (4H, m), 3,82 (2H, t, J=6.6 Hz), 2,78 (2H, t, J=6.6 Hz).

Stage 3. 2-{4-[2-Ethyl-5-(TRIFLUOROACETYL)-1H-benzimidazole-1-yl]phenyl}ethylpropane

The connection specified in the header received in accordance with the method, opisannymi stage 5 of example 1, on the basis of 1-(3-amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)-2,2,2-triptoreline (stage 2).

1H-NMR (CDCl3) δ the 7.65 (1H, s), was 7.45 (2H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), 7,06 (2H, s), to 4.38 (2H, t, J=6.9 Hz), of 3.07 (2H, t, J=6.9 Hz), and 2.79 (2H, q, J=7.4 Hz), 2,35 (2H, q, J=7.5 Hz), of 1.35 (3H, t, J=7,4 Hz)to 1.14 (3H, t, J=7.5 Hz).

Stage 4. 1-{2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}-2,2,2-triptoreline

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-{4-[2-ethyl-5-(TRIFLUOROACETYL)-1H-benzimidazole-1-yl]phenyl}ethyl-propanoate (stage 3).

1H-NMR (CDCl3) δ the 7.65 (1H, s), 7,47 (2H, d, J=8,4 Hz), 7,29 (2H, d, J=8,4 Hz), 7,06 (2H, s), 3.96 points-a 4.03 (2H, m), a 3.01 (2H, t, J=6.6 Hz), and 2.79 (2H, q, J=7,6 Hz)of 1.35 (3H, t, J=7,6 Hz).

Stage 5. 1-{1-[4-(2-Chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}-2,2,2-triptoreline

The connection specified in the header received in accordance with the method described for stage 7 example 1 from 1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}-2,2,2-triptoreline (stage 4).

1H-NMR (CDCl3) δ 7,66 (1H, s), was 7.45 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,4 Hz), 7,07 (2H, s), 3,82 (2H, t, J=7.0 Hz), 3,20 (2H, t, J=7,0 Hz), and 2.79 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

Stage 6. 1-{4-(2-Azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}-2,2,2-triptoreline

The connection specified in the header received in accordance with the method described for stage 8, the use of the 1, on the basis of 1-{1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}-2,2,2-triptoreline (stage 5).

1H-NMR (CDCl3) δ the 7.65 (1H, s), 7,46 (2H, d, J=8,4 Hz), 7,31 (2H, d, J=8,4 Hz), 7,06 (1H, s), 3,62 (2H, t, J=7.0 Hz), to 3.02 (2H, t, J=7,0 Hz), and 2.79 (2H, q, J=7.5 Hz), of 1.35 (3H, t, J=7.5 Hz).

Stage 7. 1-{1-[4-(2-amino-ethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}-2,2,2-triptoreline

The connection specified in the header received in accordance with the method described for stage 9 of example 1 from 1-{1-[4-(2-azidoethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}-2,2,2-triptoreline (stage 6).

1H-NMR (CDCl3) δ the 7.65 (1H, s), the 7.43 (2H, d, J=8.5 Hz), 7,28 (2H, d, J=8.5 Hz), 7,07 (2H, s)to 3.09 (2H, t, J=6,7 Hz), 2,89 (2H, t, J=6,7 Hz), and 2.79 (2H, q, J=7.4 Hz), of 1.35 (3H, t, J=7,4 Hz).

Stage 8. N-{[(2-{4-[2-Ethyl-5-(TRIFLUOROACETYL)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 1-{1-[4-(2-amino-ethyl)phenyl]-2-ethyl-1H-benzimidazole-5-yl}-2,2,2-triptoreline (stage 7).

MS (ESI) m/z: 547 (MH+), 545 ([M-H]-).

1H-NMR (CDCl3) δ 7,72 (2H, d, J=8,4 Hz), to 7.64 (1H, s), 7,39 (2H, d, J=8,4 Hz), 7,27-7,29 (4H, m), 7,02? 7.04 baby mortality (2H, m), of 6.75 (1H, Sirs), 3,55-3,62 (2H, m)to 2.94 (2H, t, J=6.9 Hz), and 2.79 (2H, q, J=7.5 Hz), 2,39 (3H, s), of 1.33 (3H, t, J=7.5 Hz).

Stage 9. p-Toluensulfonate N-{[(2-{4-[2-ethyl-5-(TRIFLUOROACETYL)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-IU is albenzaalbenza

The connection specified in the header received in accordance with the method described in example 231, on the basis of N-{[(2-{4-[2-ethyl-5-(TRIFLUOROACETYL)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (stage 8).

TPL: 194,1°C.

IR (KBr) v: 3589, 1701, 1627, 1521, 1458, 1330, 1091 cm-1.

Example 352

p-Toluensulfonate 2-{4-[2-ethyl-5-(TRIFLUOROACETYL)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylamino

Stage 1. 2-{4-[2-Ethyl-5-(TRIFLUOROACETYL)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 1-{2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}-2,2,2-triptoreline (example 351, stage 4).

MS (ESI) m/z:548 (MH+), 546 ([M-H]-).

1H-NMR (CDCl3) δ to 7.93 (2H, d, J=8,4 Hz), to 7.64(1H, s), 7,28-to 7.35 (4H, m), 7,20 (2H, d, J=8,4 Hz), 7,05-7,07 (2H, m), 4,37 (2H, t, J=6,6 Hz)of 3.00 (2H, t, J=6.6 Hz), was 2.76 (2H, q, J=7,6 Hz), 2,43 (3H, s)is 1.31 (3H, t, J=7,6 Hz).

Stage 2. p-Toluensulfonate 2-{4-[2-ethyl-5-(TRIFLUOROACETYL))-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 231, on the basis of 2-{4-[2-ethyl-5-(TRIFLUOROACETYL)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfanilamide (stage 1).

TPL: 92-97°C.

IR (Br) v: 1745, 1519, 1458, 1350, 1222, 1163, 1122 cm-1.

Example 353

p-Toluensulfonate 2-{4-[5-acetyl-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-ilvesniemi (4-were)sulfonylureas

Stage 1. 1-[1-[4-(2-Hydroxyethyl)phenyl]-2-(1H-pyrazole-3-yl)-1H-benzimidazole-5-yl]alanon

The connection specified in the header received in accordance with the method described for stage 1 of example 236, on the basis of 1-(3-amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)alanon (example 78, step 2).

MS (EI)m/z:345 (M+).

1H-NMR (CDCl3) δ 8,53 (1H, s), 7,94 (1H, d, J=8,4 Hz), of 7.48-7,53 (3H, m), 7,37 (2H, d, J=8,2 Hz), 7,27 (1H, s), 7,18 (1H, d, J=8,4 Hz), 6,03 (1H, Sirs), was 4.02 (2H, t, J=6.6 Hz), 3,05 (2H, t, J=6.6 Hz), 2,69 (3H, ).

Stage 2. 2-{4-[5-acetyl-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 1-[1-[4-(2-hydroxyethyl)phenyl]-2-(1H-pyrazole-3-yl)-1H-benzimidazole-5-yl]alanon (stage 1).

MS (ESI) m/z: 544 (MH+), 542 ([M-H]-).

1H-NMR (DMSO-d6) δ to 8.41 (1H, s), to 7.77-7,89 (4H, m), 7,38-7,42 (7H, m), 7,12 (1H, d, J=8.5 Hz), of 6.65 (1H, Sirs), the 4.29 (2H, t, J=6.6 Hz), 2,96 (2H, t, J=6.6 Hz), to 2.66 (3H, s)to 2.35 (3H, s).

Stage 3. p-Toluensulfonate 2-{4-[5-acetyl-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the special described in example 231, on the basis of 2-{4-[5-acetyl-2-(1H-pyrazole-3-yl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfanilamide (stage 2).

TPL: 204°C.

IR(KBr) v: 3249, 1755, 1676, 1595, 1517, 1440, 1332, 1207, 1161, 1008 cm-1.

Example 354

p-Toluensulfonate N-{[(2-{4-[6-chloro-2-[1-(metiloksi)ethyl]-5-(trifloromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. 2-(4-{[5-Chloro-2-[(2-hydroxypropanoyl)amino]-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate

The connection specified in the header received in accordance with the method described for stage 3 of example 339, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (example 339, step 2).

MS (EI)m/z:444(M).

Stage 2. 2-{4-[6-Chloro-2-(1-hydroxyethyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}acetate

The connection specified in the header received in accordance with the method described for stage 4 of example 339, based on 2-(4-{[5-chloro-2-[(2-hydroxypropanoyl)amino]-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (stage 1)

1H-NMR (CDCl3) δ to 8.14 (1H, s)of 7.48 (2H, d, J=8,4 Hz), 7,34 (2H, d, J=8,4 Hz), 7,24 (1H, s), 4,88-to 4.98 (1H, m), to 4.38 (2H, t, J=7.0 Hz), 3,66 (1H, d, J=8.1 Hz), is 3.08 (2H, t, J=7.0 Hz), is 2.09 (3H, s)of 1.57 (3H, d, J=6,6 Hz).

Stage 3. 1-[6-Chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethanol

The connection specified in the header, we shall do in accordance with the method, described for stage 6 of example 1 from 2-{4-[6-chloro-2-(l-hydroxyethyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl acetate (stage 2).

MS (ESI) m/z: 384 (M+).

1H-NMR (CDCl3) δ to 8.14 (1H, s), 7,49 (2H, d, J=8.6 Hz), 7,34 (2H, d, J=8.6 Hz), 7,25 (1H, s), 4,89-4,96 (1H, m), 3,98 (2H, t, J=6.2 Hz), to 3.36 (1H, d, J=5.5 Hz), a 3.01 (2H, t, J=6.2 Hz), and 1.54 (3H,m).

Stage 4. 1-[6-Chloro-1-[4-(2-[[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethanol

A mixture of 1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethanol (stage 3,461 mg, 1,19 mmol), tert-butyldiphenylsilyl (0.35 ml, 1.3 mmol), triethylamine (0.2 ml, 1.4 mmol) and N,N-dimethylaminopyridine (6 mg, 0.05 mmol) in dichloromethane (11 ml) was stirred atomsphere nitrogen at room temperature for 4 hours. Was added water (50 ml) and was extracted with dichloromethane (100 ml). The organic layer was washed with water (50 ml), saturated brine (50 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (3:1/1:1) to give 590 mg (80%) of the compound indicated in the title, in the form of a white amorphous substance.

1H-NMR (CDCl3) δ to 8.14 (1H, s), to 7.59-7,63 (4H, m), 7,34-7,46 (8H, m), 7,22-7,30 (3H, m), 4,87-4,96 (1H, m), of 3.94 (2H, t, J=6.4 Hz), 3,29 (1H, d, J=8.1 Hz), of 2.97 (2H, t, J=6.4 Hz), of 1.52 (3H, d, J=6.6 Hz), of 1.03 (9H, C).

Stage 5. 6-Chloro-1-[4-(-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)phenyl]-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1 H-benzimidazole

A solution of 1-[6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethanol (stage 4,590 mg, 0.95 mmol) in DMF (10 ml) was added NaH (45 mg, 1.13 mmol). Then the mixture was added MeI (0,08 ml of 1.23 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was added to water (30 ml) and was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), saturated brine (50 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira hexane/ethyl acetate (3:1), with 550 mg (91%) of the compound indicated in the title, in the form of a colorless oil.

1H-NMR (CDCl3) δ 8,17 (1H, s), 7,20-7,70 (15H, m), of 4.54 (1H, q, J=6.6 Hz), of 3.95 (2H, t, J=6.6 Hz), up 3.22 (3H, s), of 2.97 (2H, t, J=6.6 Hz), of 1.55 (3H, d, J=6.6 Hz), of 1.03 (9H, s).

Stage 6. 2-{4-[6-Chloro-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 90, from 6-chloro-1-[4-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)phenyl]-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole (step 5).

MS (ESI) m/z: 398.

1H-NMR (CDCl3) δ 8,18 (1H, s), 7,49 (2H, d, J=8,4 Hz), 7,33 (2H, d, J=8,4 Hz), 7,24 (1H, s), 4,58 (1H, q, J=6.6 Hz), 4,00 (2H, Sirs), 3,24 (3H, s), 302 (2H, t, J=6.5 Hz), 1,55-1,60 (3H, m).

Stage 7. 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 7 of example 1 from 2-{4-[6-chloro-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 6).

MS (ESI) m/z: 416 (M+).

1H-NMR (CDCl3) δ 8,18 (1H, s)of 7.48 (2H, d, J=8.5 Hz), 7,35 (2H, d, J=8.5 Hz), 7.23 percent (1H, s), to 5.57 (1H, q, J=6.6 Hz), 3,83 (2H, t, J=7,1 Hz), 3,19-3,24 (5H, m)of 1.57 (3H, d, J=6,6 Hz).

Stage 8. 1-[4-(2-Azidoethyl)phenyl]-6-chloro-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole

The connection specified in the header received in accordance with the method described for stage 8 of example 1 from 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole (stage 7).

MS (ESI) m/z: 423 (M-).

1H-NMR (CDCl3) δ 8,18 (1H, s)of 7.48 (2H, d, J=8,2 Hz), 7,35 (2H, d, J=8,2 Hz), 7,22 (1H, s), of 4.57 (1H, q, J=6.6 Hz), 3,63 (2H, t, J=6.9 Hz), 3,23 (3H, s), totaling 3.04 (2H, t, J=6.9 Hz), and 1.56 (3H, d, J=6,6 Hz).

Stage 9. 2-{4-[6-Chloro-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanamine

The connection specified in the header received in accordance with the method described for stage 7 of example 37, from 1-[4-(azidoethyl)phenyl]-6-chloro-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole (step 8).

1H-NMR (CDCl 3) δ 8,18 (1H, s), was 7.45 (2H, d, J=8,4 Hz), 7,32 (2H, d, J=8,4 Hz), 7,24 (1H, s), of 4.57 (1H, q, J=6.6 Hz), 3,23 (3H, s), 3,10 (2H, Sirs), 2,90 (2H, t, J=6.6 Hz), of 1.57 (3H, d, J=6,6 Hz).

Stage 10. N-{[(2-{4-[6-Chloro-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described for stage 10 of example 1 from 2-{4-[6-chloro-2-[l-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethanamine (stage 9).

MS (ESI) m/z: 595 (MH+), 593 ([M-H]-).

1H-NMR (CDCl3) δ 8,18 (1H, s), 7,73 (2H, d, J=8,4 Hz), 7,42 (2H, d, J=8.6 Hz), 7,27-7,34 (4H, m), 7,21 (1H, s)6,76 (1H, Sirs), of 4.57 (1H, q, J=6.6 Hz), 3,56-3,63 (2H, m), 3,23 (3H, s), 2,96 (2H, t, J=7,1 Hz), 2,41 (3H, s), and 1.56 (3H, d, J=6,6 Hz).

Stage 11. p-Toluensulfonate N-{[(2-{4-[6-chloro-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described in example 231, on the basis of N-{[(2-{4-[6-chloro-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (stage 10).

IR (KBr) v: 2873,1712, 1517,1454, 1342,1122, 1033, 1010 cm-1.

Example 355

p-Toluensulfonate 2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylamino

Stage 1. 2-{4-[2-Ethyl-5-(1-hydro is setil)-1 H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 345, based on 2-[4-(5-acetyl-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfanilamide (example 332).

MS (ESI) m/z: 508(MH+), 506 ([M-H]-).

1H-NMR (CDCl3) δ 7,94 (2H, d, J=8,3 Hz), to 7.77 (1H, s), 7.03 is-to 7.35 (8H, m), 5,04 (1H, q, J=6.4 Hz), 4,36 (2H, t, J=6.6 Hz), of 2.97 (2H, t, J=6.6 Hz), is 2.74 (2H, q, J=7.5 Hz), 2,43 (3H, s), and 1.56 (3H, d, J=6.4 Hz), of 1.28 (3H, t, J=7.5 Hz).

Stage 2. p-Toluensulfonate 2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylamino

The connection specified in the header received in accordance with the method described in example 231, on the basis of 2-{4-[2-ethyl-5-(1-hydroxyethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfanilamide (stage 1)

TPL: 96-110°C.

IR (KBr) v: 1743, 1519, 1456, 1163, 1033, 1010 cm-1.

Example 356

p-Toluensulfonate 2-{4-[2-ethyl-4-methyl-5-(metiloksi)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylamino

Stage 1. 2-(4-{[3-Methyl-4-(metiloksi)-2-nitrophenyl]amino}phenyl)ethanol

The connection specified in the header received in accordance with the method described for stage 3 of example 1 from 1-chloro-3-methyl-4-(metiloksi)-2-nitrobenzene

MS (EI) m/z: 302 (M+).

1H-NMR (CDCl3) δ 7,11-7,20 (3H, m), 6,89-of 6.96 (3H, m), 6,53 (1H, Sirs), 3,83 (5H, Sirs), of 2.81 (2H, t, J=6,4 Hz in), 2.25 (3H, s).

Stage 2. 2-(4-{[2-Amino-3-methyl-4-(metiloksi)phenyl]amino}phenyl)ethanol

The connection specified in the header received in accordance with the method described for stage 4 of example 1 from 2-(4-{[3-methyl-4-(metiloksi)-2-nitrophenyl]amino}phenyl)ethanol (step 1).

MS (EI) m/z: 272 (M+).

1H-NMR (CDCl3) δ 7,03 (2H, d, J=8.6 Hz), 6,92 (1H, d, J=8.6 Hz), to 6.57 (2H, d, J=8.6 Hz), 6,32 (2H, d, J=8.6 Hz), free 5.01 (1H, Sirs), of 3.77-are 3.90 (7H, m), was 2.76 (2H, t, J=6.4 Hz), is 2.09 (3H, s).

Stage 3. 2-{4-[2-Ethyl-4-methyl-5-(metiloksi)-1H-benzimidazole-1-yl]phenyl}ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-(4-{[2-amino-3-methyl-4-(metiloksi)phenyl]amino}phenyl)ethanol (step 2).

MS (EI) m/z: 366 (M+).

Stage 4. 2-{4-[2-Ethyl-4-methyl-5-(metiloksi)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-{4-[2-ethyl-4-methyl-5-(metiloksi)-1H-benzimidazole-1-yl]phenyl}ethyl-propanoate (stage 3).

1H-NMR (CDCl3) δ 7,42 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8.1 Hz), at 6.84 (2H, s), of 3.97 (2H, t, J=6.4 Hz), 3,86 (3H, s)to 2.99 (2H, t, J=6.4 Hz), of 2.81 (2H, q, J=7,7 Hz), 2,58 (3H, s)of 1.26 (3H, t, J=7,7 Hz).

Stage 5. 2-{4-[2-Ethyl-4-methyl-5-(metiloksi)-1H-benzimidazole-1-yl]phenyl}ethyl(4-IU is ylphenyl)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[2-ethyl-4-methyl-5-(metiloksi)-1H-benzimidazole-1-yl]phenyl}ethanol (step 4).

MS (ESI) m/z: 508(MH+), 506 ([M-H]-).

1H-NMR (CDCl3) δ 7,98 (2H, d, J=8,3 Hz), 7,33 (2H, d, J=8,9 Hz), 6,88-6,91 (6H, m), 4,28 (2H, t, J=6.0 Hz), with 3.89 (3H, s)2,84 (2H, t, J=6.0 Hz), is 2.74 (2H, q, J=7.5 Hz), of 2.56 (3H, s), 2,43 (3H, s)of 1.05 (3H, t, J=7.5 Hz).

Stage 6. p-Toluensulfonate 2-{4-[2-ethyl-4-methyl-5-(metiloksi)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 231, on the basis of 2-{4-[2-ethyl-4-methyl-5-(metiloksi)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfanilamide (stage 5).

TPL: 94-103°C.

IR (KBr) v: 1747, 1458, 1232, 1163, 1120 cm-1.

Example 357

2-[4-(2-Ethyl-5-phenyl-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[(4-Bromo-2-nitrophenyl)amino]phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 162, based on 2,5-dibromantratsena.

1H-NMR (CDCl3) δ 9,43 (1H, Sirs), to 8.34 (1H, d, J=2.4 Hz), 7,43-7,39 (1H, m), 7,30 (2H, d, J=8,3 Hz), 7,20 (2H, d, J=8,3 Hz), was 7.08 (1H, d, J=9,2 Hz), 3,94-3,88 (2H, m), 2,90 (2H, d, J=6.4 Hz), USD 1.43 (1H, t, J=5.7 Hz).

Stage 2. 2-{4-[(2-Amino-4-bromophenyl)amino]phenyl}ethanol/u>

The connection specified in the header received in accordance with the method described for step 2 of example 28, from 2-{4-[(4-bromo-2-nitrophenyl)amino]phenyl}ethanol (step 1).

1H-NMR (CDCl3) δ was 7.08 (2H, d, J=8,4 Hz), 6,97-6,93 (2H, m), at 6.84 (1H, DD, J=8,3, 2.2 Hz), 6,69 (2H, d, J=8.6 Hz), 5,04 (1H, Sirs), 3,80 (2H, Sirs), 3,82 (2H, t, J=6.4 Hz), and 2.79 (2H, t, J=6.4 Hz).

Stage 3. 2-[4-(5-Bromo-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropane

The connection specified in the header received in accordance with the method described for stage 5 of example 1 from 2-{4-[(2-Amino-4-bromophenyl)amino]phenyl}ethanol (step 2).

MS (EI)m/z 401 (M+).

Stage 4. 2-[4-(5-Bromo-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol

The connection specified in the header received in accordance with the method described for stage 6 of example 1 from 2-[4-(5-bromo-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethylpropylamine (stage 3).

1H-NMR (CDCl3) δ of 7.90 (1H, s), was 7.45 (2H, d, J=8.1 Hz), 7,26-7,30 (3H, m), of 6.96 (1H, d, J=8,4 Hz), 3,98 (2H, m)of 3.00 (2H, t, J=6.4 Hz), 2,78 (2H, q, J=7,6 Hz)of 1.34 (3H, t, J=7,6 Hz).

Stage 5. 2-[4-(2-Ethyl-5-phenyl-1H-benzimidazole-1-yl)phenyl]ethanol

To a solution of 2-[4-(5-bromo-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (step 4, 116 mg, or 0.57 mmol) in 1,2-dimethoxyethane (DME, 6 ml) was added PhB(OH)2(141 mg, of 1.16 mmol), K2CO3(240 mg, about 1.75 mmol) and Pd (PPh3)4(67 mg, 0.06 mmol). This mixture was stirred at 5° With over 11 hours. The reaction mixture was diluted with water and was extracted with CH2Cl2(4 x 10 ml). The organic layer was dried (MgSO4) and concentrated to obtain a brown oil. This mixture was purified with SiO2preparative TLC (hexane/ethyl acetate = 1/5), to obtain 52 mg (27%) of the connection specified in the header.

MS (EI) m/z 342(M+).

1H-NMR (CDCl3) δ 8,00 (1H, d, J=1.6 Hz), the 7.65 (2H, DD, J=1,6, and 8.4 Hz), 7,42-of 7.48 (5H, m), 7,32-to 7.35 (3H, m), to 7.15 (2H, d, J=8,4 Hz), 4,00 (2H, shirt), a 3.01 (2H, t, J=6.5 Hz), 2,82 (2H, q, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz).

Stage 6. 2-[4-(2-Ethyl-5-phenyl-1H-benzimidazole-1-yl)phenyl]ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-[4-(2-ethyl-5-phenyl-1H-benzimidazole-1-yl)phenyl]ethanol (stage 5).

MS (ESI) m/z 540 [M+H]+, 538 [M-H]-.

1H-NMR (CDCl3) δ 8,00 (1H, s), 7,94 (2H, d, J=8,2 Hz), the 7.65 (2H, d, J=8.6 Hz), 7,43-of 7.48 (3H, m), 7.29 trend was 7.36 (7H, m), to 7.15 (2H, d, J=8,4 Hz), 4,39 (2H, t, J=6.8 Hz), a 3.01 (2H, t, J=6.4 Hz), 2,70 (2H, q, J=7,4 Hz), 2,43 (s, 3H), of 1.35 (3H, t, J=7,6 Hz).

Example 358

2-{4-[2-Ethyl-5-(5-pyrimidinyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[2-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole-1-yl]phenyl}ethanol

To a solution of 2-[4-(5-bromo-2-ethyl-1H-benzimidazole-1-yl)phenyl]ethanol (example 357 stage , 2.5 g of 7.24 mmol) and Bisengaliev (1.84 g, from 7.24 mmol) in DMSO was added KOAc (2,13 g, and 21.7 mmol), 1,1'-bis(diphenylphosphino)ferrocene (241 mg, 0.43 mmol) and Pd(dppf) Cl2-CH2Cl2(362 mg, 0.44 mmol). This mixture was stirred at 80°C for 7 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 80 ml). The organic layer was washed with saturated saline solution, dried (MgSO4) and concentrated to obtain a black oil. This mixture was purified using neutral SiO2chromatography elwira hexane/ethyl acetate (1:4), with the receipt of 1.38 g (35%) of the compound indicated in the title, in the form of a pink solid.

MS (EI) m/z 391 [M-H]+.

1H-NMR (CDCl3) δ of 8.25 (1H, s), to 7.64 (2H, DD, J=0,8 and 8.1 Hz), was 7.45 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), was 7.08 (1H, d, J=8.1 Hz), 3,99 (2H, t, J=6.5 Hz), of 3.00 (2H, t, J=6.5 Hz), of 2.81 (2H, q, J=7,6 Hz), 1,36 (12H, s)of 1.32 (3H, t, J=7,8 Hz).

Stage 2. 2-{4-[2-Ethyl-5-(5-pyrimidinyl)-1H-benzimidazole-1-yl]phenyl}ethanol

To a solution of 2-{4-[2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 1, 100 mg, 0.26 mmol) and 5-bromopyrimidine (45 mg, 0.28 mmol) in 1,2-dimethoxyethane (3.5 ml) was added to feast upon. aqueous NaHCO3(1.2 ml) and Pd(PPh3)4(60 mg, 0.05 mmol). This mixture was stirred at 70°C for 17 hours. The reaction mixture was diluted with water and was extracted with CH2Cl2(3 x 10 ml). The organization is practical layer was dried (MgSO 4) and concentrated to obtain a light brown oil. This mixture was purified with SiO2preparative TLC (CH2Cl2/methanol = 10/1), to obtain 45 mg (50%) of the connection specified in the header.

MS (EI) m/z 344 (M+).

1H-NMR (CDCl3) δ 9,19 (1H, s), of 9.00(2H, s), to 7.99 (1H, s), 7,49 (2H, d, J=8,2 Hz), 7,31-7,42 (3H, m), 7.23 percent (1H, d, J=8,4 Hz), of 4.00 (2H, q, J=6,1 Hz), to 3.02 (2H, t, J=6.4 Hz), and 2.83 (2H, q, J=7,6 Hz)of 1.39 (3H, t, J=7,6 Hz).

Stage 3. 2-{4-[2-Ethyl-5-(5-pyrimidinyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[2-ethyl-5-(5-pyrimidinyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 2).

MS (ESI) m/z 542 [M+H]+, 540[M-H]-.

1H-NMR (CDCl3) δ 9,20 (1H, s), 8,97 (2H, s), 7,30-7,42 (4H, m), from 7.24 (2H, d, J=8,2 Hz), 7,14 (2H, d, J=8,2 Hz)to 4.41 (2H, t, J=6.4 Hz), 3,03 (2H, t, J=6,1 Hz), 2,89 (2H, q, J=7.4 Hz), 2,43 (3H, s)of 1.34 (3H, t, J=7,4 Hz).

Example 359

2-{4-[2-Ethyl-5-(4-pyridinyl)-1H-benzimidazole-1-yl]phenyl}-ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[2-Ethyl-5-(4-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 358, based on 4-bromopyridine hydrochloride (stage 2).

MS (EI) m/z 343(M)+.

1H-NMR (CDCl3) δ 8,66 (2H, d, J=6,1 Hz), and 8.0 (1H, d, J=1.2 Hz), EUR 7.57 (2H, d, J=6,1 Hz), 7,45-7,52 (3H, m), 7,34 (2H, d, J=8,4 Hz), 7,20 (1H, d, J=8,4 Hz), 4,00 (2H, Sirs), 3,03 (2H, t, J=6.6 Hz), and 2.83 (2H, q, J=7,4 Hz)of 1.39 (3H, t, J=7,4 Hz).

Stage 2. 2-{4-[2-Ethyl-5-(4-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[2-ethyl-5-(4-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 1).

MS (ESI) m/z 541 [M+H]+, 539 [M-H]-.

1H-NMR (CDCl3) δ charged 8.52 (2H, d, J=5.8 Hz), 8,00 (1H, s), 7,94 (2H, d, J=8.1 Hz), of 7.48 (2H, d, J=5.8 Hz), 7.23 percent-yield of 7.40 (5H, m), 7,20 (2H, d, J=8.1 Hz), 7,00 (2H, d, J=8,2 Hz)to 4.41 (2H, t, J=5.8 Hz), to 3.02 (2H, t, J=5.8 Hz), was 2.76 (2H, q, J=7.4 Hz), 2,39 (3H, s)of 1.32 (3H, t, J=7,4 Hz).

Example 360

2-{4-[2-Ethyl-5-(3-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[2-Ethyl-5-(3-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 358, based on 3-bromopyridine.

MS (EI) m/z 343 (M)+.

1H-NMR (CDCl3) δ 8,91 (1H, d, J=1,8 Hz), 8,55-8,61 (1H, m), of 8.00 (1H, s), of 7.90-of 7.97 (1H, m), of 7.48 (2H, d, J=8,2 Hz), 7,42 (1H, d, J=8.7 Hz), 7,35 (2H, d, J=8,2 Hz), 7,21 (1H, d, J=8,4 Hz), 4,00 (2H, m), to 3.02 (2H,, t, J=6.5 Hz), and 2.83 (2H, q, J=7,6 Hz), 1,92 (1H, s)of 1.39 (3H, t, J=7,6 Hz).

Stage 2. 2-{4-[2-Ethyl-5-(3-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Connect the tion, specified in the header received in accordance with the method described in example 3 from 2-{4-[2-ethyl-5-(3-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 1).

MS (ESI) m/z 541 [M+H]+, 539 [M-H]-.

1H-NMR (CDCl3) δ 8,76 (1H, s), 8,63 (1H, m), 7,87 shed 8.01 (4H, m), 7,22-to 7.50 (6H, m), 7.23 percent-yield of 7.40 (5H, m), 7,16 (2H, d, J=8,2 Hz), 7,00 (1H, d, J=8,2 Hz), 4,42 (2H, Sirs), a 3.01 (2H, Sirs), is 2.74 (2H, q, J=7.4 Hz), 2,43 (3H, C)to 1.31 (3H, t, J=7,4 Hz).

Example 361

2-{4-[2-Ethyl-5-(2-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[2-Ethyl-5-(2-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 358, based on 2-bromopyridine.

MS (EI) m/z 343 (M)+.

1H-NMR (CDCl3) δ to 8.70 (1H, DD, J=1,5, with 5.3 Hz), 8,32 (1H, d, J=1.5 Hz), 8,00 (1H, DD, J=1,5, and 8.4 Hz), 7,76-7,80 (2H, m), of 7.48 (2H, d, J=8,2 Hz), 7,35 (2H, d, J=8,2 Hz), 7,16-of 7.23 (2H, m), 3,93-of 4.05 (2H, m), 3,01 (2H, t, J=6.6 Hz), and 2.83 (2H, q, J=7,6 Hz), at 1.91 (1H, s)to 1.38 (3H, t, J=7,6 Hz).

Stage 2. 2-{4-[2-Ethyl-5-(2-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[2-ethyl-5-(2-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 1).

MS (ESI) m/z 541 [M+H]+, 539[M-H]-.

1H-NMR (CDCl3) δ 8,68 (1H, d, J=4.6 Hz), 8,31 1H, C)7,88-7,98 (3H, m), 7,73-of 7.82 (2H, m), 7,17-7,26 (5H, m), 7,07-7,17 (3H, m), the 4.29 (2H, t, J=6.3 Hz), 2,90 (2H, t, J=6.4 Hz), 2,73 (2H, q, J=7,6 Hz), a 2.36 (3H, s)of 1.28 (3H, t, J=7,6 Hz).

Example 362

2-{4-[2-Ethyl-5-(4-pyridinyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

Stage 1. 2-{4-[2-Ethyl-5-(1-methyl-1H-pyrazole-4-yl)-1H-benzimidazole-1-yl]phenyl}ethanol

The connection specified in the header received in accordance with the method described for stage 1 of example 358, based on 4-bromo-1-methyl-1H-pyrazole (Huettel et al.,Liebigs Ann. Chem., 1955, 593, 179).

MS (EI) m/z 343 (M+).

1H-NMR (CDCl3) δ 7,86 (1H, s), 7,78 (1H, s), 7,46 (2H, d, J=8,4 Hz), 7,28-to 7.35 (3H, m), to 7.09 (2H, d, J=8,2 Hz), 3,99 (2H, m), a 3.01 (2H, t, J=6.4 Hz), of 2.81 (2H, q, J=7,6 Hz)of 1.36 (3H, t, J=7,6 Hz).

Stage 2. 2-{4-[2-Ethyl-5-(1-methyl-1H-pyrazole-4-yl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from 2-{4-[2-ethyl-5-(1-methyl-1H-pyrazole-4-yl)-1H-benzimidazole-1-yl]phenyl}ethanol (step 1).

MS (ESI) m/z 544 [M+H]+, 542 [M-H]-.

1H-NMR (CDCl3) δ to 7.95 (1H, s), 7,92 (1H, s), 7,86 (4H, m), to 7.77 (1H, s), a 7.62 (1H, s), 7.24 to 7,40 (7H, m), 7,06 (21H, d, J=7,7 Hz), 4,39 (2H, t, J=6.0 Hz), of 3.97 (3H, s), to 3.02 (2H, q, J=6.3 Hz), 2,78 (2H, q, J=the 7.4 Hz), 2,44 (3H, s)of 1.35 (3H, t, J=7,4 Hz).

Example 363

2-{4-[6-Chloro-2-[3-oxo-3-(1-pyrrolidinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 339, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (example 339, step 2) and 4-oxo-4-(1-pyrrolidinyl)butane acid (McCasland; Proskow,J. Org. Chem., 1957, 22, 122.).

TPL: 98-105°C.

IR (KBr) v: 2875, 1747, 1624, 1517, 1400, 1346, 1130, 1085 cm-1.

MS (ESI) m/z: 663 (MH+), 661([M-H]-).

1H-NMR (CDCl3) δ 8,08 (1H, s), 7,92 (2H, d, J=8,2 Hz), 7,22 and 7.36 (7H, m), to 4.38 (2H, t, J=6.6 Hz), 3,49 (2H, t, J=6.8 Hz), of 3.43 (2H, t, J=6.8 Hz), 2,97-of 3.07 (4H, m), is 2.88 (2H, m), is 2.44 (3H, s), 1,94-to 1.98 (2H, m), 1,82 is 1.86 (2H, m).

Example 364

2-{4-[6-Chloro-2-[3-oxo-3-(1-piperidinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 339, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (example 339, step 2) and 4-oxo-4-(1-piperidinyl)butane acid (Becker, Frederick F.; Banik, Service K.,Bioorg.Med. Chem. Lett., 1998, 20, 2877).

TPL: 210°C.

IR (KBr) v: 1753, 1649, 1515, 1433, 1406, 1366, 1161, 1118, 1091 cm-1.

MS (ESI) m/z: 677 (MH+), 675 ([M-H]-).

1H-NMR (CDCl3) δ to 8.14 (1H, s), 7,78 (2H, d, J=8,4 Hz), 7,47-7,56 (4H, m), 7,42 (2H, d, J=8,4 Hz), 7,31 (1H, s), the 4.29 (2H, t, J=6.6 Hz), 3,37 is 3.40 (4H, m), 2,92-2,99 (6H, m), a 2.36 (3H, s), 1,50-of 1.56 (4H, m), 1,35-of 1.36 (2H, m).

Example 365

2-{4-[6-Chloro-2-[3-(2-oxo-1-pyrrolidinyl)propyl]-5-(thrift rmutil)-1 H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 339, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (example 339, step 2) and 4-(2-oxo-1-pyrrolidinyl)butane acid (Miyano, Seiji; Fujii, Shinichiro; Yamashita, Osamu; Toraishi, Naoko; Sumoto, Kunihiro,J. Heterocycl. Chem.,1982, 19, 1465).

TPL: 85-90°C.

IR (KBr) v: 1745, 1624, 1517, 1433, 1348, 1299, 1161, 1130, 1085 cm-1.

MS (ESI) m/z: 663(MH+), 661 ([M-H]-).

1H-NMR (CDCl3) δ of 8.09 (1H, s), to $ 7.91 (2H, d, J=8.5 Hz), 7,19-7,33 (7H, m), 4,42 (2H, t, J=6.0 Hz), to 3.38 (2H, t, J=7.0 Hz), with 3.27 (2H, t, J=7,0 Hz)of 3.00 (2H, t, J=6.0 Hz), 2.70 height is 2.75 (2H, m), 2,42 (3H, s), is 2.37-2.40 a (2H, m), 1.93 and-2,04 (4H, m).

Example 366

2-{4-[6-Chloro-2-[3-(2-oxo-1-piperidinyl)propyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 339, based on 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (example 339, step 2) and 4-(2-oxo-1-piperidinyl)butane acid (Miyano, Seiji; Fujii, Shinichiro; Yamashita, Osamu; Toraishi, Naoko; Sumoto, Kunihiro,J. Heterocycl. Chem.,1982, 19, 1465).

TPL: 98-105°C.

IR (KBr) v: 1745, 1618, 1433, 1348, 1301, 1230, 1161, 1130, 1085 cm-1.

MS (ESI) m/z: 677 (MH+), 675 ([M-H]-).

1H-NMR (CDCl3) δ 8,08 (1H, s), 7,89 (2H, d, J=8.0 Hz), 7,16-7,29 (7H, m), and 4.40 (2H, t, J=5,9 Hz), the 3.35 (2H, the, J=7.2 Hz), 3.25 to of 3.27 (2H, m), 2,98 (2H, t, J=5,9 Hz), 2,73 (2H, t, J=7.2 Hz), 2,35-to 2.40 (5H, m), 1,92 of 1.99 (2H, m), of 1.73 to 1.76 (4H, m).

Example 367

N-{[(2-{4-[6-chloro-2-(1-hydroxyethyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. 1-[6-Chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethanol

The connection specified in the header received in accordance with the method described in example 339, step 3, example 1, step 5, from 4-chloro-N2-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1,2-benzydamine and lactic acid.

1H-NMR (CDCl3) δ to 8.14 (1H, s), 7,49 (2H, d, J=8,2 Hz), 7,37 (2H, d, J=8,2 Hz), 4,90-4,96(1H, m), 3,83 (2H, t, J=6,8 Hz in), 3.75 (1H, d, J=8.1 Hz), up 3.22 (2H, t, J=6.8 Hz), of 1.57 (3H, d, J=6,9 Hz).

Stage 2. N-{[(2-{4-[6-Chloro-2-(1-hydroxyethyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described in example 1 from 1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethanol (step 1).

TPL: 220°C.

IR (KBr) v: 3348, 1706, 1533, 1519, 1434, 1344, 1328, 1126 cm-1.

MS (ESI) m/z: 581 (MH+), 579 ([M-H]-).

1H-NMR (CDCl3) δ 8,23 (1H, s), 7,78 (2H3d, J=8.1 Hz), 7,32 is 7.50 (7H, m), to 6.58 (1H, Sirs), to 5.66 (1H, Sirs), 4,78 (1H, Sirs), 3,30-of 3.32 (2H, m), 2,79-2,82 (2H, m), of 2.34 (3H, s)and 1.51 (3H, d, J=6,8 Hz).

Example 368

N-{[(2{4-[2-Acetyl-6-chloro-5-(trifluoromethyl)-1 H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. 1-[6-Chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]alanon

A solution of 1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethanol (example 367, stage 1, 400 mg, 1 mmol) in CH2Cl2added MnO2(2.7 g, 32 mmol). The mixture was stirred at room temperature for 24 hours. This substance was directly purified column flash chromatography, elwira hexane/ethyl acetate (4:1), to obtain 350 mg (88%) of the compound indicated in the title, in the form of a white solid.

1H-NMR (CDCl3) δ 8,31 (1H, s), 7,44 (2H, d, J=8.1 Hz), 7.23 percent-7,28 (3H, m), 3,82 (2H, t, J=7,3 Hz), 3,21 (2H, t, J=7,3 Hz), 2,80 (3H, s).

Stage 2. N-{[(2-{4-[2-Acetyl-6-chloro-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described in example 1 from 1-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethanone (stage 1)

TPL: 225°C.

IR (KBr) v: 3350, 1697, 1519, 1326, 1294, 1134, 1083 cm-1.

MS (ESI) m/z: 579 (MH+), 577 ([M-H]-).

1H-NMR (CDCl3) δ 8,31 (1H, s), 7,74 (2H, d, J=8,4 Hz), 7,21-7,39 (7H, m)6,70 (1H, Sirs), 3,55-3,62 (2H, m)to 2.94 (2H, t, J=7.2 Hz), of 2.81 (3H, s), is 2.40 (3H, s).

Example 369

N-{[(2-{4-[6-chloro-2-(1-hydroc the and-1-methylethyl)-5-(trifluoromethyl)-1 H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

Stage 1. 2-[6-Chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]-2-propanol

The connection specified in the header received in accordance with the method described in example 339, step 3 & example 1, step 5 starting from 2-hydroxyisovaleric acid and 4-chloro-N2-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1,2-benzydamine.

1H-NMR (CDCl3) δ 8,13 (1H, s), 7,46 (2H, d, J=8,2 Hz), 7,34 (2H, d, J=8,2 Hz), 7,00 (1H, s), a-3.84 (2H, t, J=7.0 Hz), 3,38 (1H, s), up 3.22 (2H, t, J=7,00 Hz)of 1.53 (6H, s).

Stage 2. N-{[(2-{4-[6-Chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described in example 1 from 2-[6-chloro-1-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]-2-propanol (step 1).

1H-NMR (CDCl3) δ 8,13 (1H, s), 7,73 (2H, d, J=8,2 Hz), 7,30-7,39 (6H, m), of 6.99 (1H, s), of 6.68 (1H, Sirs), 3,55-3,66 (2H, m), 2,95 (2H, t, J=6.6 Hz), 2,42 (3H, s)of 1.13 (6H, d, J=6.2 Hz).

Example 370

Mono p-toluensulfonate N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described in example 231, on the basis of N-{[2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1 H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (example 369).

TPL: 146-150°C.

IR (KBr) v: 1685, 1515, 1448, 1340, 1124, 1089,1010 cm-1.

Example 371

N-{1-[6-chloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazole-2-l}ndimethylacetamide

Stage 1. 1,1-Dimethylethyl 1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethylcarbamate

The connection specified in the header received in accordance with the method described in example 339, step 3 & example 1, step 5 starting from N-(tert-butoxycarbonyl)-alanine and 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (example 339, step 2).

MS (EI) m/z:483(M+).

1H-NMR (CDCl3) δ to 8.12 (1H, s)to 7.50 (2H, d, J=8.6 Hz), 7,35-7,37 (2H, m), 7,24 (1H, s), 5,46 (1H, Sirs), 4,92-to 4.98 (1H, m), 3.95 to as 4.02 (2H, m)of 3.00 (2H, t, J=6.5 Hz), USD 1.43 (3H, s)of 1.40 (9H, s).

Stage 2. 1,1-Dimethylethyl 1-[6-chloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethylcarbamate

The connection specified in the header received in accordance with the method described in example 1, based on 1,1-dimethylethyl 1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethylcarbamate (stage 1).

1H-NMR (CDCl3) δ 8,13 (1H, s), 7,79 (2H, d, J=8,2 Hz), 7,15-to 7.35 (7H, m), 6,50 (1H, Sirs), of 5.55 (1H, d, J=86 Hz), 4,88-is 4.93 (1H, m), 3.46 in-to 3.52 (2H, m), 2,87-2,96 (2H, m), is 2.41 (3H,s)of 1.40 (12H,s).

Stage 3. N-{[2-{4-[2-(1-amino-ethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazole-1-l}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

To a solution of 1,1-dimethylethyl 1-[6-chloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethylcarbamate (stage 2, 190 mg, 0.28 mmol) in CH2Cl2(2 ml) was added triperoxonane acid (1 ml) and stirred at room temperature for 2 hours. The mixture was added to water (10 ml) and was extracted with CH2Cl2(20 ml). The organic layer was washed with saturated saline (10 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira CH2Cl2/MeOH (10:1/5:1), to obtain 160 mg (99%) of the compound indicated in the title, in the form of a white solid.

MS (ESI) m/z: 580 (MH+), 578 ([M-H]-).

Stage 4. N-{1-[6-chloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethyl}ndimethylacetamide

A mixture of N-{[(2-{4-[2-(1-amino-ethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (stage 3, 100 mg, 0,17 mmol) in CH2Cl2(12 ml) was added acetylchloride (0.01 ml, 0.18 mmol) and stirred at room temperature T. the value of 5 hours. The mixture was added to water (10 ml) and was extracted with CH2Cl2(20 ml). The organic layer was washed with saturated saline (10 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira CH2Cl2/MeOH (10:1), with 59 mg (53%) of the compound indicated in the title, in the form of a white solid.

MS (ESI) m/z: 622 (MH+), 620 ([M-H]-).

1H-NMR (CDCl3) δ to 8.14 (1H, s), 7,80 (2H, d, J=8,2 Hz), 7,25-7,40 (7H, m), 7,00 (1H, Sirs), 6,03 (1H, Sirs), 5,15-5,20 (1H, m), 3,43-3,68 (2H, m), 2,88 are 2.98 (2H, m), 2,39 (3H, s)a 1.96 (3H, s)and 1.51 (3H, d, J=6,9 Hz).

Example 372

Mono-p-toluensulfonate N-{1-[6-Chloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethyl}ndimethylacetamide

The connection specified in the header received in accordance with the method described in example 231, proceeding from N-{1-[6-chloro-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazole-2-yl]ethyl}ndimethylacetamide (example 371).

TPL: 135-142°C.

IR (KBr) v: 3267, 1676, 1517, 1456, 1236, 1163, 1122, 1010 cm-1.

Example 373

2-{4-[2-Ethyl-5-(phenylcarbamoyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

Stage 1. (3-Amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)(phenyl)metano

The connection specified in the header, received and in accordance with the method, described in example 78, on the basis of (4-chloro-3-nitrophenyl)(phenyl)methanone.

1H-NMR (CDCl3) δ to 7.77 (2H, d, 3=6.9 Hz), 7,42-of 7.55 (3H, m), of 7.36 (1H, s), 7,14-of 7.25 (4H, m), 6,97 (2H, d, J=8.5 Hz), 5,64 (1H, s), 3,83-to 3.89 (2H, m)to 3.64 (2H, Sirs), 2,84 (2H, t, J=6.6 Hz), 1,47 (1H, Sirs).

Stage 2. {2-Ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}(phenyl)metano

The connection specified in the header received in accordance with the method described in example 1 from (3-amino-4-{[4-(2-hydroxyethyl)phenyl]amino}phenyl)(phenyl)methanone (stage 1).

1H-NMR (CDCl3) δ 8,21 (1H, s), 7,80-to 7.84 (3H, m), 7,44-EUR 7.57 (5H, m), 7,27-7,34 (2H, m), 7,18 (1H, d, J=8,4 Hz), 3,98-a 4.03 (2H, m), to 3.02 (2H, t, J=6.3 Hz), of 2.81 (2H, q, J=7,6 Hz), 1,89 (1H, t, J=5.4 Hz), of 1.37 (3H, t, J=7,6 Hz).

Stage 3. 2-{4-[2-Ethyl-5-(phenylcarbamoyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from {2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}(phenyl)methanone (stage 2).

MS (ESI) m/z: 568 (MH+), 566 ([M-H]-).

1H-NMR (CDCl3) δ 8,21 (1H, s), 7,92 (2H, d, J=8,4 Hz), 7,79-to 7.84 (3H, m), 7,44-7,58 (3H, m), 7.23 percent and 7.36 (6H, m), to 7.15 (1H, d, J=8.6 Hz), 4,37 (2H, t, J=6.6 Hz), a 3.01 (2H, t, J 6.6 Hz), and 2.79 (2H, q, J=7,6 Hz), 2,42 (3H, s)of 1.34 (3H, t, J=7,6 Hz).

Example 374

Mono-p-toluensulfonate 2-{4-[2-ethyl-5-(phenylcarbamoyl)-1H-benzimidazole-1-yl]phenyl)ethyl (4-were)sulfonylamino

<> The connection specified in the header received in accordance with the method described in example 231, on the basis of 2-{4-[2-ethyl-5-(phenylcarbamoyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfanilamide (example 373).

TPL: 102-107°C.

IR (KBr) v: 1747, 1654, 1517, 1448, 1033, 1008 cm-1.

Example 375

N-{[(2-{4-[2-Ethyl-5-(phenylcarbamoyl)-1H-benzimidazole-1-yl]phenyl)ethyl)amino]carbonyl)-4-methylbenzenesulfonamide

Stage 1. N-{[(2-{4-[2-Ethyl-5-(phenylcarbamoyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described in example 78, on the basis of {2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-yl}(phenyl)methanone (example 373, stage 2).

MS (ESI) m/z: 567 (MH+), 565 ([M-H]-).

1H-NMR (CDCl3) δ to 8.20 (1H, s), 7,72-7,83 (5H, m), 7,28-of 7.60 (9H, m), to 7.15 (1H, d, J=8.6 Hz), 6,74 (1H, Sirs)and 3.59 (2H, m)to 2.94 (2H, t, J=7,1 Hz), 2,82 (2H, q, J=7.4 Hz), 2,39 (3H, s)of 1.35 (3H, t, J=7,4 Hz).

Example 376

Mono p-toluensulfonate N-{[(2-{4-[2-ethyl-5-(phenylcarbamoyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide

The connection specified in the header received in accordance with the method described in example 231, on the basis of N-{[(2-{4-[2-ethyl-5-(phenylcarbamoyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (example 375).

TPL: 198�B0; C.

IR (KBr) v: 1697, 1660, 1596, 1519, 1446, 1319, 1035 cm-1.

Example 377

2-{4-[2-[1-(Acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl-(4-were)sulfonylureas

Stage 1. 2-{4-[6-chloro-2-(1-chloro-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}acetate

To a solution of 2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}acetic acid ethyl ester (300 mg, of 0.68 mmol) in dichloromethane (15 ml) was added thionyl chloride (0,07 ml of 1.02 mmol) and the reaction mixture is boiled under reflux during the night. The reaction mixture was poured into water (10 ml) and the mixture was extracted with dichloromethane (30 ml). The organic layer was washed with saturated saline (10 ml), then dried (Na2SO4). The solvent was removed to obtain 273 mg (87%) of the compound indicated in the title, in the form of a white amorphous substance.

MS (EI) m/z: 458 (M+).

Stage 2. 2-{4-[2-(1-Azido-1-methylethyl)-6-chloro-5-trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}acetate

A mixture of 2-{4-[6-chloro-2-(1-chloro-1-methylethyl)-5-(trifluoromethyl)-1Hthe benzimidazole-1-yl]phenyl}ethyl acetate (stage 1, 273 mg of 0.68 mmol), sodium azide (88 mg, of 1.36 mmol), KI (112 mg, of 0.68 mmol) in DMF (8 ml) was stirred under nitrogen atmosphere at room temperature for 5 hours. The reaction mixture was poured into water (5 ml) and the aqueous mixture was extragonadal with ethyl acetate (30 ml). the content of inorganic fillers layer was washed with water (5 ml) and saturated saline (10 ml), then was dried (Na2SO4). After removal of solvent the crude product was purified flash chromatography on a column elwira hexane/ethyl acetate (2/1), to obtain 133 mg (42%) of the compound indicated in the title, in the form of a yellow oil.

MS (EI) m/z: 465 (M+).

1H-NMR (CDCl3) δ 8,17 (1H, s), 7,46 (2H, d, J=8,4 Hz), 7,35 (2H, d, J=8,4 Hz), 7,02 (1H, s), 4,39 (2H, t, J=7,0 Hz)to 3.09 (2H, t, J=7.0 Hz), of 2.08 (3H, s)to 1.70 (6H, s).

Stage 3. 2-{4-[2-(1-Amino-1-methylethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}acetate

A mixture of 2-{4-[2-(1-azido-1-methylethyl)-6-chloro-5-(trifluoromethyl)-1-benzimidazole-1-yl]phenyl}ethyl acetate (stage 2, 133 mg, 0.28 mmol) and Lindlar catalyst (Lindlar) (13 mg) in methanol (5 ml) was stirred in an atmosphere of H2at room temperature for 2.5 hours. The catalyst was removed by filtering through a thick layer of celite and the filtrate was concentrated to obtain the connection specified in the header, in the form of a yellow oil (121 mg, 98%).

MS (EI) m/z: 439 (M+).

Stage 4. 2-{4-[2-[1-(Acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}acetate

To a solution of 2-{4-[2-(1-amino-1-methylethyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl acetate (stage 3, 121 mg, 0.27 mmol) in dichloromethane (5 ml) was added acetylchloride (0,02 ml, 0.3 mmol). The reaction mixture was stirred at room temperature for 7 hours. To the reaction is Oh mixture was added water (5 ml) and the aqueous mixture was extracted with dichloromethane (30 ml). The organic layer was washed with water (5 ml) and saturated saline (10 ml), then dried (Na2SO4). After removal of solvent the crude product was purified column flash chromatography, elwira CH2Cl2/methanol (10/1), to obtain 76 mg (57%) of the compound indicated in the title, in the form of a white amorphous substance.

MS (EI) m/z: 481 (M+).

1H-NMR (CDCl3) δ to 8.14 (1H, s), 7,42 (2H, d, J 8.2 Hz), 7,28 (2H, d, J=8,4 Hz)6,91 (HI, C)to 4.38 (2H, t, J=6.6 Hz), of 3.07 (2H, t, J=6.6 Hz), to 2.06 (3H, s)of 1.75 (6H, s), by 1.68 (3H,s).

Stage 5. N-{1-[6-Chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]-1-methylethyl}ndimethylacetamide

The connection specified in the header received in accordance with the method described for stage 6, example 1 2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl acetate (stage 4).

1H-NMR (CDCl3) δ 8,13 (1H, s), 7,44 (2H, d, J=8,4 Hz), 7,27 (2H, d, J=8,4 Hz), 6,92 (1H, s), 5,95 (1H, Sirs), 3,98 (2H, t, J=6.4 Hz), 2,99 (2H, t, J=6.4 Hz), 1,68 is 1.75 (9H, m).

Stage 6. 2-{4-[2-[1-(Acetylamino-1-l-6-chloro-5-trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl(4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 3 from N-{1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazole-2-yl]-1-methylethyl}ndimethylacetamide (stage 5).

MS (ESI) m/z: 637 (MH +), 635 ([M-H]-).

1H-NMR (CD3OD) δ of 8.04 (1H, s), 7,83 (2H, d, J=8,4 Hz), was 7.45 (2H, d, J=8,4 Hz), 7,34 (2H, d, J=8.5 Hz), 7,26 (2H, d, J=8.5 Hz), 6,93 (1H, s), 4,32 (2H, t, J=6.4 Hz), to 3.02 (2H, t, J=6.4 Hz), is 2.37 (3H, s), 1,75 (6H, s)of 1.53 (3H, s).

Example 378

p-Toluensulfonate 2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl (4-were)sulfonylureas

The connection specified in the header received in accordance with the method described in example 231, on the basis of N-{[(2-{4-[6-chloro-2-[1-(metiloksi)ethyl]-5-(trifluoromethyl)-1H-benzimidazole-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (example 377)

IR (KBr) v: 1751, 1508, 1450, 1340, 1161, 1122 cm-1.

Example 379

6-Chloro-2-ethyl-1-(4-{2-[methyl({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide

Stage 1. 2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazole-1-yl]phenyl}ethyl methanesulfonate

A mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (example 111, step 4, 500 mg, 1,45 mmol), triethylamine (293 mg, 2,90 mmol) and methanesulfonyl chloride (322 mg, 2.9 mmol) in dichloromethane (20 ml) was stirred at room temperature for 6 hours. The reaction mixture was poured into water and was extracted with dichloromethane (50 ml). The organic layer was washed with saturated saline (50 ml), then dried (Na2SO ). After removal of solvent the crude product was purified by TLC, hexane/ethyl acetate (1:1), with 304 mg (50%) of the compound indicated in the title, in the form of a white solid.

MS (ESI) m/z: 422 ([M+H]+).

1H-NMR (CDCl3) δ 7,54 (1H, s), 7,44 (2H, d, J and 8.3 Hz), 7,29 (2H, d, J=8,3 Hz), 7,13 (1H, s), 3,82 (2H, t, J=7.0 Hz), 3,19 (2H, t, J=7.0 Hz), 2,82 (6H, s)of 2.75 (2H, q, J=7,6 Hz)of 1.35 (3H, t, J=7,6 Hz).

Stage 2. 6-chloro-2-ethyl-1-{4-[2-(methylamino)ethyl]phenyl}-1H-benzimidazole-5-carboxamide

A mixture of 2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazole-1-yl]phenyl}ethylmethanesulfonate (stage 1, 304 mg, to 0.72 mmol), a solution of methylamine (40% in methanol, 10 ml) and water (5 ml) in a sealed tube was heated overnight at 100°C. the Reaction mixture was distributed between dichloromethane (30 ml) and water (30 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic phases were washed with saturated brine (50 ml) and dried (Na2SO4). After removal of solvent the crude product was purified by TLC, dichloromethane/methanol (10:1), with 154 mg (60%) of the compound indicated in the title, in the form of a yellow solid.

1H-NMR (CDCl3) δ 7,54 (1H, s), the 7.43 (2H, d, J=8,2 Hz), 7,29 (2H, d, J=8,2 Hz), 7,12 (1H, s), 3,62 (2H, t, J=7.0 Hz), a 3.01 (2H, t, J=7.0 Hz), 2,82 (6H, s)of 2.75 (2H, q, J=7,6 Hz)of 1.34 (2H, t, J=7,6 Hz).

Stage 3. 6-Chloro-2-ethyl-1-(4-{2-[methyl({[(4-methyl who enyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1 H-benzimidazole-5-carboxamide

The interaction was carried out according to the method described for stage 10 of example 1 from 6-chloro-2-ethyl-1-{4-[2-(methylamino)ethyl]phenyl}-1H-benzimidazole-5-carboxamide (stage 2).

MS (ESI) m/z: 554 (M+H+), 552 ([M-H]-).

1H-NMR (CDCl3) δ of 8.09 (1H, s), 7,97-7,94 (211, d, J=8,4 Hz), 7,40-7,31 (4H, m), 7,16-7,13 (2H, d, J=8,4 Hz), 7,07 (1H, s), 6,36 (1H, W), to 3.52 (2H, W), 2,98 (2H, W), of 2.93 (3H, s), 2,78-2,69 (2H, d, J=7,6 Hz), 2,42 (3H, s), 1,34 of 1.28 (3H, t, J=7,6 Hz).

Example 380

6-Chloro-2-ethyl-1-(4-{2-[methyl({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide sodium salt

The connection specified in the header received in accordance with the method described in example 2 from 6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide (example 379).

MS (ESI)m/z: 554(M+H+), 552 ([M-H]-).

EP4 Antagonists: azole compounds of formula II

Preferred examples of the azole compounds (II) are the following compounds:

R1represents lower alkyl, substituted carboxy; carboxy; protected carboxy; carbarnoyl; heterocyclic group; lower alkoxy substituted by carbamoyl; aryl, substituted carboxy, carbamoyl or heterocyclic group; or amino, optionally substituted lower alkyls what fonila (more preferably, lower alkyl, substituted carboxy; carboxy; carbarnoyl; tetrazolyl; lower alkoxy substituted by carbamoyl; aryl, substituted carboxy or carbamoyl),

R2 represents hydrogen or lower alkyl,

Q represents[where-A1- represents a single bond or lower alkylene (more preferably methylene),

represents a cyclo(C5-C9)alkene, cyclo(C3-C9)alkane or bicyclo(C6-C9)alkene, bicyclo(C5-C9)alkane (more preferably, cyclo(C5-C7)alkene, cyclo(C5-C7)alkane, bicyclo[2.2.1]heptan or bicyclo[2.2.1]heptane), and-A3- represents a single bond or lower alkylene (more preferably, a single bond)], and X represents O.

The assays of the present invention

On the basis of several facts suggested that the interaction of cytokines and prostaglandins is important for the development of diseases associated with atherosclerosis. However, the specific mechanisms of formation of atherosclerotic plaques and relation between the formation of plaques and prostaglandins and cytokines are not described. To date, the relationship between the production of cytokines and PGE2investigated using selected cells or cell lines, that is, macro is AGI, monocytes and T-cellsin vitro(Zeng, L. I. et al., J. Pharmacol. Exp. Ther., 1998, 286, 1420-1426; Blaine, T. A. et al., 1997, J. Bone Joint Surg., 79-A, 1519-1528). For example, the production of IL-6 T-cell leukemia human HSB.2 cultivated lines were grown in the presence of PGE2. Cells HSB.2 simultaneously Express EP2, EP3 and EP4 subtypes of PGE2 receptors. In these cells misoprostol, a selective agonist of the receptor EP4/EP2/EP3, but not selective agonist receptor EP3 M&B28767, caused increased production of IL-6 (Zeng, et al., 1998). Increased production of IL-6 under the influence of PGE2 was repeated in the presence of dibutyryl-camp and inhibited by an inhibitor of protein kinase A, which suggests that the EP4 receptors and/or EP2 cause PGE2-induced increase in the production of IL-6 T-cells HSB.2 through a camp dependent mechanism. Conversely, agonists EP4 and EP2 inhibit the production of IL-6 caused by IL-1, synovial fluid lymphocytes in rats with arthritis (Kurihara, Y. et al., Clin. Exp. Immunol. Vol. 123, 323-330, 2001).

Thus, modulation of cytokine production under the influence of PGE2 in peripheral mononuclear cells in each case varies. In atherosclerotic plaques detected by macrophages and T-cells (van der Wal, A. C. et al., Circulation, 1994, 89, 36-44). However, the interaction of cytokines and PG in atherosclerotic plaques is not clear. There is therefore a need in the medical mistaway system for monitoring the activation of monocytes and T-the bee entrance.

In this invention, the authors found that only the use of PGE2 in the cells of whole human blood significantly increases the production of IL-6. This invention is more specific therapeutic micheneau system for controlling the production of IL-6. In addition, this system is an effective way to detect molecular targets of atherosclerosis and diseases mediated by IL-6.

The test agents used for analysis of the present invention, can be selected individually or obtained from a library of compounds. Such agents include peptides, the combination of chemically-derived molecules library of D - and/or L-configuration amino acids, phosphopeptides, antibodies against EP4, antisense nucleic acid EP4 and small organic and inorganic compounds. Libraries include biological libraries, libraries of natural products, peptide libraries (libraries of molecules with functions of peptides, but with the new ones chain, which are resistant to enzymatic degradation, remaining bioactive) (see, e.g., Zuckermann, J. Med. Chem. 37: 2678-85, 1994), spatial library available parallel solid phase or soluble phase methods for the synthesis of libraries required deconvolution, library way "one-bead one-compound" and the ways synthesized libraries, IP is by using selection for affinity chromatography.

Examples of methods for the synthesis of molecular libraries can be found in this area, e.g., DeWitt et al., Proc. Natl. Acad. Sci. 90:6909, 1993; Erd et al., Proc. Natl. Acad. Sci. 91:11422, 1994; Zuckermann et al., J. Med. Chem. 37:2678, 1994; Cho et al., Science, 261:1303,1995; Carrell et al., Angew. Chem. Int. Ed. Engl. 33:2061, 1994; and Gallop et al., J. Med. Chem. 37:1233, 1994.

Libraries of compounds may be present in solution (e.g., Houghten, Biotechniques, 13:412-421, 1992), or on beads (Lam, Nature 354:82-84, 1991), chips (Fodor, Nature 364:555-556, 1993), bacteria or disputes (Ladner, U. S. Patent No. 5,223, 409), plasmids (Cull et al., Proc. Natl. Acad. Sci. USA. 89:1865-1869, 1992) or on phage (Scott et al., Science 249:386-390, 1990; Devlin, Science 249:404-406, 1990; Cwirla et al., Proc. Natl. Acad. Sci. (USA) 87:6378-6382, 1990; Felici, J. Mol. Biol. 222:301-310, 1991; Ladner, supra).

1. The use of receptor antagonist OR when getting medicines for the treatment of diseases mediated by IL-6 where the above-mentioned receptor antagonist AR is a compound of formula I

or its pharmaceutical salt,

where Y1and Y3independently selected from CH or C(L);

One of the Y2and Y4represents N or independently selected from CH or C(L);

R1represents a C1-8alkyl;

Rather it represents a phenyl;

Represents a C1-6alkylen;

W represents NH or O;

R2represents N;

Z p is ecstasy a phenyl, replaced With1-4by alkyl;

L represents a halogen, With1-4alkyl, halogen-substituted C1-4alkyl or C1-4alkoxy;

and where a disease mediated by IL-6, selected from the group including cirrhosis with alcoholism, amyloidosis, atherosclerosis, heart disease, multiple sclerosis and reactions by transplantation of organs.

2. The use of receptor antagonist ER according to claim 1, where the specified receptor antagonist AR is a

N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5b]pyridine-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide;

sodium salt of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5b]pyridine;

2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5C]pyridine;

5-acetyl-2-ethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenethyl-(4-were)sulfonylureas.

3. The use of receptor antagonist ER according to claim 1 or 2, where a disease mediated by IL-6, represents atherosclerosis.

4. Pharmaceutical composition for the treatment of diseases mediated by IL-6, including receptor antagonist OR where the above-mentioned diseases mediated by IL-6 is selected from the group, what with cirrhosis with alcoholism, amyloidosis, atherosclerosis, heart disease, multiple sclerosis and reactions in organ transplantation, and where specified antagonist OR receptor is a compound of formula I

or its pharmaceutically acceptable salt,

where Y1and Y3independently selected from CH or C(L);

one of the Y2and Y4represents N or independently selected from CH or C(L);

R1represents a C1-8alkyl;

Rather it represents a phenyl;

Represents a C1-6alkylen;

W represents NH or O;

R2represents N;

Z represents phenyl, substituted C1-4by alkyl;

L represents a halogen, With1-4alkyl, halogen-substituted C1-4alkyl or C1-4alkoxy.

5. The pharmaceutical composition according to claim 4, where the specified receptor antagonist AR is a

N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5b]pyridine-3-yl)phenyl]ethyl} amino)carbonyl]-4-methylbenzenesulfonamide;

sodium salt of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo [4,5b]pyridine;

2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5C]pyridine;

5-acetyl-2-ethyl-3-4-{2-[({[(4-were)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;

4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazole-1-yl)phenethyl-(4-were)sulfonylureas.

6. The pharmaceutical composition according to claims 4 and 5, where the said disease mediated by IL-6, represents atherosclerosis.



 

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to the improved thrombopoietin TPO) mimetic representing 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-yliden]hydrazine]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine). Also, invention relates to a pharmaceutical composition based on indicated salt of the compound, method for treatment of thrombocytopenia in mammal, method for enhancing platelets producing in mammal and methods for preparing indicated pharmaceutical composition and indicated salt of the compound. Invention provides the enhanced solubility of proposed salt as compared with free acid that results to alleviation in preparing the pharmaceutical composition and enhancing biological availability in using indicated salt as agonist of TPO receptors for enhancing platelets producing and in treatment of thrombocytopenia also.

EFFECT: improved and valuable medicinal properties of acid.

19 cl, 2 tbl, 5 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to formulations comprising heparin as an active component and a base consisting of lipid and polymeric components for oral using. The lipid component is able preferably to enhance effect of the main component while the polymeric component possesses ability to dissolving or swelling, and at least part of the lipid component is incorporated into the polymeric matrix being in the molecular-dispersed state. Invention provides the sufficient complete absorption of active substance in digestive tract after its oral intake.

EFFECT: valuable properties of formulation.

9 cl, 2 dwg, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 5-amidino-2-hydroxybenzenesulfonamide of the general formula (I): wherein R2 means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (A): wherein (A) means -COORA, -CONRBRC, 3-7-membered monocyclic heterocycloalkyl group comprising one or two heteroatom in ring chosen from atoms N, O, S that can comprise oxo-group and 5-6-membered monocyclic aromatic heterocyclic group comprising one-three heteroatoms in ring chosen from atoms N, O, S that can comprise oxo-group or lower alkyl wherein RA means hydrogen atom (H), 3-7-membered monocyclic aliphatic alkyl group, lower alkyl that can comprises a substitute chosen from the group (i) wherein (i) means -COORA1 wherein RA1 means hydrogen atom (H), -OCORA2 wherein RA2 means lower alkyl group, -OCOORA3 wherein RA3 means lower alkyl, -ORA4 wherein RA4 means hydrogen atom (H), lower alkyl -CONRA5RA6 wherein RA5 and RA6 mean independently hydrogen atom (H), lower alkyl, or -NRA5RA6 forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; wherein RB and RC mean independently hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (ii), or -NRBRC forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; (ii) means -COORB1 wherein RB1 means hydrogen atom (H), lower alkyl; T means oxygen atom (O), sulfonyl group; or TR1 means -SO2NRB3RC3 wherein RB3 and RC3 means independently hydrogen atom (H), lower alkyl; R2 means lower alkyl, phenyl that can comprise one-three substitutes chosen from the group (B) wherein (B) means halogen atom, -COORE, sulfamoyl, lower alkylsulfonyl wherein RE means lower alkyl; Q means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (D) wherein (D) means 5-6-membered monocyclic aromatic heterocyclic group that can comprise one-three heteroatom chosen from atoms N, O, S that can comprise a substitute chosen from the group (iv) wherein (iv) means oxo-group, lower alkyl; Z means hydrogen atom (H), hydroxyl group (OH), -COORN wherein RN means lower alkyl that can comprise a substitute chosen from the group (viii) wherein (viii) means -OCOR5 wherein RN5 means lower alkyl that can comprise -OCORN51 wherein RN51 means lower alkyl; or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit activated factor X in blood coagulation system that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and compositions.

12 cl, 5 tbl

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: method involves administration of amlodipine in the dose 5 mg, once in the same time and metformin in the dose 500 mg, 2 times per 24 h in patients at the background of individually selected hypocaloric diet. Treatment is carried out for 8 weeks, not less. Method provides optimization of intravascular activity of platelets due to correction of primary homeostasis and the level of their antioxidant protection. Invention can be used for rapid optimization of functions of platelets at metabolic syndrome.

EFFECT: improved and enhanced method for optimization.

2 ex

FIELD: medicine, cardiology, endocrinology.

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EFFECT: improved correction method.

2 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of phenylglycine of the formula (I) , to their hydrates or solvates, and/or to physiologically acceptable salts and/or physiologically acceptable esters possessing inhibitory effect on amidolytic activity of the complex factor VIIa/tissue factor that can be used for therapeutic and/or prophylactic treatment of diseases, for example, thrombosis. In the formula (I) R1 means (C1-C6)-alkyl; R2 means hydrogen atom, hydroxy-(C1-C6)-alkoxy-, (C1-C6)-alkoxycarbonyloxy-, (C1-C6)-alkoxy-group or halogen-(C1-C6)-alkoxycarbonyloxy-(C1-C6)-alkoxy-group; R3 means hydrogen atom, (C1-C6)-alkoxy- or heterocycloalkyloxy-group wherein heterocycloalkyl group means 5-6-membered ring comprising a heteroatom taken among nitrogen and oxygen atom; R4 means hydrogen atom or ester residue that is cleaved off under physiological conditions. R5 means hydrogen atom, hydroxy-group, (C1-C6)-alkoxycarbonyl, halogen-(C1-C6)-alkoxycarbonyl, (C6)-aryloxycarbonyl,(C6)-arylalkoxycarbonyl, (C1-C6)-alkoxy-(C1-C6)-alkoxy(C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkyloxycarbonyl, (C2-C6)-alkynyloxycarbonyl, 5-methyl-2-oxo[1,3]dioxol-4-yl-methoxycarbonyl, (C6)-arylcarbonyloxy-, (C1-C6)-alkylaminocarbonyloxy-group, (C1-C6)-alkylcarbonyl, arylcarbonyl, arylaminocarbonyl or heteroarylcarbonyl wherein heteroaryl represents 5-6-membered ring comprising nitrogen atom the cycle; X means atom F, Cl or Br. Also, invention relates to a method for preparing compounds, intermediates substances and pharmaceutical composition and a method for treatment.

EFFECT: improved preparing method, valuable medicinal properties of agents and composition.

29 cl, 5 ex

FIELD: medicine, hematology, cardiology, endocrinology.

SUBSTANCE: one should introduce individually matched hypocaloric diet calculated in kcal by the following formula for women: age of 18-30 - (0.0621 x body weight, kg + 2.0357) x 240; age of 31-60 - (0.0342 x body weight, kg + 3.5377) x 240; age above 60 - (0.0377 x body weight, kg + 2.7545) x 240; for men: age of 18-30 - (0.0630 x body weight, kg + 2.8957) x 240; age of 31-60 - (0.0484 x body weight, kg + 3.6534) x 240; age above 60 - (0.0491 x body weight, kg + 2.4587) x 240 and amlodipine 5 mg once at one and the same daytime. The present innovation enables to decrease adhesion and aggregation of thrombocytes at optimizing their intravascular activity, increase antioxidant protection of blood platelets and normalizing cholesterol/phospholipids gradient in their membranes that, in its turn, favors the prophylaxis of complications of cardio-vascular diseases, shortens invalidism and lethality.

EFFECT: higher efficiency of normalization.

2 ex

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

SUBSTANCE: invention describes a novel pentasaccharide conjugate of the formula (I):

wherein R represents independently -SO-3 or -CH3; insert represents a flexible insert of length 13-25 atoms. Charge of a pentasaccharide residue is equilibrated with positively charged counterions and the total amount of sulfate groups in a pentasaccharide residue is 4, 5 or 6. Also, invention relates to a method of its preparing and pharmaceutical composition based on thereof and used in treatment of diseases mediated or associated with thrombin.

EFFECT: improved preparing method, valuable medicinal properties of conjugate.

9 cl, 2 ex

FIELD: medicine, hematology.

SUBSTANCE: invention proposes an agent for reducing blood and plasma viscosity. Agent represents "Reamberin-1.5% for infusion" known early as an antioxidant and detoxifying agent. Invention provides normalization of blood rheological properties expressed as plasma viscosity and blood viscosity indices in patients, among them, in children and elimination of hemodynamic indices and in the absence of undesirable adverse effects.

EFFECT: valuable medicinal properties of preparation.

2 tbl, 2 ex

FIELD: pharmaceutical industry, in particular phospholipid-based pharmaceutical composition hawing hepatoprotective and metabolism normalizing activity in form of tablets, pellets, capsules, injection solutions, etc.

SUBSTANCE: claimed composition contains both pla