2-pyridyl-substituted imidazols as alk5 and/or alk4 receptor inhibitors

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I or its pharmaceutically acceptable salts: , where R1 is phenyl group optionally substituted by substitutes selected out of halogen atom, -O-C1-6-alkyl; or R1 is phenyl condensed with aromatic or non-aromatic 5-7-member ring where the ring can optionally include up to three heteroatoms selected independently out of N, O and S; R2 is hydrogen, -O-C1-6-alkyl, -C1-6-alkyl or halogen atom; R3 is C1-6-alkyl, -(CH2)P-NO2, -(CH2)p-NR4R5, -(CH2)P-CONHOH, -(CH2)p-CN, -(CH2)P-CO2H, -(CH2)p-CO2R4, -(CH2)P-CONR4R5, -(CH2)p-OR4, -(CH2)p-NHCOR4 or -(CH2)p-NHSO2R4; R4 and R5 are independently hydrogen or C1-6-alkyl; p is 0, 1, 2, 3 or 4; X is C1-10-alkylene group; one of A1 and A2 is nitrogen atom, while the other is NR7; and R7 is hydrogen atom or OH-group. Also invention concerns pharmaceutical composition, method of TGF-β and/or activine signal transit route inhibition, method of reduction of excessive exocellular matrix accumulation for mammals, method of tumour cell metastasis inhibition for mammals, method of treatment of cancer neoplasm caused by TGF-β superexpression by TGF-β signal transit route inhibition for mammals, method of disease treatment, and method of thrombosis inhibition for mammals.

EFFECT: new compounds with useful biological properties.

16 cl, 19 ex, 2 tbl, 8 dwg

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to 2-pyridyl-substituted the imidazoles, which are inhibitors of receptor type I transforming growth factor-β (TGF-β) (ALK5) and/or receptor type I activin (ALK4), methods for their preparation and to their use in medicine, particularly in the treatment and prevention of diseases mediated by these receptors.

PRIOR art

TGF-β refers to a family of proteins, TGF-β1, TGF-β2 and TGF-β3, which are pleiotropic modulators of cell proliferation and differentiation, wound-healing process, production of extracellular matrix and suppression of the immune response. Other members of this superfamily are actively, inhibin, morphogenetic proteins, bone growth factors, and differentiation and inhibiting substance Muller.

TGF-β1 transmits signals through two highly homologous single transmembrane serine/threonine kinases, i.e. via receptor type I (ALK5) and type II TGF-β. After oligomerization induced by the ligand, receptor type II hyperphosphorylated serine/threonine residues in the field GS in ALK5, which leads to activation of ALK5 by creating binding sites for Smad proteins. Activated ALK5, in turn, phosphorylates proteins Smad2 and Smad3 at the C-terminal SSXS-motive, so the way causing their dissociation from the receptor and education heteromera complex with Smad4. The Smad complexes translucida in the nucleus, associate with specific DNA-binding cofactors and camodulator, ultimately activating the transcription of extracellular matrix components and inhibitors of matrix-destructive proteases.

Actively transmit signals in a manner analogous to the method of TGF-β. Actively join serine/Trainin the kinase, receptor, type II activin (ActRIIB), and the activated receptor type II hyperphosphorylated serine/threonine residues in the field GS in ALK4. Activated ALK4, in turn, phosphorylates Smad2 and Smad3. The subsequent formation of a heterocomplex with Smad Smad4 leads to activin-inducible control of gene transcription.

Numerous experimental animal studies have shown the relationship between glomerular expression of TGF-β and fibrosis, including Thy-1 modelproliferative glomerulonephritis in rats with anti-GBM glomerulonephritis in rabbits, and 5/6 model nephrectomy focal segmental glomerulosclerosis in rats, as recently described in the review (for example, Bitzer, M. et al., Kidney Blood Press. Res. 21:1-12 (1998)). Neutralizing antibodies to TGF-β improves glomerular histology on Thy-1 model jade (e.g., Border, W. A. et al., Nature 346: 371-374 (1990)).

Hyperglycemic conditions increase the number of m-RNA of TGF-β and increase protein synthesis in murine Proxima is lnyh trubkovich cells, human mesangial cells (for example, Wahab, N. A. et al., Biochem. J. 316:985-992 (1996); Rocco, M. V. et al., Kidney Int. 41: 107-114 (1992)). Diabetic patients with a primary disorder of the kidneys revealed increased accumulation of m-RNA of TGF-β and protein in the glomeruli (e.g., Yoshioka, K. et al., Lab. Invest. 68: 154-163 (1993)). In kidneys with chronic renal interstitial fibrosis are characteristic thickening of the basal membrane of the tubules and increase interstitially component, with interstitial fibrosis, which is characterized by increased concentrations of collagens I, III, V, VII, and laminin (e.g., Eddy, A. A, J. Am. Soc. Nephrol. 7: 2495-2508 (1996)).

The gene expression of TGF-β and production of the protein increases in the case of various animal models pneumovirus, including bleomycin, silicagel, asbestos and radiation (e.g., Phan, S. H., and Kunkel, S. L, Exp. Lung Res. 18: 29-43 (1992); Williams, A. O. et al., Am. J. Pathol. 142: 1831-1840 (1993); Rube, C. E. et al., Int. J Radial Oncol. Biol. Phys. 47: 1033-1042 (2000)). When human pulmonary fibrotic diseases was observed a concomitant increase in protein TGF-β1 and increased gene expression of collagen in the tissue adjacent to the idiopathic pneumovirus (for example, Broekelmann, T. J. et al., Proc. Natl. Acad. Sci. USA 88:6642-6646 (1991)). Increased production of TGF-β has been described in patients with sarcoidosis, pneumoconiosis, asbestos pneumoconiosis and radiation-induced fibrosis (e.g., Khalil, N. et al., Am. J. Respir. Cell. Mol. Biol. 14: 131-138 (1996); Jagirdar, J. et al., Environ. Health Perspect. 105: 1197-1203 (1997)). Antibodies to TGF-β and soluble receptors of TGF-β could partially inhibit fibrosis in bleomycin-induced pulmonary fibrosisin rodent models (e.g., Giri, S. N. et al., Thorax 48: 959-966 (1993); Wang, Q. et al., Thorax 54: 805-812 (1999)). I believe that tobacco smoke is one of the most important factors that can cause small airway disease, with subsequent development of chronic obstructive pulmonary disease (COPD) (e.g., Wright, J. M. et al., Am. Rev. Respir. Dis. 146: 240-262 (1992)). COPD is a slowly progressive and irreversible disease characterized by functional abnormality of airway obstruction. According to one hypothesis, TGF-β participates in the rebuilding of the respiratory tract found in chronic inflammatory disorders of the respiratory tract, such as COPD (for example, Takizawa, H. Int. J. Mol. Med. 1: 367-378 (1998); Ning, W. et al., Proc. Natl. Acad. Sci. USA 101:14895-14900 (2004)).

Stellate liver cells (HSC) are the main source of extracellular matrix proteins in hepatic fibrosis. The production of extracellular matrix by activated hepatic stellate cells is significantly increased under the action of TGF-βl (e.g., Friedman, S. L, Prog. Liver Dis. 14: 101-130 (1996); Pietrangelo, A, Semin. Liver Dis. 16:13-30 (1996)). In transgenic mice, which sverkhekspressiya TF-β l in the liver, hepatic fibrosis develops as well as extrahepatic pathology such as renal fibrosis (e.g., Sanderson, N. et al., Proc. Natl. Acad. Sci. USA 92:2572-2576 (1995)).

TGF-βl and its receptor sverkhekspressiya in injured blood vessels and fibroproliferative vascular damage, which leads to overproduction extracellular matrix (for example, Saltis, J. et al., Clin. Exp. Pharmacol. Physiol. 23: 193-200 (1996); McCaffrey, T. A. et al., J. Clin. Invest. 96: 2667-2675 (1995)).

Antibodies to TGF-β reduce scarring and improve cellular architecture of the new layers of skin in rats (e.g., Shah, M, J. Cell. Sci. 108: 985-1002(1995)), improve the healing of corneal wounds in rabbits (e.g., Moller-Pedersen T, Curr. Eye Res. 17:736-747 (1998)), and accelerate the wound-healing process of gastric ulcers in rats (e.g., Ernst, H, Gut 39: 172-175 (1996)).

Radiation fibrosis is a common consequence of therapeutic or accidental radiation overexposure in normal human tissues. TGF-βl plays a Central role in the initiation, development and sustainability radiation fibrosis, as recently described in a review (e.g., Martin, M. et al., Int. J. Radiat Oncol. Biol. Phys. 47:277-290 (2000)).

Organ transplantation is complicated in many cases of chronic rejection and for some organs such as the kidney, it is the basic form of the loss of the transplanted organ. In the case of sick people with chronic ottorini is of transplants lung and kidney is associated with increased expression of TGF-β in the tissue (e.g., El-Gamel, A. et al., Eur. J. Cardiothorac. Surg. 13: 424-430 (1998); Shihab, F. S. et al., J. Am. Soc. Nephrol. 6:286-294 (1995)).

TGF-β involved in the formation of the peritoneal spiek (for example, Saed, G. M. et al., Wound Repair Regeneration 7: 504-510 (1999)). Peritoneal and subcutaneous fibrations adhesions can be prevented by inhibitors of ALK5 and/or ALK4.

Tumor cells and stromal cells in tumors in the last stages of various cancers usually sverkhekspressiya TGF-β. This leads to stimulation of angiogenesis and cell motility, suppression of the immune system and to increased interaction of tumor cells with the extracellular matrix (for example, Hojo, M. et al., Nature 397: 530-534 (1999)). Therefore, tumor cells become more invasive and metastasize to distant organs (for example, Maehara, Y. et al., J. Clin. Oncol. 17: 607-614 (1999); Picon, A. et al., Cancer Epidemiol. Biomarkers Are Prev. 7:497-504 (1998)).

Profibrinolytic-activating inhibitor-1 (PAI-1) is the primary physiological inhibitor as profibrinolytic-activator, tissue type, and profibrinolytic-activator urokinase type. Elevated levels of PAI-1 are associated with thrombosis and vascular disorders, suggesting that high levels of PAI-1 in plasma can cause a hypercoagulable state by disrupting the natural balance between fibrinolysis and coagulation (e.g., Vaughan, D. E., J. Invest. Med. 46: 370-376 (1998)). You know, TGF-β stimulates the expression of PAI-1 (for example, Dennler, S. et al., EMBO J. 17: 3091-3100 (1998)). Accordingly, inhibition of the production of PAI-1 inhibitor transmission signal TGF-β may lead to new fibrinolytic therapy.

Signal transmission of activin and overexpression of activin associated with pathological disorders, which include accumulation of extracellular matrix and fibrosis (for example, Matsuse, T. et al., Am. J. Respir. Cell Mol. Biol. 13:17-24 (1995); Inoue, S. et al., Biochem. Biophys. Res. Comm. 205:441-448 (1994); Matsuse, T. et al., Am. J. Pathol. 148:707-713 (1996); De Bleser et al., Hepatology 26:905-912 (1997); Pawlowski, J. E, et al., J. Clin. Invest. 100:639-648 (1997); Sugiyama, M. et al., Gastroenterology 114:550-558 (1998); Munz, B. et al., EMBO J. 18:5205-5215 (1999)), inflammatory response (e.g., Rosendahl, A. et al., Am. J. Respir. Cell Mol. Biol. 25:60-68 (2001), cachexia or depletion (Matzuk, M. M. et al., Proc. Natl. Acd. Sci. USA 91:8817-8821 (1994); Coerver, K. A. et al., Mol. Endocrinol. 10:534-543 (1996); Cipriano, S. C. et al., Endocrinology 141:2319-2327 (2000)), diseases or pathological responses of the Central nervous system (e.g., Logan, A. et al., Eur. J. Neurosci. 11:2367-2374 (1999); Logan, A. et al., Exp. Neurol. 159:504-510 (1999); Masliah, E., et al., Neurochem. Int. 39:393-400 (2001); De Groot, C. J. A. et al., J. Neuropathol. Exp. Neurol. 58:174-187 (1999); John, G. R. et al., Nat. Med. 8:1115-1121 (2002)) and hypertension (for example, Dahly, A. J. et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 283: R757-767 (2002)). Studies have shown that TGF-β and activin can act synergistically, increasing the production of extracellular matrix (e.g., Sugiyama, M. et al., Gastroenterology 114; 550-558 (1998)).

Consequently, the mill is entirely obvious, the inhibition of ALK5 and/or ALK4-dependent phosphorylation of Smad2 and Smad3 preferred compounds of the present invention can be used for the treatment and prevention of disorders, including those of the transmission signal.

In applications WO 00/61576 and US 2003/0149277Al described derivatives triarylmethane and their use as inhibitors of ALK5. In WO 01/62756Al described derivatives pyridinedimethanol and their use as inhibitors of ALK5. In WO 02/055077Al described the use of derivatives imidazolyl-cyclic acetals as inhibitors of ALK5. And also in WO 03/087304A2 described tizanidine heteroaryl and their use as inhibitors of ALK5 and/or ALK4.

A DETAILED DESCRIPTION of the PREFERRED embodiments

Now unexpectedly discovered that the class of 2-pyridyl-substituted imidazoles acts as a potent and selective inhibitors of ALK5 and/or ALK4 and, therefore, they can be used in the treatment and prevention of various diseases mediated by ALK5 and/or ALK4, such as glomerulonephritis, diabetic nephropathy, lupus nephritis, nephropathy induced hypertension, renal interstitial fibrosis, renal fibrosis resulting from complications of drug use, HIV-related nephropathy, transplantant necrophelia, hepatic fibrosis all of etiology, liver, dysfuncti is, associated with various infections, hepatitis caused by alcohol, disorders of the bile ducts, pneumovirus, acute pulmonary insufficiency, respiratory distress syndrome in adults, idiopathic pneumovirus, chronic obstructive pulmonary syndrome, pulmonary disease due to infectious or toxic agents, post-infarction cardiac fibrosis, congestive heart failure, cardiomyopathy when dilatation, myocarditis, vascular stenosis, restenosis, atherosclerosis, and scarring of the lens, scarring of the cornea, the proliferating vitreoretinopathy, excessive or hypertrophic scars or keloids on the skin in the healing process of wounds received in traumatic or surgical injury, peritoneal and subcutaneous spikes, scleroderma, tissue, progressive systemic sclerosis, dermatomyositis, polymyositis, arthritis, osteoporosis, ulcers, neurological dysfunction, erectile dysfunction in men, Alzheimer's disease, Raynaud's disease, fibrations kinds of cancer, the growth of tumor metastases, radiation-induced fibrosis and thrombosis.

In the embodiment of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt:

where R1is naftilos, entre Deux is senilnoe or phenyl group, optionally substituted by substituents selected from a halogen atom, OH group, -O-C1-6-alkyl, -S-C1-6-alkyl, C1-6-alkyl, C1-6-halogenoalkane, -O-(CH2)n-Ph, -S-(CH2)n-Ph, cyano group, phenyl and CO2R, where R is hydrogen or C1-6-alkyl, and n is 0, 1, 2 or 3; or R1is phenyl or pyridium condensed with an aromatic or non-aromatic 5-7 membered ring, where the said ring may optionally contain up to three heteroatoms, independently selected from N, O and S, and condensed phenyl or pyridyl may further be optionally substituted by a halogen atom, an OH group, -O-C1-6-alkyl, -S-C1-6-alkyl, C1-6-alkyl, C1-6-halogenation, cyano group, phenyl or =O;

R2is hydrogen, an OH group, -O-C1-6-alkyl, -S-C1-6-alkyl, C1-6-alkyl, phenyl, C1-6-halogenation, NH2group, a NH(CH2)n-Ph, NH-C1-6-alkyl, a halogen atom, a CN group, NO2-group, CONHR or SO2Other, where R is hydrogen or C1-6-alkyl, and n is 0, 1, 2 or 3;

R3is hydrogen, C1-6-alkyl, C3-7-cycloalkyl, -(CH2)P-NO2, -(CH2)P-NR4R5, -(CH2)P-CHO, -(CH2)P-CONHOH, -(CH2)P-CN, -(CH2)P-CO2H, -(H 2)P-CO2R4, -(CH2)P-CONR4R5, -(CH2)P-tetrazole, -(CH2)P-COR4, -(CH2)q(OR6)2, -(CH2)P-OR4, -(CH2)P-CH=CH-CN, -(CH2)P-CH=CH-CO2H, -(CH2)P-CH=CH-CO2R4, -(CH2)P-CH=CH-CONR4R5, -(CH2)P-NHCOR4, -(CH2)pNHCO2R4, -(CH2)P-CONHSO2R4, -(CH2)P-NHSO2R4or -(CH2)P-CH=CH-tetrazolo;

R4and R5are, independently, hydrogen or C1-6-alkyl; R6is C1-4-alkyl; p is 0, 1, 2, 3 or 4; q is 1, 2, 3, or 4; X is C1-10-alkalinous group, C2-10-alkynylamino group or a C2-10-alkynylamino group; one of A1and A2is a nitrogen atom and the other is NR7; and R7is a hydrogen atom, an OH group, a C1-6-alkyl or C3-7-cycloalkyl.

The double bond indicated by the dashed line in formula (I)represents the possible tautomeric forms of the cycle for compounds that fall in the scope of this invention, the double bond is unsubstituted nitrogen atom.

Preferably R1is optionally substituted naphthyl or phenyl. More preferably R1the C is a phenyl, optionally substituted by substituents selected from a halogen atom, an OH-those people, -O-C1-6-alkyl, -S-C1-6-alkyl and phenyl; or R1is a phenyl fused with an aromatic or non-aromatic 5-7 membered ring, where the said ring may optionally contain up to two heteroatoms, independently selected from N, O and S, and condensed phenyl or pyridyl may further be optionally substituted by a halogen atom, an OH group, -O-C1-6-alkyl, -S-C1-6-alkyl, C1-6-alkyl, C1-6-halogenation or =O. for Example, R1represents benzo[1,3]dioxole, 2,3-dihydrobenzo[1,4]dioxines, benzoxazolyl, benzothiazolyl, benzo[1,2,5]oxadiazolyl, benzo[1,2,5]thiadiazolyl, honokalani, dihydrobenzofuranyl, benzimidazolyl, C1-6-benzimidazolyl, [1,2,4]triazolo[1,5-α]pyridyl, benzo[1,4]oxazin-3-one, benzoxazolyl-2-he or benzo[1,4]oxazinyl.

Preferably R2is other than hydrogen Deputy. If R2is other than hydrogen Deputy, it is preferably in ortho-position to the nitrogen atom peredelnogo cycle. R2preferably is C1-4-alkyl.

Preferably R3is -(CH2)P-CONHOH, -(CH2)P-CN, -(CH2)P-CO2H, -(CH2)P-CONR4R5or -(CH2)Pthose what razolam.

Preferably R4and R5are, independently, hydrogen or C1-3-alkyl. Preferably p is 0, 1 or 2. Preferably X represents a C1-6-alkylenes group. Preferably one of the A1and A2is a nitrogen atom and the other is NR7where R7is a hydrogen atom.

Typical compounds of the present invention that may be mentioned include the following compounds and their pharmaceutically acceptable salts:

4-((4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile;

4-((4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile;

3-((4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

4-(2-(4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)ethyl)benzonitrile;

4-(2-(4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

4-(3-(4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)propyl)benzonitrile;

4-(3-(4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)propyl)benzamide;

4-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

4-((5-(6-ethylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

<> 4-((5-(6-n-propylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

4-((5-(6-isopropylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

4-((5-(6-n-butylparaben-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile;

3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((5-(6-ethylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((5-(6-n-propylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((5-(6-isopropylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((5-(6-n-butylparaben-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

4-(2-(5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

4-(2-(5-(6-ethylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

4-(2-(5-(6-n-propylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

4-(2-(5-(6-isopropylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

4-(2-(5-(6-n-butylparaben-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

3-(2-(5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

3-(2-(5-(6-ethylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

3-(2-(5-(6-n-propylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imida the ol-2-yl)ethyl)benzamide;

3-(2-(5-(6-isopropylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

3-(2-(5-(6-n-butylparaben-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide.

Compounds of the present invention are typically small organic molecules (small ones molecule), typically less than about 1000 daltons mass. Preferred ones small molecules have a molecular weight less than about 750 daltons, more preferably less than about 500 daltons, and even more preferably less than about 300 daltons.

The compounds of formula (I) can also be supplied in the form of a "prodrug"which is intended to release the compounds of formula (I) with the introduction of the subject. Methods of making prodrugs are well known in the art and depend on the substituents contained in the compound of formula (I). For example, Deputy containing hydroxyl, could join the media, which makes the connection biologically inactive until then, until it is cleaved by endogenous enzymes or enzymes that are focused on special receptor or site in the body of the patient.

The compound of formula (I), which is acidic in nature (for example, having a carboxyl or phenolic hydroxyl group)may form a pharmaceutical is acceptable salt, such as sodium, potassium, calcium salt or a salt of gold. Also in the scope of the present invention are salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines followed, hydroxyethylamine, and N-methylglucamine. The compound of formula (I) may be treated with acid with the formation of salt accession acid. Examples of such acids include hydrochloric acid, Hydrobromic acid, yodiewonderdog acid, sulfuric acid, methanesulfonate acid, phosphoric acid, para-brompheniramine acid, carbonic acid, succinic acid, citric acid, benzoic acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, ascorbic acid, maleic acid, acetic acid and other mineral and organic acids, are well known to specialists in this field. Salt accession acid can be obtained by treating the compounds of formula (I) in the form of its free base sufficient amount of acid (e.g. hydrochloric acid) with the formation of salt accession acid (for example, cleaners containing hydrochloride salt). Salt accession acid can be converted back to the form of the free base with the appropriate processing of salt diluted water based races is a thief (for example, sodium hydroxide, sodium bicarbonate, potassium carbonate or ammonia).

Some of the compounds of this invention may be crystallized or recrystallized from solvents such as water and organic solvents. In this case, may form a solvate. This invention includes within its scope stoichiometric solvate, including hydrates as well as compounds containing various amounts of water, which may be formed in processes such as freeze drying.

The compounds of formula (I) may contain one or more asymmetric centers and thus may exist as enantiomers or diastereoisomers. It is clear that the invention includes both mixtures and separate individual compounds of the formula (I). Further, certain compounds of formula (I), which contain alkeneamine groups can exist as CIS - or TRANS-isomers. In each case, the invention includes both mixtures and separate individual isomers.

The compounds of formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.

Also included in this invention radioactive-labeled derivatives of the compounds of formula (I)which are applicable to biological research.

Used is here, the term "alkyl" group refers to a saturated aliphatic hydrocarbon group, containing 1-10 (e.g., 1-6 or 1-4) carbon atoms. The alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl and 2-ethylhexyl. The alkyl group may be optionally substituted by one or more substituents such as halogen atom, alkoxy, cycloalkane-, amino-, nitro-, carboxy-, cyano-, hydroxy-, sulfo - or mercapto-group.

Used here, the term "Allenova" group refers to a saturated aliphatic hydrocarbon group containing 1-10 (e.g., 1-6 or 1-4) carbon atoms. Allenova group can be linear or branched. Examples alkalinous groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, n-pentile, n-heptylene and 2-ethylhexyl. Allenova group may be optionally substituted by one or more substituents such as halogen atom, alkoxy, cycloalkane-, amino-, nitro-, carboxy-, cyano-, hydroxy-, sulfo - or mercapto-group.

Used here, the term "Alcanena" group refers to an aliphatic hydrocarbon group which contains 2 to 10 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like the alkyl is a new group alkenylamine group can be linear or branched. Examples alkenylamine groups include, but are not limited to, allele, isoprene, 2-butylen and 2-hexarelin. Alkenylamine group may be optionally substituted by one or more substituents such as halogen atom, alkoxy, cycloalkane, heterocyclizations, aryloxy, heteroaromatic, aralkylated, heteroarylboronic-, amino-, nitro-, carboxy-, cyano-, hydroxy-, sulfo-, mercapto-, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, aminocarbonyl, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarboxamide, aralkylamines, geterotsiklicheskikh, geterotsiklicheskikh, heteroarylboronic, heteroarylboronic-, uraidla, coreena, alfamarine, sulfa, alkoxycarbonyl or alkylcarboxylic-group.

Used here, the term "akinlana" group refers to an aliphatic hydrocarbon group which contains 2 to 10 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond. Akinlana group can be linear or branched. Examples alkynylamino groups include, but are not limited to, propargite and boutinere. Akinlana group may be optionally substituted by one or more substituents, such as the atom halog is on, alkoxy, cycloalkane, heterocyclizations, aryloxy, heteroaromatic, aralkylated, heteroarylboronic-, amino-, nitro-, carboxy-, cyano-, hydroxy-, sulfo-, mercapto-, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, aminocarbonyl, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarboxamide, aralkylamines, geterotsiklicheskikh, geterotsiklicheskikh, heteroarylboronic, heteroarylboronic-, uraidla, coreena, alfamarine, sulfa, alkoxycarbonyl or alkylcarboxylic-group.

Used here, the term "cycloalkyl" group refers to an aliphatic carbocyclic group including 3-10 (e.g., 4 to 8) carbon atoms. Examples cycloalkyl groups are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, substituted, norbornyl, Kubel, octahedrons, decahydronaphthalene, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl and bicyclo[3.2.3]nonyl.

Used here, the term "alkoxy"group refers to alkyl-O-group, where "alkyl" has been defined above as the "alkyl" group.

Used here, the term "halogenation" group refers to an alkyl group containing one or more atoms of halogen. Examples halogenating groups include formati is inuu, chlormethine, bromatology and triptorelin group.

Used herein, the term "halogen" or "halide group" refers to fluorine, chlorine, bromine or iodine.

Used here, the term "inhibitor of ALK5 and/or ALK4" refers to a compound other than an inhibitor of various types of Smad, such as Smad6 and Smad7, which selectively inhibits receptors, ALK5 and/or ALK4, preferably in relation to the receptor p38 or receptor type II.

Used here, the term "ALK5 and/or ALK4-dependent disease" refers to any disease that is mediated (or modulated) by ALK5 and/or ALK4, for example a disorder that is modulated by the inhibition of phosphorylation of Smad2 and Smad3 in the signal transduction pathways of TGF-β and/or activin.

Used here, the term "ulcer" is used to refer to diseases, including, without limitation, diabetic ulcers, chronic ulcers, gastric ulcers and duodenal ulcers.

The compounds of formula (I) can be obtained by using a number of known methods from commercially available or known starting materials. If the original materials are not available from commercial sources, they can be obtained by procedures known in the level of technology.

Scheme 1

In one method, compounds of formula (I), where A1is a nitrogen atom, and A2 is NH, or A1is NH, and A2is a nitrogen atom, receive according to scheme 1. In particular, optionally substituted 2-methylpyridin (II) deprotonated under the action of a base, such as LDA or LiHMDS, before interaction with R1COOR8(III)where R8is C1-6is an alkyl group, R1COCl (IV) or methoxyethylamine R1-substituted carboxylic acid (V), with the formation of the ketone (VI). Methoxyethylamine (V) can be obtained by interaction of the corresponding carboxylic acid (IV) with N,O-dimethylhydroxylamine. The ketone (VI) can be oxidized to the diketone (VII) Dammam HBr in DMSO. This diketone (VII) can then be condensed with an appropriately substituted aldehyde (VIII), or substituted derivatives of aldehyde in the presence of ammonium acetate, which leads to the compound of formula (I). R1, R2, R3and X are defined above. The aldehyde (VIII) can be obtained according to the methods described in WO 02/096875Al and Liquid Crystals 10:273-287 (1991). Alternative ketone (VI) may be treated with sodium nitrite in HCl or acetic acid with the formation of α-ketoxime (IX), which can then be condensed with an appropriately substituted aldehyde (VIII), or substituted derivatives of aldehyde in the presence of ammonium acetate with the formation of N-hydroxymidazolam. Treatment of these compounds triethyl what svetom leads to the compound of formula (I).

In another way, when R3in the compounds of formula (I) is -(CH2)P-CN or -(CH2)P-CH=CH-CN-group, the compound may be further functionalized with the formation of the compounds of formula (I), as shown in scheme 2. R1, R2X and P are defined above, and R4and R5are, independently, hydrogen or C1-6is an alkyl group.

Scheme 2

The compounds of this invention represented by formulas (I)to(IX), can be separated and purified by appropriate conventional means, such as column chromatography and recrystallization.

The compounds of this invention can be administered by any suitable route, such as oral, buccal, sublingual, rectal, vaginal, nazalnam, local or parenteral administration (including intravenous, intramuscular, subcutaneous and transvenous).

Compositions for topical application of the present invention can be represented as, for example, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents, facilitating penetration of the medication, and softeners in oils and creams.

The composition can also contain the compatible conventional carriers, such as bases for creams or ointments and ethanol or alerby alcohol lotion. Such media can comprise from approximately 1% to approximately 98% of the composition. Usually they will make up approximately 80% of the composition.

For administration to man for the treatment or prevention of disease, defined earlier, oral, buccal or sublingual dosage of the compounds of formula (I), will usually be in the range of 50-5000 mg per day for an average adult patient (70 kg). Thus, for a typical adult patient, individual tablets or capsules contain from 25-500 mg of active compound in the appropriate pharmaceutically acceptable excipient or carrier, for administration in single or multiple doses, once or several times a day. Dosage for parenteral administration will typically be in the range of 25-250 mg for a single dose as needed. In practice, the physician will determine the actual mode of reception, which will be more tailored to suit the individual patient and will vary depending on the age, weight and response of the individual patient. The above dosages are exemplary for the average case, but there may be individual cases in which can be applied to larger or smaller ranges of dosages, and it is the amount given to the CSOs of the invention.

For use in humans, the compound of formula (I) may be one, but will generally be administered in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and conventional medical practices. For example, the connection may be oral, buccal or sublingual in the form of tablets containing excipients such as starch or lactose, or in capsules, or in Beulah, or one, or in a mixture with excipients, or in the form of elixirs or suspensions containing flavouring agents or coloring agents. Such liquid preparations can be obtained by using pharmaceutically acceptable additives such as suspendisse agent (for example, methylcellulose, semisynthetic glycerides, such as witepsol, or a mixture of glycerides, such as a mixture of seed oil apricot and esters PEG-6, or a mixture of PEG-8 Caprylic/capric triglycerides contents). The connection may also be injected parenterally, for example intravenously, intramuscularly, subcutaneously or intracardiac. For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example salts or monosaccharides, such as mannitol or glucose, to make the solution was isotonic with blood.

Thus, in this aspect of the invention is a pharmaceutical composition is Yu, containing the compound of formula (I)or its pharmaceutically acceptable salt or MES, together with a pharmaceutically acceptable diluent or carrier.

The invention is also the compound of formula (I) or its pharmaceutically acceptable salt or MES, or a pharmaceutical composition containing any of these compounds, for use in the treatment.

Further this invention is the use of compounds of formula (I) or its pharmaceutically acceptable salt or MES, or a pharmaceutical composition containing any of these compounds, for the manufacture of a medicinal product for the treatment of diseases mediated by ALK5 and/or ALK4 receptors in mammals.

ALK5 and/or ALK4-mediated diseases include, without limitation, diseases such as glomerulonephritis, diabetic nephropathy, lupus nephritis, nephropathy induced hypertension, renal interstitial fibrosis, renal fibrosis resulting from complications of drug use, HIV-related nephropathy, transplantant necrophelia, hepatic fibrosis all of etiology, liver dysfunction associated with various infections, hepatitis caused by alcohol, disorders of the bile ducts, pneumovirus, acute pulmonary insufficiency, respiratory distresssindroma adults idiopathic pneumovirus, chronic obstructive pulmonary syndrome, pulmonary disease due to infectious or toxic agents, post-infarction cardiac fibrosis, congestive heart failure, cardiomyopathy when dilatation, myocarditis, vascular stenosis, restenosis, atherosclerosis, and scarring of the lens, scarring of the cornea, the proliferating vitreoretinopathy, excessive or hypertrophic scars or keloids on the skin in the healing process of wounds received in traumatic or surgical injury, peritoneal and subcutaneous adhesions, scleroderma, tissue, progressive systemic sclerosis, dermatomyositis, polymyositis, arthritis, osteoporosis, ulcers, neurological dysfunction, erectile dysfunction in men, Alzheimer's disease, Raynaud's disease, fibrations kinds of cancer, the growth of tumor metastases, radiation-induced fibrosis and thrombosis.

This invention further provides a method of inhibiting the transmission of signals of TGF-β and/or activin in mammals, for example, inhibiting the phosphorylation of Smad2 or Smad3 by ALK5 and/or ALK4.

Further, the invention is a method of reducing the accumulation of excess extracellular matrix in mammals by inhibiting the signal transduction pathways of TGF-β and/or advance the and, for example, inhibiting the phosphorylation of Smad2 or Smad3 by ALK5 and/or ALK4.

Further, the invention provides a method of inhibiting metastasis of tumor cells in mammals by inhibiting the transmission signal of TGF-β.

Further, the invention provides a method of treatment of cancer-mediated overexpression of TGF-β in mammals by inhibiting the transmission signal of TGF-β.

BRIEF DESCRIPTION of DRAWINGS

The aforementioned aspects and other features of the present invention will be explained in the following description, considered in connection with the accompanying drawings, where:

the figure 1 shows the effect of the compounds of examples 6, 9, 10, 13 and 31 on TGF-β1-induced activity of the reporter SBE-Luc cells HepG2,

the figure 2 shows the effect of compound of example 41 on TGF-β1-induced activity of the reporter SBE-Luc cells HepG2,

the figure 3 shows the effect of compound of example 41 on TGF-β1-induced activity of the reporter 3TP-Lux in HepG2 cells,

the figure 4 shows the effect of compound of example 41 on TGF-β1-induced activity of the reporter PAI-1 promoter-Luc cells HepG2,

the figure 5 shows the effect of compound of example 41 on TGF-β1-induced expression of PAI-1 in human keratinocytes HaCaT,

in figure 6 demonstrates the effect is soedineniya example 41 on TGF-β 1-induced phosphorylation of Smad2 and Smad3 in human skin fibroblasts,

in figures 7A and 7B shows the effect of compound of example 41 on liver fibrosis in rats by ligation of the bile duct,

table 1 presents the structure and data1H-NMR spectra and mass spectra for compounds of examples 1-61, and

the figure 8 shows the effect of compound of example 41 on the activity of protein kinasesin vitro.

EXAMPLES

The present invention is further illustrated by the following examples, which should not be used to limit the scope of the present invention described in the claims. In the examples of mass spectra with ionization elektrorazpredelenie (ESI-MS) were obtained on a mass spectrometer Q-Tof2 (Micromass, Manchester, UK).

Example obtain 1: Obtain 3-((4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile (example 5).

To a stirred solution of 1-(benzo[1,3]dioxol-5-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-dione (50 mg, 0,19 mmol) (obtained according to the method described in WO 01/62756A1) in AcOH (3 ml) was added 3-(formylmethyl)benzonitrile (28 mg, 0,19 mmol) (obtained according to the method described in WO 02/096875 Al) and NH4OAc (86 mg, 1.11 mmol)and the mixture was heated at 120°C for 3 hours. the pH of the cooled reaction mixture was brought to pH 7-8 with 0°C with 28% NH4OH, and reacts the traditional mixture was extracted with CH 2Cl2(10 ml). A solution of CH2Cl2washed with water (5 ml) and saturated saline (5 ml), dried (over anhydrous Na2SO4), filtered and evaporated to dryness under reduced pressure. The residue was purified liquid medium pressure chromatography (MPLC) on silica gel using a mixture of MeOH and CH2Cl2(1:19 by volume)as eluent, which gave 26 mg (36%) of 3-((4-benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile in the form of solids. MS (ESI) m/z: 395,13 (MH+).1H-NMR spectrum (400 MHz, CDCl3): δ 7,52 (s, 1H), 7,46 (m, 1H), 7,40 (t, 1H), 7,33 (d, 1H), 7,32-7,26 (m, 2H), 7,09? 7.04 baby mortality (m, 2H), 6.90 to (d, 1H), PC 6.82 (d, 1H), 5,96 (s, 2H), 4,10 (s, 2H), of 2.38 (s, 3H).

Example of getting 2: Obtain 3-((4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzamide (Example 6)

To a stirred solution of 3-((4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile (70 mg, 0,17 mmol) in EtOH (4 ml) at room temperature was added 30% H2O2(0.59 mmol) and 6 n NaOH solution (0.04 mmol). The mixture was heated to 50-60°C and was stirred for 3 hours, and the resulting solution was added 1 n HCl solution, bringing the pH to 7-8 with 0°C. the Ethanol was evaporated under reduced pressure, and the residue was dissolved in CH2Cl2(30 ml). A solution of CH2Cl2washed with water (15 ml) and saturated salt solution (15 ml), was dried (over anhydrous Na2SO4), filtered and evaporated to dryness under reduced pressure. The residue was purified liquid chromatography (MPLC) on silica gel using a mixture of MeOH and CH2Cl2(1:9 (by volume)as eluent, which gave 23 mg (33%) of 3-((4-benzo[1,3]dioxol-5-yl)-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzamide in the form of solids. MS (ESI) m/z: 413,11 (MH+).1H-NMR spectrum (400 MHz, CDCl3): δ to 7.59 (s, 1H), 7,52 (d, 1H), 7,37 (DD, 1H), 7,24 (m, 2H), 7,15 (t, 1H), 7,01 (overlaps with neighboring signal, 1H), 7,00 (s, 1H), to 6.88 (d, 1H), 6.75 in (d, 1H), 6,70 (ush. s, 1H), 6,02 (ush. s, 1H), of 5.92 (s, 2H), 4.00 points (s, 2H), 2,34 (s, 3H).

Example of getting 3: Obtain 4-((1(3)-hydroxy-5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile (Example 30)

To a stirred solution of 1-(6-methylpyridin-2-yl)-2-(cinoxacin-6-yl)ethane-1,2-dione 1-oxime (67 mg, 0.23 mmol) (obtained according to the method described in WO 01/62756 A1) in tert-butylmethylether ether (2.5 ml) was added 4-(formylmethyl)benzonitrile (101 mg, 0.69 mmol) (obtained according to the method described in WO 02/096875 Al) and NH4OAc (89 mg, 1.15 mmol)dissolved in MeOH (1.2 ml)and the mixture was stirred at room temperature overnight. the pH of the reaction mixture was brought to pH 7-8 with 0°C the action of a saturated solution of NaHCO3. The reaction mixture was distributed between CH2Cl2(40 m is) and water (40 ml). The aqueous layer was re-extracted with CH2Cl2(3 × 15 ml). A combined solution of CH2Cl2was dried (over anhydrous Na2SO4), filtered and evaporated to dryness under reduced pressure. The residue was purified MPLC on silica gel using a mixture of MeOH and CH2Cl2(1:30, then 1:19 (by volume)as eluent, which gave 38 mg (40%) of 4-((1(3)-hydroxy-5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile in the form of solids. MS (ESI) m/z: 419,23 (MH+).1H-NMR spectrum (400 MHz, CDCl3): δ 8,86 (m, 2H), 8,35 (d, 1H), 8,17 (d, 1H), of 8.06 (DD, 1H), 7.62mm (m, 2H), 7,56 (m, 2H), 7,52 (t, 1H), was 7.36 (d, 1H), 7,06 (d, 1H), or 4.31 (s, 2H), 2,61 (s, 3H).

Example 4: Obtain 4-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide (Example 31)

To a stirred solution of 4-((1(3)-hydroxy-5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile (264 mg, 0,631 mmol) in ethanol (16 ml) and DMSO (4 ml) at room temperature was added 30% H2O2(6.62 mmol) and 6 n NaOH (0.47 mmol). The mixture was heated to 50-60°C and was stirred overnight and the resulting solution was added 1 n HCl solution, bringing the pH to 7-8 with 0°C. the Ethanol was evaporated under reduced pressure, and the residue was distributed between CH2Cl2(30 ml) and H2O (50 ml). The aqueous layer was saturated with NaCl and extra is Aravali CH 2Cl2(3 × 30 ml). United solutions CH2Cl2was washed with saturated saline solution (30 ml), dried (over anhydrous Na2SO4), filtered and evaporated to dryness under reduced pressure. The residue was dissolved in anhydrous DMF (20 ml) and treated with triethylphosphite (2,39 mmol). The mixture was heated at 110°C for 3 days, cooled to room temperature and was evaporated to dryness under reduced pressure. The reaction mixture was distributed between CH2Cl2(30 ml) and water (50 ml)and the aqueous layer was extracted with CH2Cl2(2 × 30 ml). A combined solution of CH2Cl2was washed with saturated solution of NaHCO3(40 ml) and saturated saline (50 ml), dried (over anhydrous Na2SO4), filtered and evaporated to dryness under reduced pressure. The residue was purified MPLC on silica gel using a mixture of MeOH and CH2Cl2(1:9, then 1:5 (by volume)as eluent, which gave 96 mg (36%) of 4-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide in the form of solids. MS (ESI) m/z: 421,14 (MH+).1H-NMR spectrum (400 MHz, CDCl3): δ 12,01 (ush. s, 1H), 8,83 (m, 2H), scored 8.38 (s, 1H), 8,15 (DD, 2H), 7,55 (d, 2H), 7,42 (DD, 1H), 7,33 (d, 1H), 7,21 (d, 2H), 6,95 (d, 1H), 6,62 (ush. s, 1H), of 5.83 (ush. s, 1H), 4,13 (s, 2H), to 2.29 (s, 3H).

Example of getting 5: Obtain 4-(2-(5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)be samida (Example 48)

To a stirred solution of 4-(2-(1,3-dioxolane-2-yl)ethyl)benzonitrile (1.50 g, 7,34 mmol) (obtained according to the method described in Kelly, S. M, Liquid Crystals 10: 273-287 (1991)) in MeOH (50 ml) at room temperature was added 30% H2O2(25,70 mmol) and 6 n NaOH solution (7,34 mmol). The mixture was heated to 50-60°C and was stirred for 2 hours, and the resulting solution was added 1 n HCl solution, bringing the pH to 7-8 with 0°C. the Methanol was evaporated under reduced pressure, and the residue was extracted with CH2Cl2(3 × 30 ml). A solution of CH2Cl2was washed with saturated saline solution (30 ml), dried (over anhydrous Na2SO4), filtered and evaporated to dryness under reduced pressure. The residue was purified MPLC on silica gel using a mixture of MeOH and CH2Cl2(1:19, then 1:9 (by volume)as eluent, which gave 1,58 g (97%) of 4-(2-(1,3-dioxolane-2-yl)ethyl)benzamide in the form of a solid substance.1H-NMR spectrum (400 MHz, CDCl3): δ 7,74 (DD, 2H), 7,29 (d, 2H), 6,01 (ush. s, 1H), 5,71 (ush. s, 1H), 4,89 (t, 1H), 3,99 (m, 2H), 3,88 (m, 2H), 2,80 (m, 2H), 1,99 (m, 2H).

To a stirred solution of 4-(2-(1,3-dioxolane-2-yl)ethyl)benzamide (0.50 g, of 2.26 mmol) in THF (22 ml) was added 1 n HCl solution (20 ml) at room temperature. The mixture was heated to 80-90°C for 1 hour and cooled to room temperature. After saturation with NaCl, the reaction mixture was extracted with repeating what about CHCl 3(5 × 20 ml). United solution CHCl3was dried (over anhydrous Na2SO4), filtered and evaporated under reduced pressure, which gave 0.40 g (98%) of 4-(2-formylated)benzamide in the form of a solid, which was used in the next stage without further purification.1H-NMR spectrum (400 MHz, CDCl3): δ 9,82 (t, 1H), 7,74 (m, 2H), 7,27 (m, 2H), 6,14 (ush. s, 1H), 6,03 (ush. s, 1H), 3,01 (m, 2H), 2,81 (m, 2H).

To a stirred solution of 1-(6-methylpyridin-2-yl)-2-(cinoxacin-6-yl)ethane-1,2-dione (1,05 g, with 3.79 mmol) (obtained according to the method described in WO 02/055077 A1) in a mixture of tert-butyl methyl ether (35 ml) and MeOH (25 ml) was added 4-(2-formylated)benzamide (1,00 g, 5,69 mmol) and NH4OAc (1,46 g, 18,95 mmol)and the mixture was stirred at room temperature overnight. the pH of the reaction mixture was brought to pH 7-8 with 0°C saturated solution of NaHCO3. After removal of solvent, the reaction mixture was extracted with CH2Cl2(3 × 25 ml), a solution of CH2Cl2was dried (over anhydrous Na2SO4), filtered and evaporated to dryness under reduced pressure. The residue was purified MPLC on silica gel using a mixture of MeOH and CH2Cl2(1:19, then 1:9 (by volume)as eluent, which gave 1.08 g (66%) of 4-(2-(5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethylbenzamide in the form of solids. MS (ESI) m/z: 435,19.1H-NMR spectrum (400 MHz, CDCl3): ; 8,82 (m, 2H), at 8.36 (s, 1H), 8,09 (d, 2H), to 7.64 (d, 2H), 7,43 (t, 1H), 7,32 (d, 1H), 7,17 (d, 2H), 6,99 (d, 1H), 6,58 (ush. s, 1H), 6,09 (ush. s, 1H), 3,06 (s, 4 H), of 2.45 (s, 3H).

An example of obtaining 6: Obtain 4-(3-(4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)propyl)benzonitrile (Example 13)

To a stirred solution of 1-(benzo[1,3]dioxol-5-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-dione (230 mg, 0.86 mmol) in AcOH (8 ml) was added 4-(3-formylpropyl)benzonitrile (156 mg, 0.90 mmol) (obtained according to the method described in Kelly, S. M, Liquid Crystals 10: 273-287 (1991)) and NH4OAc (396 mg, 5,14 mmol)and the mixture was heated at 120°C for 3 hours. the pH of the cooled reaction mixture was brought to pH 7-8 with 0°C 28% NH4OH, and the reaction mixture was extracted with CH2Cl2(3 × 30 ml). A combined solution of CH2Cl2was dried (over anhydrous Na2SO4), filtered and evaporated to dryness under reduced pressure. The residue was purified MPLC on silica gel using a mixture of MeOH and CH2Cl2(1:30, then 1:19 (by volume)as eluent, which gave 130 mg (36%) of 4-(3-(4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)propyl)benzonitrile in the form of solids. MS (ESI) m/z: 423,14.1H-NMR spectrum (400 MHz, CDCl3): δ 10,63 (ush. s, 1H), 7,51 (d, 2H), 7,42 (DD, 1H), 7,30 (d, 1H), 7,24 (d, 2H), 7,10? 7.04 baby mortality (m, 2H), 6,93 (d, 1H), PC 6.82 (d, 1H), 5,98 (s, 2H), 2,74 (m, 4 H), 2,47 (s, 3H), 2,07 (m, 2H).

Example of getting 7: P who receive 3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile (Example 40)

To a solution of 1-(6-methylpyridin-2-yl)-2-(cinoxacin-6-yl)ethane-1,2-dione (40,0 g, 144,26 mmol) (obtained according to the method described in WO 02/055077 A1) in a mixture of tert-butyl methyl ether (350 ml) and MeOH (350 ml) was added 3-(formylmethyl)benzonitrile (to 23.03 g, 158,69 mmol) (obtained according to the method described in WO 02/096875 A1 ) in tert-butylmethylether ether (350 ml) and NH4OAc (111,00 g, 1.44 mol) in MeOH (350 ml), the mixture was stirred at 45°C during the night. the pH of the reaction mixture was brought to pH 7-8 with 0°C saturated solution of NaHCO3. After removal of solvent, the reaction mixture was extracted with CH2Cl2(3 × 800 ml), a solution of CH2Cl2was dried (over anhydrous MgSO4), filtered and evaporated to dryness under reduced pressure. The residue was purified MPLC on silica gel using a mixture of MeOH and CH2Cl2(1:19, then 1:9 (by volume)as eluent, which gave 28,98 g (50%, untreated connection) 3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile in the form of solids. MS (ESI) m/z: 403,14 (MH+).1H-NMR spectrum (400 MHz, CDCl3): δ 8,84 (m, 2H), 8,39 (s, 1H), 8,15 (s, 2H), 7,56 (s, 1H), 7,46 (m, 3H), 7,37 (d, 1H), 7,32 (m, 1H), 6,99 (d, 1H), 4,17 (s, 2H), is 2.37 (s, 3H).

Example obtain 8: Obtain 3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide (Example 41)

To re esibaevna to a solution of 3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile (28,98 g, 72,58 mmol) in EtOH (250 ml) was added 30% H2O2(4,85 ml, 39,92 mmol) and 1 n NaOH solution (250 ml). The mixture was heated to 40°C for 30 minutes, and then to the resulting solution was added 30% H2O2(4,85 ml, 39,92 mmol). After 30 minutes the reaction mixture was added 1 N. HCl at 0°C, bringing the pH to 7-8. After removal of solvent the residue was extracted repeatedly CH2Cl2(3 × 450 ml). The combined solution of CH2Cl2was dried (over anhydrous MgSO4), filtered and evaporated to dryness under reduced pressure. The residue was purified MPLC on silica gel using a mixture of MeOH and CH2Cl2(1:9, then 1:5 (by volume)as eluent, which gave be 18.49 g (61%) of 3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide in the form of solids. MS (ESI) m/z: 421,23 (MH+).1H-NMR spectrum (400 MHz, CDCl3): δ 8,79 (s, 2H), 8.34 per (s, 1H), of 8.06 (s, 2H), 7,71 (s, 1H), 7,55 (d, 1H), 7,41 (t, 1H), 7,34 (d, 1H), 7,29 (d, 1H), 7,19 (t, 1H), of 6.96 (d, 1H), 6,83 (ush. s, 1H), 6.30-in (ush. s, 1H), 4,13 (s, 2H), a 2.36 (s, 3H).

Example of getting 9: Obtain the hydrochloride of 3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide (Example 58)

3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide (5.0 g, 11,89 mmol) was dissolved in dry CH2Cl2(40 ml), filtered through a glass filter and washed with dry CH2Cl22Cl2was cooled to 0°C and to it was added a 1.0 M HCl in Et2O (18 ml, 18 mmol). The reaction mixture was stirred at room temperature for 15 minutes, evaporated to dryness under reduced pressure and dried overnight over the P2O5that gave the 5.25 g (97%) of the hydrochloride of 3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide in the form of a slightly yellow powder.1H-NMR spectrum (400 MHz, DMSO-d6): δ 9,03 (s, 2H), 8,48 (d, 1H), 8,19 (d, 1H), 8,11 (m, 1H), of 8.06 (d, 1H), 8,04 (d, 1H), 7,83 (m, 1H), 7,80 (t, 1H), 7,74 (m, 1H), of 7.48 (m, 2H), 7,45 (ush. s, 1H), 7,38 (d, 1H), of 4.54 (s, 2H), 2,54 (s, 3H).

Example 10: Getting sulfate 3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide (Example 59)

To a stirred solution of 3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide (50 mg, 0.12 mmol) in dry CH2Cl2(2 ml) was added 10% H2SO4in EtOH (80 μl, 0.14 mmol)and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added MeOH (1 ml) and then quickly poured in anhydrous Et2O (15 ml). Precipitated solid precipitate was collected by filtration and dried overnight over the P2O5that gave 54 mg (88%) sulfate 3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide in the form of a slightly yellow powder. 1H-NMR spectrum (400 MHz, DMSO-d6): δ 9,03 (s, 2H), to 8.41 (d, 1H), they were 8.22 (d, 1H), 8,01-7,88 (m, 3H), 7,83 (m, 1H), 7,79 (t, 1H), 7.62mm (d, 1H), 7,49 (t, 1H), 7,44 (ush. s, 1H), 7,39 (d, 1H), 7,35 (d, 1H), of 4.45 (s, 2H), 2,58 (s, 3H).

The compounds listed in the following Table 1 were obtained by methods similar to those described in the examples get 1-10 earlier. The data of mass spectrometry of these compounds are included in Table 1.

Table 1
ExampleStructure1H NMRMass spectrum (ESI),

m/z(MH+)
1(400 MHz, CDCl3): δ 11,20 (ush. s, 1H), at 8.36 (d, 1H), 7,50 (m, 2H), 7,44 (d, 2H), 7,27 (d, 2H), 7,08-7,02 (m, 3H), PC 6.82 (d, 1H), 5,97 (s, 2H), 4,10 (s, 2H)381,11
2(400 MHz, CDCl3): δ 11,70 (ush. s, 1H), with 8.33 (d, 1H), 7,49 (m, 2H), 7,47 (d, 2H), 7,14 (d, 2H), 7,08-7,00 (m, 3H), to 6.80 (d, 1H), 6,38 (ush. s, 1H), 5,96 (s, 2H), 5,90 (ush. s, 1H), 4,06 (s, 2H)399,12
3(400 MHz, CDCl3): δ 11,40 (ush. s, 1H), 7,45 (d, 2H), 7,44 (overlaps with neighboring signal, 1H), 7,33 (d, 1H), 7,25 (d, 2H), 7,10 (d, 1H), 7,07 (s, 1H), 6,93 (d, 1H), at 6.84 (d, 1H), 6,00 (s, 2H), 4.09 to (s, 2H), 2,34 (s, 3H)395,13
4 (400 MHz, CDCl3): δ 11,70 (ush. s, 1H), 7,45 (d, 2H), 7,39 (DD, 1H), 7,27 (d, 1H), 7,10 (d, 2H), 7,06 (overlaps with neighboring signal, 1H), 7,05 (s, 1H), 6.87 in (d, 1H), 6,80 (d, 1H), 6,39 (ush. s, 1H), 5,95 (s, 2H), 5,78 (ush. s, 1H), was 4.02 (s, 2H), and 2.27 (s, 3H)413,11
5(400 MHz, CDCl3): δ 7,52 (s, 1H), 7,46 (m, 1H), 7,40 (t, 1H), 7,33 (d, 1H), 7,32-7,26 (m, 2H), 7,09? 7.04 baby mortality (m, 2H), 6.90 to (d, 1H), PC 6.82 (d, 1H), 5,96 (s, 2H), 4,10 (s, 2H), of 2.38 (s, 3H)395,13
6(400 MHz, CDCl3): δ to 7.59 (s, 1H), 7,52 (d, 1H), 7,37 (DD, 1H), 7,24 (m, 2H), 7,15 (t, 1H), 7,01 (overlaps with neighboring signal, 1H), 7,00 (s, 1H), to 6.88 (d, 1H), 6.75 in (d, 1H), 6,70 (ush. s, 1H), 6,02 (ush. s, 1H), of 5.92 (s, 2H), 4.00 points (s, 2H), 2,34 (s, 3H)413,11
7(400 MHz, CDCl3): δ 10,22 (ush. s, 1H), of 8.47 (d, 1H), 7,58 (DD, 2H), 7,52 (m, 2H), 7,32 (d, 2H), 7,13-7,03 (m, 3H), 6,86 (d, 2H), 6,01 (s, 2H), 3,19 (m, 2H), of 3.07 (m, 2H)395,12
8(400 MHz, CD3OD): δ 8,51 (m, 1H), 7,80 (d, 2H), of 7.70 (DDD, 1H), 7,43 (d, 1H), 7,34 (d, 2H), 7.23 percent (m, 1H), 6,92 (DD, 1H), 6.89 in (d, 1H), 6,83 (d, 1H), 5,97 (s, 2H), 3.15 in (m, 2H), to 3.09 (m, 2H)413,15
9(400 MHz, CDCl3): δ 10,53 (ush. s, 1H), 7,56 (d, 2H), 7,43 (DD, 1H), 7,31 (m, overlaps with neighboring signals is om, 1H) 7,29 (d, 2H), 7,07 (d, 1H),? 7.04 baby mortality (d, 1H), 6,94 (d, 1H), at 6.84 (d, 1H), 6,00 (s, 2H), 3,13 (m, 2H), 3,05 (m, 2H), 2,48 (s, 3H)409,13
10(400 MHz, CDCl3): δ 10,85 (ush. s, 1H) 7,66 (d, 2H), 7,42 (t, 1H), 7,30 (d, 1H), 7,19 (d, 2H), 7,07 (d, overlapped with the neighboring signal, 1H), 7,05 (s, 1H), 6,93 (d, 1H), PC 6.82 (d, 1H), 6,37 (ush. s, 1H), of 5.99 (s, 2H), 5,69 (ush. s, 1H), 3.04 from (m, 2H), 3,01 (m, 2H), of 2.45 (s, 3H)427,10
11(400 MHz, CDCl3): δ 10,50 (ush. s, 1H), of 8.47 (d, 1H), EUR 7.57-7,47 (m, 4H), 7,25 (d, 2H), 7,10-7,03 (m, 3H), at 6.84 (d, 1H), of 5.99 (s, 2H), was 2.76 (m, 4H), 2,10 (m, 2H)409,13
12(400 MHz, CDCl3): δ for 10.68 (ush. s, 1H) of 8.47 (d, 1H), 7,68 (d, 2H), 7,54 was 7.45 (m, 2H), 7,21 (d, 2H), 7,10-7,00 (m, 3H), 6,83 (d, 1H), 6,20 (ush. s, 1H), 5,98 (s, 2H), 2,75 (m, 4H), 2,11 (m, 2H)427,12
13(400 MHz, CDCl3): δ 10,63 (ush. s, 1H), 7,51 (d, 2H), 7,42 (DD, 1H), 7,30 (d, 1H), 7,24 (d, 2H), 7,10? 7.04 baby mortality (m, 2H), 6,93 (d, 1H), PC 6.82 (d, 1H), 5,98 (s, 2H), 2,74 (m, 4H), 2,47 (s, 3H), 2,07 (m, 2H)423,14
14(400 MHz, CDCl3): δ or 10.60 (ush. s, 1H) to 7.68 (d, 2H), 7,41 (DD, 1H), 7,30 (d, 1H), 7,20 (m, 2H), 7,10-7,05 (m, 2H), 6,92 (d, 1H), PC 6.82 (d, 1H), 6,25 (ush. s, 1H), 5,98 (s, 2H), 5,75 (ush. s, 1H), 2,73 (m, 4H), 2.49 USD (s, 3H), 2,07 (m, 2H)441,12
15 (400 MHz, CDCl3): δ 11,07 (USS, 1H), to 8.41 (d, 1H), 7,56-7,49 (m, 4H), 7,35 (d, 2H), 7,33 (overlaps with neighboring signal, 1H), 7.23 percent-7,17 (m, 2H), was 7.08 (m, 1H), 6,93 (m, 1H), 4,17 (s, 2H), 3,83 (s, 3H)367,10
16(400 MHz, CDCl3): δ to 12.28 (ush. s, 1H), at 8.36 (d, 1H), EUR 7.57-7,49 (m, 2H), 7,45 (d, 2H), 7,29 (m, 1H), 7,22-7,17 (m, 2H), 7,11 (d, 2H), 7,07 (m, 1H), 6.89 in (m, 1H), 6,60 (ush. s, 1H), 6.22 per (ush. s, 1H), 4,07 (s, 2H), of 3.78 (s, 3H)385,08
17(400 MHz, CDCl3): δ 11,10 (ush. s, 1H), 7,43 (d, 2H), 7,35 (DD, 1H), 7,30-to 7.18 (m, 4H), 7,16-to 7.09 (m, 2H), 6.89 in-for 6.81 (m, 2H), 4,07 (s, 2H), 3,74 (s, 3H), of 2.30 (s, 3H)381,08
18(400 MHz, CD3OD): δ 7,80 (d, 2H), 7,51 (m, 1H), 7,41 (d, 2H), 7.23 percent (m, 2H), 7,10-7,01 (m, 3H), 6,85 (d, 1H), 4,17 (s, 2H), of 3.73 (s, 3H), of 2.50 (s, 3H)399,11
19(400 MHz, CDCl3): δ 10,54 (ush. s, 1H), 8,45 (d, 1H), 7,58 (d, 2H), 7,54 (m, 1H), of 7.48 (d, 1H), 7,44-7,38 (m, 3H), 7,38-7,33 (m, 2H), 7,11 (m, 1H), 7,05 (m, 1H), is 4.21 (s, 2H)355,10
20(400 MHz, CDCl3): δ 10,92 (ush. s, 1H), 8,42 (d, 1H), to 7.64 (d, 2H), 7,54 (m, 1H), 7,47 (d, 1H), 7,43 (d, 1H), 7,40-7,34 (m, 2H), 7,30 (m, 2H), 7,12-7,03 (m, 2H), 6,15 (ush. s, 1H), of 5.82 (ush. s, 1H), 4,19 (s, 2H)373,11
21(400 MHz, CDCl3): δ 10,27 (ush. s, 1H), 7,60 (d, 2H), 7,46-7,40 (overlaps with neighboring signal, 2H), 7,42 (d, 2H), was 7.36 (m, 2H), 7,29 (d, 1H), 7,05 (m, 1H), 6,97 (d, 1H), 4,22 (s, 2H), 2,48 (s, 3H)369,11
22(400 MHz, CDCl3): δ 10,94 (ush. s, 1H), 7,63 (d, 2H), 7,46-7,40 (m, 2H), 7,40-to 7.32 (m, 2H), 7,29 (overlaps with neighboring signal, 1H), 7,28 (d, 2H),? 7.04 baby mortality (m, 1H), 6,94 (d, 1H), 6,16 (ush. s, 1H), 5,71 (ush. s, 1H), 4.16 the (s, 2H), 2.40 a (s, 3H)387,19
23(400 MHz, CDCl3): δ 10,47 (ush. s, 1H), 8,44 (d, 1H), EUR 7.57 (d, 2H), 7,53 (d, 1H), of 7.48 (d, 1H), 7,39 (d, 2H), was 7.36 (overlaps with neighboring signal, 2H), to 7.09 (DD, 1H), 7,01 (t, 1H), 4,19 (s, 2H), of 3.94 (s, 3H)385,13
24(400 MHz, CDCl3): δ 10,94 (ush. s, 1H), 8,40 (d, 1H), 7.62mm (d, 2H), 7,53 (m, 1H), 7,47 (d, 1H), 7,41-7,35 (m, 2H), 7,29 (d, 2H), was 7.08 (m, 1H), 7,00 (DD, 1H), 6,18 (ush. s, 1H), of 5.84 (ush. s, 1H), 4,17 (s, 2H), of 3.94 (s, 3H)403,18
25(400 MHz, CDCl3): δ of 10.25 (ush. s, 1H), to 7.59 (d, 2H), 7,41 (d, 2H), 7,47-7,34 (overlaps with neighboring signal, 3H), 7,29 (d, 1H), 7,00 (t, 1H), 6,95 (d, 1H), 4,20 (s, 2H), of 3.94 (s, 3H), 2,47 (s, 3H)399,15
26 (400 MHz, CDCl3): δ 10,97 (ush. s, 1H), to 7.61 (d, 2H), 7,45-7,34 (m, 3H), 7,30-7,24 (m, 3H), of 6.99 (DD, 1H), 6,93 (d, 1H), 6,20 (ush. s, 1H), 5,70 (ush. s, 1H), 4,14 (s, 2H), 3,93 (s, 3H), 2,39 (s, 3H)417,15
27(400 MHz, CDCl3): δ 8,42 (d, 1H), 7,71 (d, 2H), 7,52 (m, 2H), was 7.36 (d, 2H), 7,15 (d, 1H), 7,10 (DD, 1H), 7,05 (m, 1H), 6.90 to (d, 1H), 6,12 (ush. s, 1H), 5,59 (ush. s, 1H), 4,29 (m, 4H), 4,20 (s, 2H)413,13
28(400 MHz, CDCl3): δ 10,80 (ush. s, 1H), to 7.64 (d, 2H), 7,41 (DD, 1H), 7,34 (d, 1H), 7,29 (d, 2H), 7,15 (s, 1H), 7,11 (d, 1H), 6.90 to (d, 1H), 6.89 in (d, 1H), 6,20 (ush. s, 1H), 5,55 (ush. s, 1H), 4,29 (m, 4H), 4,14 (s, 2H), of 2.38 (s, 3H)427,19
29(400 MHz, CDCl3): δ to 11.52 (ush. s, 1H), cent to 8.85 (s, 2H), to 8.41 (d, 1H), 8,39 (s, 1H), 8,16 (s, 2H), to 7.64 (d, 2H), 7,52 (m, 2H), 7,32 (d, 2H), 7,11 (m, 1H), 6,34 (ush. s, 1H), 5,85 (ush. s, 1H), 4,23 (s, 2H)407,13
30(400 MHz, CDCl3): δ 8,86 (m, 2H), 8,35 (d, 1H), 8,17 (d, 1H), of 8.06 (DD, 1H), 7.62mm (m, 2H), 7,56 (m, 2H), 7,52 (t, 1H), was 7.36 (d, 1H), 7,06 (d, 1H), or 4.31 (s, 2H), 2,61 (s, 3H)419,23
31(400 MHz, CDCl3): δ 12,01 (ush. s, 1H), 8,83 (m, 2H), scored 8.38 (s, 1H), 8,15 (DD, 2H), 7,55 (d, 2H), 7,42 (DD, 1H), 7,33 (d, 1H), 7,21 (d, 2H), 6,95 (d, 1H), 6,62 (ush. s, 1H), of 5.83 (ush. s, 1H), 4,13 (s, 2H), to 2.29 (s, 3H)421,14
32(400 MHz, CDCl3): δ 8,86 (m, 2H), at 8.36 (d, 1H), 8,17 (d, 1H), 8,07 (DD, 1H), 7.62mm (m, 2H), EUR 7.57 (m, 2H), 7,54 (t, 1H), 7,37 (d, 1H), was 7.08 (d, 1H), 4,32 (s, 2H), 2,90 (square, 2H), to 1.38 (t, 3H)433,18
33(400 MHz, CDCl3): δ are 11.62 (ush. s, 1H), 8,83 (s, 2H), 8,39 (s, 1H), 8,15 (DD, 2H), to 7.59 (d, 2H), 7,45 (t, 1H), 7,33 (d, 1H), 7,26 (d, 2H), 6,99 (d, 1H), 6,45 (ush. s, 1H), of 5.83 (ush. s, 1H), 4,17 (s, 2H), 2,65 (square, 2H), of 1.09 (t, 3H)435,19
34(400 MHz, CDCl3): δ 8,86 (m, 2H), at 8.36 (d, 1H), 8,17 (d, 1H), 8,07 (DD, 1H), 7.62mm (m, 2H), EUR 7.57 (m, 2H), 7,54 (t, 1H), 7,37 (d, 1H), 7,06 (d, 1H), 4,32 (s, 2H), and 2.83 (t, 2H), equal to 1.82 (m, 2H), of 1.02 (t, 3H)447,19
35(400 MHz, CDCl3): δ 8,86 (m, 2H), at 8.36 (d, 1H), 8,17 (d, 1H), 8,07 (DD, 1H), 7.62mm (m, 2H), EUR 7.57 (m, 2H), 7,55 (t, 1H), 7,37 (d, 1H), to 7.09 (d, 1H), 4,32 (s, 2H), 3.13 (wireless septet, 1H), 1,38 (s, 3H), of 1.37 (s, 3H)447,22
36(400 MHz, CDCl3): δ 10,33 (ush. s, 1H), 8,84 (m, 2H), 8,42 (s, 1H), 8,15 (s, 2H), 7,76 (m, 2H), 7,44 (m, 3H), 7,33 (d, 1H), 7,01 (d, 1H), 6,10 (ush. s, 1H), ceiling of 5.60 (ush. s, 1H), 4,28 (s, 2H), 3,01(septet, 1H), 1.27mm (s, 3H), 1,25 (s, 3H)449,23
37(400 MHz, CDCl3): δ 8,86 (m, 2H), 8,35 (d, 1H), 8,17 (d, 1H), of 8.06 (DD, 1H), 7.62mm (m, 2H), 7.5 (m, 2H), 7,53 (t, 1H), was 7.36 (DD, 1H), 7,06 (d, 1H), or 4.31 (s, 2H), 2,85 (t, 3H), of 1.76 (m, 2H), 1,42 (m, 2H), and 0.98 (t, 3H)461,20
38(400 MHz, CDCl3): δ 11,47 (ush. s, 1H), 8,84 (s, 2H), 8,40 (s, 1H), 8,16 (m, 2H), to 7.61 (d, 2H), 7,43 (t, 1H), 7,33 (d, 1H), 7,28 (d, 2H), 6,97 (d, 1H), 6.35mm (ush. s, 1H), 5,68 (ush. s, 1H), 4,19 (s, 2H), 2,64 (t, 2H), 1,45 (m, 2H), 1,24 (m, 2H), 0,81 (t, 3H)463,24
39(400 MHz, CDCl3): δ 8,86 (m, 2H), at 8.36 (d, 1H), 8,18 (d, 1H), 8,08 (DD, 1H), 7,76 (s, 1H), of 7.70 (d, 1H), 7,53 (m, 1H), 7,51 (d, 1H), 7,43 (t, 1H), 7,37 (d, 1H), 7,07 (d, 1H), 4,29 (s, 2H), 2.63 in (s, 3H)419,20
40(400 MHz, CDCl3): δ 8,84 (m, 2H), 8,39 (s, 1H), 8,15 (s, 2H), 7,56 (s, 1H), 7,46 (m, 3H), 7,37 (d, 1H), 7,32 (m, 1H), 6,99 (d, 1H), 4,17 (s, 2H), is 2.37 (s, 3H).403,14
41(400 MHz, CDCl3): δ 8,79 (s, 2H), 8.34 per (s, 1H), of 8.06 (s, 2H), 7,71 (s, 1H), 7,55 (d, 1H), 7,41 (t, 1H), 7,34 (d, 1H), 7,29 (d, 1H), 7,19 (t, 1H), of 6.96 (d, 1H), 6,83 (ush. s, 1H), 6.30-in (ush. s, 1H), 4,13 (s, 2H), a 2.36 (s, 3H)421,23
42(400 MHz, CDCl3): δ cent to 8.85 (m, 2H), at 8.36 (d, 1H), 8,17 (d, 1H), 8,07 (DD, 1H), of 7.75 (s, 1H), of 7.70 (d, 1H), 7,54 (m, 2H), 7,42 (t, 1H), 7,38 (d, 1H), 7,07 (d, 1H), 4,29 (s, 2H), 2,90 (square, 2H), to 1.38 (t, 3H)433,24
43 (400 MHz, CDCl3): δ 8,84 (m, 2H), 8,40 (s, 1H), 8,13 (d, 2H), a 7.85 (s, 1H), 7,72 (m, 1H), EUR 7.57 (m, 1H), 7,44 (m, 2H), 7,34 (ush. d, 1H), 7,00 (DD, 1H), 6,20 (ush. s, 1H), ceiling of 5.60 (ush. s, 1H), 4,28 (s, 2H), 2,80 (square, 2H), 1.28 (in t, 3H)435,22
44(400 MHz, CDCl3): δ 8,86 (m, 2H), at 8.36 (d, 1H), 8,18 (d, 1H), 8,08 (DD, 1H), 7,76 (m, 1H), 7,71 (m, 1H), 7,54 (m, 2H), 7,43 (t, 1H), 7,38 (DD, 1H), 7,10 (DD, 1H), 4,30 (s, 2H), 3,14 (septet, 1H), 1.39 in (s, 3H), 1,37 (, 3H)447,22
45(400 MHz, CDCl3): δ 8,81 (m, 2H), of 8.37 (s, 1H), 8,11 (m, 2H), 7,71 (s, 1H), 7,65 (m, 1H), 7,50 (d, 1H), 7,46 (t, 2H), was 7.36 (t, 1H), 7,35 (overlaps with neighboring signal, 1H), 7,02 (DD, 1H), 6,37 (ush. s, 1H), 5,70 (ush. s, 1H), 4,22 (s, 2H), 2,99 (septet, 1H), 1,24 (s, 3H), 1,22 (s, 3H)449,25
46(400 MHz, CDCl3): δ cent to 8.85 (m, 2H), 8,35 (d, 1H), 8,17 (d, 1H), 8,07 (DD, 1H), of 7.75 (s, 1H), of 7.70 (m, 1H), 7,53 (m, 2H), 7,42 (t, 1H), 7,37 (d, 1H), 7,05 (d, 1H), 4,29 (s, 2H), 2,85 (t, 2H), 1,76 (m, 2H), 1,43 (m, 2H), and 0.98 (t, 3H)461,27
47(400 MHz, CDCl3): δ 8,83 (m, 2H), to 8.41 (s, 1H), 8,13 (s, 2H), 7,81 (s, 1H), of 7.70 (d, 1H), 7,55 (d, 1H), 7,42 (m, 2H), 7,32 (ush. d, 1H), 6,98 (d, 1H), 6,20 (ush. s, 1H), ceiling of 5.60 (ush. s, 1H), 4,27 (s, 2H), 2,77 (t, 2H), and 1.63 (m, 2H), 1,38 (m, 2H), of 0.93 (t, 3H)463,25
48 (400 MHz, CDCl3): δ 8,82 (m, 2H), at 8.36 (s, 1H), 8,09 (d, 2H), to 7.64 (d, 2H), 7,43 (t, 1H), 7,32 (d, 1H), 7,17 (d, 2H), 6,99 (d, 1H), 6,58 (ush. s, 1H), 6,09 (ush. s, 1H), 3,06 (s, 4H), of 2.45 (s, 3H)435,19
49(400 MHz, CDCl3): δ 11,40 (ush. s, 1H), 8,82 (m, 2H), of 8.37 (s, 1H), 8,11 (m, 2H), to 7.64 (d, 2H), 7,47 (t, 1H), 7,35 (ush. d, 1H), 7,19 (d, 2H), 7,01 (d, 1H), 6,50 (ush. s, 1H), 5,90 (ush. s, 1H), is 3.08 (s, 4H), 2,74 (square, 2H), 1,19 (t, 3H)449,20
50(400 MHz, CDCl3): δ 11,40 (ush. s, 1H), 8,82 (m, 2H), of 8.37 (s, 1H), 8,11 (m, 2H), 7,63 (d, 2H), 7,46 (t, 1H), was 7.36 (ush. d, 1H), 7,19 (d, 2H), 6,99 (DD, 1H), 6,50 (ush. s, 1H), 5,85 (ush. s, 1H), of 3.07 (s, 4H), to 2.67 (t, 3H), of 1.61 (m, 2H), of 0.87 (t, 3H)463,22
51(400 MHz, CDCl3): δ 10,75 (ush. s, 1H), 8,83 (m, 2H), scored 8.38 (s, 1H), 8,12 (m, 2H), of 7.70 (m, 2H), 7,46 (t, 1H), 7,34 (ush. s, 1H), 7,27 (d, 2H), 7,02 (d, 1H), 6,33 (ush. s, 1H), 5,85 (ush. s, 1H), 3,14 (m, 4H), 3.00 and (septet, 1H), 1.26 in (s, 3H), 1,24 (s, 3H)463,21
52(400 MHz, CDCl3): δ 11,55 (ush. s, 1H), 8,83 (m, 2H), at 8.36 (s, 1H), 8,11 (m, 2H), a 7.62 (d, 2H), 7,46 (t, 1H), was 7.36 (ush. d, 1H), 7,18 (d, 2H), 7,00 (DD, 1H), 6,50 (ush. s, 1H), 5,80 (ush. s, 1H), of 3.07 (s, 4H), 2,69 (t, 2H), and 1.54 (m, 2H), 1.27mm (m, 2H), of 0.82 (t, 3H)477,23
53(400 MHz, CDCl3): δ 8,82 (m, 2H), 8,35 (s, 1H), 8,08 (s, H), a 7.62 (m, 2H), 7,43 (t, 1H), 7,32 (m, 2H), 7,29 (d, 1H), 6,99 (d, 1H), 6,63 (ush. s, 1H), 6,10 (ush. s, 1H), is 3.08 (m, 4H), to 2.46 (s, 3H)435,20
54(400 MHz, CDCl3): δ 8,80 (s, 2H), 8.34 per (t, 1H), of 8.06 (s, 2H), to 7.59 (m, 2H), 7,47 (t, 1H), 7,33 (d, 1H), 7.23 percent (t, 1H), 7,01 (DD, 1H), 6,80 (ush. s, 1H), 6,25 (ush. s, 1H), 3,06 (m, 2H), 3,01 (m, 2H), 2,71 (square, 2H), of 1.16 (t, 3H)449,26
55(400 MHz, CDCl3): δ 8,80 (s, 2H), with 8.33 (t, 1H), of 8.06 (s, 2H), 7,58 (m, 2H), 7,46 (t, 1H), 7,34 (d, 1H), 7,26 (m, 1H), 7,21 (t, 1H), 7,00 (DD, 1H), 6,85 (ush. s, 1H), 6,33 (ush. s, 1H), 3,05 (m, 2H), 2,98 (m, 2H), 2,65 (t, 2H), and 1.56 (m, 2H), from 0.84 (t, 3H)463,24
56(400 MHz, CDCl3): δ 8,82 (s, 2H),of 8.37(c, 1H), 8,10 (m, 2H), 7,69 (t, 1H), 7.62mm (m, 1H), 7,46 (t, 1H), 7,34 (m, 2H), 7,31 (m, 1H), 7,02 (DD, 1H), 6,50 (ush. s, 1H), 6,00 (ush. s, 1H), 3,13 (s, 4H), 3.00 and (septet, 1H), 1,25 (s, 3H), 1,24 (s, 3H)463,26
57(400 MHz, CDCl3): δ 8,79 (s, 2H), 8,32 (t, 1H), with 8.05 (m, 2H), 7,56 (m, 1H), 7,52 (s, 1H), 7,47 (t, 1H), 7,34 (d, 1H), 7.23 percent (overlaps with neighboring signal, 1H), 7,19 (t, 1H), 7,00 (DD, 1H), 6.90 to (ush. s, 1H), 6,23 (ush. s, 1H), 3.04 from (m, 2H), equal to 2.94 (m, 2H), 2,66 (t, 2H), 1,48 (m, 2H), 1,23 (m, 2H), 0,78 (t, 3H)477,30
58(400 MHz, DMSO-d6): δ 9,03 (s, 2H), 8,48 (d, 1H), 8,19 (d, 1H), 8,11 (m, 1H), of 8.06 (d, 1H),8,04 (d, 1H), 7,83 (m, 1H), 7,80 (t, 1H), 7,74 (m, 1H), of 7.48 (m, 2H), 7,45 (ush. s, 1H), 7,38 (d, 1H), of 4.54 (s, 2H), 2,54 (s, 3H)
59(400 MHz, DMSO-d6): δ 9,03 (s, 2H), to 8.41 (d, 1H), they were 8.22 (d, 1H), 8,01-7,88 (m, 3H), 7,83 (m, 1H), 7,79 (t, 1H), 7.62mm (d, 1H), 7,49 (t, 1H), 7,44 (ush. s, 1H), 7,39 (d, 1H), 7,35 (d, 1H), of 4.45 (s, 2H), 2,58 (s, 3H)
60(400 MHz, DMSO-d6): δ 8,91 (m, 2H), to 8.41 (s, 1H), 8,17 (DD, 1H), 8,04 (d, 1H), 7,98 (s, 1H), to 7.93 (s, 1H), of 7.75 (d, 1H), to 7.67 (t, 1H), 7,55 (d, 1H), 7,46 (ush. s, 1H), 7,42 (t, 1H), was 7.36 (s, 1H), 7,16 (d, 1H), 4,18 (s, 2H), 2,47 (s, 3H)
61(400 MHz, DMSO-d6): δ 8,90 (m, 2H), 8,40 (s, 1H), 8,17 (d, 1H), 8,03 (d, 1H), of 7.97 (s, 1H), 7,92 (s, 1H), of 7.75 (d, 1H), to 7.67 (t, 1H), 7,55 (d, 1H), 7,46 (ush. s, 1H), 7,41 (t, 1H), 7,35 (s, 1H), 7,16 (d, 1H), 4,35 (ush. s, 1H), 4,17 (s, 2H), 2,70 (DD, 4H, citrate), the 2.46 (s, 3H)

DATA for BIOLOGICAL studies

The biological activity of the compounds of this invention can be tested using the following tests:

Cell-free test for assessing the inhibition of ALK5 kinase phosphorylation of Smad3

Constitutively active, His-tagged ALK5 (T204D) and a full-sized protein Smad3 was expressively in insect cells using the expression system is the baculovirus Invitrogen BacNBlue. Expressed protein was purified in the column with polymer Qiagen Ni-NTA. Purified protein Smad3, 200 ng, was mixed with 100 μl of 0.1 M sodium bicarbonate covering the buffer and put it in the flash die with a pipette. The plate was covered and incubated at 4°C for 16 hours. Then plates were washed 3 times with 200 μl covering the buffer and left blocked with 1% BSA in PBS at room temperature for 1 hour. Purified protein ALK5, 100 ng, was mixed with 100 µl of reaction buffer containing 20 mm Tris-HCl (pH of 7.4), 5 mm MgCl2, 1 mm CaCl2, 1 mm DTT, 1 μm ATP and 2 µci γ-32P-ATP, and 1 μl each of the test compounds of formula (I), in the form of a solution in 100% DMSO at various concentrations. Then the test was started by adding the reaction mixture ALK5 in a flash die, covered with Smad3, and then incubated at 30°C for 3 hours. After incubation analytical buffer was removed and washed 3 times with 200 ál of 10 mm solution of sodium pyrophosphate. Then flash the plates were dried in air and count on the counter Packard TopCount.

The compounds of formula (I) generally showed the value of the IC50less than 10 μm; some showed the value of the IC50less than 1 micron; and some even showed the value of the IC50less than 50 nm.

Cell-free test for assessing the inhibition of ALK4 kinase phosphorylation of Smad3

Inhibition of ALK4 kinase phosphorylation of Smad3 by test compounds of formula (I) can be determined way is, similar to that described above for inhibition of ALK5, except that a similarly His-tagged ALK4 was used in place of constitutive active, His-tagged ALK5.

The compounds of formula (I) generally showed the value of the IC50less than 10 μm; some showed the value of the IC50less than 1 micron.

A study to assess the cellular inhibition of signaling TGF-β

The biological activity of the compounds of formula (I) was determined by measuring their ability to inhibit TGF-β1-induced activity of the reporter Smad-binding element luciferase (SBE-Luc) and the activity of the reporter PAI-1-luciferase (p3TP-Lux) in HepG2 cells. The HepG2 cells was short transfusional or reporter construct SBE-Luc, or reporter construct p3TP-Lux, grown in DMEM containing 10% FBS, 100 U/ml penicillin, 100 μg/ml streptomycin, 2 mm L-glutamine, 1 mm sodium pyruvate, and nonessential amino acids. Transfetsirovannyh the cells were then added at a concentration of 2.5 × 104cells/well in 96-well plates and overburden within 3-6 hours in medium with 0.5% FBS at 37°C incubator with 5% CO2. The cells are then stimulated with 5 ng/ml ligand TGF-β1 in minimal medium containing 1% DMSO or in the presence or absence of test compounds of formula (I), and incubated at 37°C in an incubator with 5% CO2within 2 hours. Wednesday was washed, and the luciferase activity in cell lysates was determined using luciferase system for analysis (Promega).

The compounds of formula (I) generally showed the value of the IC50less than 10 μm; some showed the value of the IC50less than 1 micron; and some even showed the value of the IC50less than 50 nm.

Application

An example of obtaining 11: Obtain 3-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl-1H-imidazol-2-yl)methyl)benzonitrile (Example 5)

To a stirred solution of 1-(quinoline-6-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-dione (80,1 g, 0.29 to say.) (obtained according to the method described in WO 01/62756 A1) in the Meon (700 ml) was added NH4OAc (446,3 g, 5,79 mol) and 4-(formylmethyl)benzonitrile (84,2 g of 0.58 mol.) (obtained according to the method described in WO 02/096875 A1) in tert-butyl methyl ether (700 ml) and the mixture was stirred at 40-50°C for 18 hours. The reaction mixture was evaporated under reduced pressure and the pH was brought to pH 8 with saturated solution of NaHCO3. The resulting mixture was extracted with CH2Cl2(1000 ml × 2) and the organic layer was washed with water (200 ml) and brine (200 ml), dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified on silica gel using a mixture of Meon and CH2Cl2(1:10 (by volume)as eluent, which gave specified in the header connection (46,5 g, 40%).

An example of the output is 12 I: Getting 3-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl)methyl)benzamide (Example 6)

To a solution of 3-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl-1H-imidazol-2-yl)methyl)benzonitrile (Example 5) (510 mg, 1.25 mmol) in ethanol (5 ml) was added 1 N. NaOH (of 8.3 ml, 8.3 mmol) and 30% H2O2(282 μl, 2.49 mmol)and the mixture was stirred at 60°C. After stirring for 6 hours the mixture was cooled to 0°C, diluted with H2O (5 ml), neutralized water 2 N. HCl solution to pH 7-8, and was stirred for 24 hours. The precipitated solid was collected on a filter, washed with water and Et2O, and dried under vacuum. The solid was purified MPLC on silica gel using a mixture of Meon and CH2Cl2(1:19, then 1:9(by volume)as eluent, which gave specified in the title compound (337 mg, 50%).

An example of obtaining 13: Obtain 3-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl)methyl)benzoic acid (Example 7)

3-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl)methyl)benzamide (Example 6) (200 mg, 0.50 mmol) was dissolved in conc. HCl (2 ml) and was heated at the boil under reflux. After stirring for 15 hours, the reaction mixture was cooled to room temperature and the pH was brought to pH 9 with 6 M aqueous NaOH solution. The resulting mixture was washed CH2Cl2and acidified to pH 4-5 1 N. aqueous solution of HCl. The precipitated solids were collected by filtration, washed with water and dried under reduced pressure. Solid is e substance was purified by recrystallization from a mixture of the Meon and CH 3CN obtaining specified in the title compound (146 mg, 69%).

An example of obtaining 14: Obtain methyl 3-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl)methyl)benzoate (Example 21)

To a solution of 3-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl)methyl)benzoic acid (Example 7) (50 mg, 0,119 mmol) in Meon (2 ml) was added H2SO4(0.2 ml) and was heated at the boiling point under reflux. After stirring for 3 hours the reaction mixture was cooled to room temperature and was evaporated to dryness under reduced pressure.

The residue was dissolved in a saturated solution of NaHCO3and the mixture was extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered and evaporated to dryness under reduced pressure, which gave specified in the title compound (50 mg, 97%).

An example of obtaining 15: Obtain N-hydroxy-3-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl)methyl)benzamide (Example 13)

Methyl 3-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl)methyl)benzoate (Example 21) (50 mg, 0,115 mmol) was dissolved in a solution of 2.3 M NH2OH in the Meon (2 ml) and stirred at room temperature. After 15 hours the pH of the reaction mixture was brought to pH 6 with 1 N. aqueous HCl. The resulting mixture was extracted with a mixture of Meon and CH2Cl2(1:10(by volume)). The organic layer was dried (Na2SO 4), filtered and evaporated under reduced pressure. The residue was purified MPLC on NH-silica gel, using a mixture of the Meon and CH2Cl2(1:10(by volume)as eluent, which gave specified in the title compound (19 mg, 38%).

Example 16: 3-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl)methyl)phenol (Example 16)

To a solution of 6-(2-(3-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline (Example 15) (300 mg, of 0.74 mmol) in acetic acid (5 ml) was added 48% aqueous HBr solution (5 ml) and stirred at 105°C for 15 hours. The reaction mixture was cooled to room temperature and was evaporated to dryness under reduced pressure. The residue was dissolved in a saturated solution of NaHCO3and were extracted with a mixture of Meon and CH2Cl2(1:9(by volume)). The organic layer was dried (Na2SO4), filtered and evaporated to dryness under reduced pressure. The residue was purified MPLC on silica gel, using a mixture of the Meon and CH2Cl2(1:9(by volume)as eluent, which gave specified in the title compound (260 mg, 90%).

An example of obtaining 17: Obtain 4-((5-(6-methylpyridin-2-yl)-4-(chinolin-6-yl)-1H-imidazol-2-yl)methyl)benzamine (Example 23)

6-(2-(4-Nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline (Example 20) (93,6 mg, 0.22 mmol) and SnCl2(210,5 ml, 1.11 mmol) suspended in the Meon (3 ml)and the mixture was stirred at 50°C. On the Le stirring for 5 hours the reaction mixture was evaporated to dryness under reduced pressure, diluted H2O, neutralized with 2 M aqueous NaOH solution to pH 8. The precipitated solids were collected by filtration, washed with water and Et2O, and dried under vacuum (74 mg, 85%).

An example of obtaining 18: Obtain N-(4-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl)methyl)phenyl)ndimethylacetamide (Example 31)

To a solution of 4-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl) methyl)benzamine (Example 23) (40 mg, is 0.102 mmol in pyridine (1.5 ml) was added acetylchloride (8, 0 μl, 0,112 mmol) and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure, diluted with water N2O, acidified 4 N. aqueous solution of HCl to pH 2, and pH of the resulting solution was brought to pH 9. The precipitated solids were collected by filtration, washed with water and Et2O, and dried under vacuum (of 42.3 mg, 96%).

An example of obtaining 19: Obtaining N-(4-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl)methyl)phenyl)methanesulfonamide (Example 36)

To a solution of 4-((5-(6-methylpyridin-2-yl)-4-(quinoline-6-yl)-1H-imidazol-2-yl)methyl)benzamine (Example 23) (40 mg, is 0.102 mmol) in pyridine (1.5 ml) was added methanesulfonamide (8,7 μl, 0,112 mmol) and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure, diluted with H2O, acidified 4 N. aqueous solution of HCl to pH 2, and pH of the received RA is brought down to a pH of 9. The precipitated solids were collected by filtration, washed with water and Et2O, and dried under vacuum (of 45.3 mg, 95%).

The compounds listed in the following Table 2 were obtained by methods similar to those described in the examples get 11-19 above. Data1H NMR spectra and mass spectrometry of these compounds are included in Table 2.

Table 2
Example No.Structure1C NMRMass spectrum m/z (MN+)
1(300 MHz, CDCl3) δ to 3.92 (3H, s), 4,25 (2H, s), to 6.58 (1H, d), 7,10 (1H, USS), 7,41 (1H, d), 7,42 (1H, t), 7,46 (1H, d), a 7.62 (3H, m), of 7.96 (1H, DD), 8,10 (1H, d), 8,16 (1H, t), 8,19 (1H, d), of 8.92 (1H, DD)418

2(300 MHz, COCl3) δ of 3.84 (3H, s), 4,22 (2H, s)5,80 (1H, ush. C), 6,32 (1H, ush. C)6,56 (1H, DD), was 7.08 (1H, ush. C), 7,35-7,42 (3H, m)to 7.50 (1H, d), 7,66 (1H, d), of 7.82 (1H, s), 7,95 (1H, d), 8,06-to 8.14 (3H, m), of 8.90 (1H,DD)436
3(300 MHz, CDCl3) δ of 4.25 (2H, s), 7,26-7,37 (2H, m), 7,41-7,49 (3H, m), 7,56-to 7.64 (3H, m), to 7.93 (1H, DD), 8,13-to 8.20 (3H, m), to 8.94 (1H, DD)468
4 (300 MHz, CBCl3) δ 2,48 (3H, s)to 4.16 (2H, s), of 6.96 (1H, d), 7,15-7,26 (3H, m), of 7.36-to 7.50 (4H, m), of 7.96 (1H, DD), 8,11 (1H, d), 8,17 (2H, m), of 8.92 (1H, DD), the 10.40 (1H, ush. C)456
5(300 MHz, CDsOD) § 2,52 (3H, s), 4,25(2H, s), 7,16(1H, d), 7,50-7,56(MN, m), 7,63(1H, m), of 7.70 (1H, m), 7,76(1H, s), 7,89(1H, m), to 7.99(1H, d), to 8.12(1H, s), 8,32(1H, d), 8,83(1H, DD)402

6(300 MHz, CD3OD) δ of 2.51 (3H, s), 4,25 (2H, s), 7,16 (1H, d), 7,17 (1H, m), 7,44 (1H, t), 7,53 (1H, DD), 7,55 (1H, m), EUR 7.57 (1H, m), of 7.75 (1H, dt), 7,87 (1H, m), to $ 7.91 (1H, m), 7,98 (1H, d), to 8.12 (1H, s), 8,31 (1H d), 8,82 (1H,DD)420
7(300 MHz, CD3OD) δ to 2.57 (3H, s), 4,37 (2H, s), 7,27 (2H, t), 7,49 (1H, t), to 7.59 (1H, DD), 7,63-of 7.69 (2H, m), 7,89 (1H, DD), of 7.96 (1H, dt), 8,06-8,08 (2H, m), 8,18 (1H, d), scored 8.38 (1H, m), 8,89 (1H, DD)421
8(300 MHz, CDCl3) 5 4,24 (2H, s), 7,29 (1H, m), 7,37 (1H, m), 7,50-7,56 (2H, m), a 7.62 (1H, m), to 7.67 (1H, m), of 7.70 (1H, m), 7,76 (1H, s), to 7.84 (1H, m), of 8.00 (1H, d), 8,10 (1H, s), 8,32 (1H, d), 8,55 (1H, m), 8,83 (1H, DD)388
9(300 MHz, CD3OD) δ,26(2H, s), 7,29 (1H, DDD), 7,42-to 7.59 (4H, m), 7,69-to 7.77 (2H, m), a 7.85 (1H, DD), of 7.90 (1H, m), 8,00 (1 is, d), 8,10 (1H, d), 8,32 (1H, m), 8,55 (1H, DDD), 8,84 (1H, DD)406

10(300 MHZ, CDaOD) 5 2,52(3H, s), 3,12 is 3.23(4H, m), 7,16(1H, d), 7,21(1H, m), 7,45-to 7.64(6N, m), a 7.85(1H, d), of 8.00(1H, d), 8,10(1H, s), with 8.33(1H, m), 8,84(1H, DD)416
11(300 MHz, CD3OD) δ of 2.50 (3H, s), 3,13-up 3.22 (4H, m), to 7.15 (1H, d), 7,25 (1H, d), of 7.36-7,46 (2H, m), 7,54 (1H, DD), to 7.59 (1H, t), 7,71 (1H, dt), 7,79 (1H, m), a 7.85 (1H, DD), 7,98 (1H, d), of 8.09 (1H, d), 8,32 (1H, d), 8,83 (1H, DD)434
12(300 MHz, CDCl3) to 2.55 (3H, s), 3,12-of 3.27 (4H, m), 6,98 (1H, d), 7,26 (1H, d), 7,35-7,45 (4H, m), 7,60 (2H, m), 7,95 (1H, DD), to 8.12 (1H, d), 8,14 (1H, s), 8,16 (1H, DD), 8,93 (1H, DD)416
13(300 MHz, CO3OD) δ of 2.51 (3H, s), 4,24 (2H, s), 7,16 (1H, d), 7,27 (1H, m), the 7.43 (1H, t), 7,52-to 7.64 (4H, m), to 7.77 (1H, m), 7,87 (1H, m), of 8.00 (1H, d), 8,11 (1H, d), 8,32 (1H, m), 8,83 (1H, DD)436
14(300 MHz, CD3OD) δ 2,47 (3H, s), 4,32 (2H, s), 7,16 (1H, d), from 7.24 (1H, m), 7,54 (1H, d), EUR 7.57 (1H, m), 7,60 (1H, t), 7,80 (1H, d), 7,87 (1H,422

m), to 7.99 (1H, d) to 8.14 (2H, m), 8,32 (2H, m), 8,83 (1H, DD)
15(300 MHz, COCl3) δ 2,48 (3H, s), of 3.80 (3H, s), 4,20 (2H, s), PC 6.82 (1H, DD), 6,91-of 6.96 (3H, m), 7.23 percent-7,30 (2H, m), 7,37 (1H, t, 7,41 (1H, DD), of 7.97 (1H, DD), 8,11(1H, d), 8,17 (2H, m), of 8.92 (1H, DD), 10,15 (1H, ush. C)407
16(300 MHz, CDCl3) δ of 2.45 (3H, s)4,06 (2H, s), to 6.58 (2H, d), 6,97 (3H, m), 7,22 (1H, d), 7,37 (2H, m), 7,92 (1H, d), 8,05-to 8.14 (3H, m), 8,88 (1H, d)393
17(300 MHz, CO3OD) δ of 2.33 (3H, s), of 2.51 (3H, s), 4,14 (2H, s), 7,05 (1H, m), 7,15-of 7.23 (5H, m), 7,53 (1H, DD), 7,58 (1H, m), 7,86 (1H, m), of 7.97 (1H, d), 8,11 (1H, s), 8,32 (1H, m), 8,82 (1H, DD)391
18(300 MHz, CD3OD) δ of 2.51 (3H, s), 3,76 (3H, s), 4,11 (2H, s), to 6.88 (2H, dt), to 7.15 (1H, d), 7,25 (1H, m), 7,28 (2H, dt), 7,53 (1H, DD), 7,58 (1H, m), 7,86 (1H, d), 7,98 (1H, d), 8,11 (1H, s), 8,31 (1H, d), 8,82 (1H, DD)407

19(300 MHz, CDCl3) δ of 2.45 (3H, s)4,06 (2H, s), to 6.58 (2H, d), 6,94-7,01 (3H, m), 7,22 (1H, d), 7,35-7,39 (2H, m), 7,92 (1H, d), 8,05-to 8.14 (3H, m), 8,88 (1H, d)393
20(300 MHz, CD3OD) δ of 2.51 (3H, s), 4,32 (2H, s), 7,16 (1H, d), 7,26 (1H, d), 7,54 (1H, DD), to 7.59 (1H, t), to 7.61 (2H, dt), 7,87 (1H, DD), of 8.00 (1H, d), to 8.12 (1H, d), 8,21 (2H, dt), 8,32 (1H, m), 8,83 (1H, DD)422
21(300 MHz, CD3OD) δ 2,52 (3H, s)to 3.92 (3H, s), 4,30 (2H, s), of 6.96 (1H, d), 7,27 (1H, m), of 7.36-7,47 (3H, m), to 7.59 (1H, m), of 7.96 (1H, m), 7,98 (1H, d), 8,07 (1H, s), 8,11 (1H, d), 8,18 (2H, m), of 8.92 (1H, DD)435
22(300 MHz, CD3OD) δ of 2.50 (3H, s), 3,11-3,24 (4H, m), to 7.15 (1H, d, 7,26 (1H, m), of 7.36 (2H, m), 7,54 (1H, DD), to 7.59 (1H, t), of 7.82 (2H, dt), a 7.85 (1H, d), to 7.99 (1H, d), of 8.09 (1H, d), 8,32 (1H, m), 8,83 (1H, DD).434

23(300 MHz, CD3OD) δ 2,49 (3H, s), Android 4.04 (2H, s)6,70 (2H, dt), 7,12 (2H, dt), to 7.15 (1H, d), 7,26 (1H, d), 7,52 (1H, DD), 7,58 (1H, d), a 7.85 (1H, DD), of 7.97 (1H, d), 8,10 (1H, d), 8,30 (1H, m), 8,81 (1H, DD)392
24(300 MHz, CDCl3) δ 4,18 (2H, s), 7,07-7,11 (1H, m), 7.23 percent (2H, m), 7,40-7,51 (5H, m), of 7.97 (1H, DD), 8,12-8,19 (3H, m), 8,48 (1H, m), 8,93 (1H, DD)443
25(300 MHz, CDCIs) 5 3,91(MN, C)4,20(2H, s), to 6.57(1H, d), 7,05(1H, d), 7,26(2H, m), of 7.36-7,44(2H, m), 7,51(2H, m), to 7.99(1H, DD), 8,11-8,18 (MN, m)of 8.92(1H, DD)473
26(300 MHz, CD3OD) δ of 2.51 (3H, s), 4,28 (2H, s), 7,16 (1H, d), 7,26 (1H, d), 7,52-to 7.61 (4H, m), of 7.70 (2H, dt), 7,86 (1H, DD), to 7.99 (1H, d), to 8.12 (1H, d), 8,32 (1H, m), 8,83 (1H, DD)402
27(300 MHz, CD3OD) δ of 2.51 (3H, s), 4,25 (2H, s), to 7.15 (1H, d), from 7.24 (1H, m), 7,47 (2H, d), 7,52 (1H, DD), EUR 7.57 (1H, m), a 7.85 (2H, d), 7,89 (1H, m), to 7.99 (1H, d), to 8.12 (1H,420

C)8,30 (1H, d), 8,82 (1H, DD)
28(300 MHz, CD3OD) δ 2,62 (3H, s), of 4.45 (2H, s), 7,31 (2H, t), 7,52 (2H, d), 7,63 (1H, DD), of 7.70 (1H, t), to $ 7.91 (1H, DD), with 8.05 (2H, m)to 8.12 (1H, d), 8,23 (1H, d), 8,44 (1H, m), to 8.94 (1H, DD)421
29(300 MHz, CDCl3) δ of 3.80 (3H, s), is 4.21 (2H, s), PC 6.82 (1H, DD), 6, 92-6,97 (2H, m), to 7.09 (1H, m), 7,27 (1H, t), 7,40-7,46 (3H, m), of 7.96 (1H, DD), 8,11-8,19 (3H, m), of 8.47 (1H, dt), 8,93 (1H, DD), of 10.25 (1H, ush. C)393
30(300 MHz, CDCl3) δ of 3.80 (3H, s), 4,18 (2H, s), 6.89 in (2H, m), 7,05-7,10 (1H, m), 7,28 (2H, m), 7,40-7,46 (3H, m), of 7.97 (1H, d), 8,11-8,19 (3H, m), 8,48 (1H, m), 8,93 (1H, DD), becomes 9.97 (1H, ush. C)393

31(300 MHz, CDsOD) 5 of 2.10(3H, s), of 2.51(MN, C)to 4.15(2H, s), 7,16(1H, d), 7,17(1H, m), 7,32(2H, m), 7,49-of 7.55(4H, m), 7,86(1H, m), 7,98(1H, d), 8,11(1H, s) 8,32(1H, d), 8,82(1H, DD)434
32(300 MHz, CD3CD) δ of 3.77 (3H, s), 4,11 (2H, s), 6.89 in (2H, m), 7,28 (2H, m), 7,39 (1H, d), 7,53 (2H, m), 7,54 (1H, DD), to 7.93 (1H, DD), 8,03 (1H, d), 8,21 (1H, s), 8,35 (1H, d), 8,84 (1H, DD)473
33(300 MHz, CDCl3) δ to 2.35 (3H, s), 4,20 (2H, s), 7,06-7,28 (5H, m), 7,42 (1H, DD), 7,45 is 7.50 (2H, m), of 7.97 (1H, DD), to 8.12 (1H, d), 8,18 (2H, m), 8,48 (1H, dt), of 8.92 (1H, d), for 9.90 (1H, ush. C)377
34(300 MHz, CDCl3) δ is 2.37 (3H, s), 3,83 (3H, s), 4,22 (2H, s), 6,55 (1H, m), 7,05-7,31 (5H, m), 7,38 (1H, m), 7,41 (1H, DD), 8,00 (1H, DD), 8,11 (1H, d), 8,17 (2H, m), of 8.92 (1H, DD), 9,60 (1H, ush. C)407

35(300 MHz, CD3OD) δ 3,12-3,232 (4H, m), 7,29-7,26-7,30 (1H, m), 7,43-to 7.50 (2H, m), 7,53-to 7.64 (4H, m), 7,72 (1H, t), to 7.84 (1H, m), 8,01 (1H, d), 8,08 (1H, m), a 8.34 (1H, d), 8,55 (1H, d), 8,84 (1H, DD)402
36(300 MHz, CD3OD) δ of 2.51 (3H, s), of 2.92 (3H, s), 4,17 (2H, s), 7,17 (1H, d), 7,21-7,28 (M, m), 7,37 (2H, m), 7,54 (1H, DD), 7,60(1H, t), 7,86 (1H, DD), to 7.99 (1H, d), to 8.12 (1H, d) 8,32 (1H, m), 8,83 (1H, DD)470
37(300 MHz, CD3OD) δ 3,13-3,26 (4H, m) 7,30-7,28 (1H, m), 7,44-of 7.48 (3H, m), 7,55 (1H, DD), 7,66 (2H, m), 7,72 (1H, TD), to 7.84 (1H, DD), 8,01 (1H, d), 8,07 (1H, d), with 8.33 (1H, m), 8,54 (1H, d), 8,84 (1H, DD)402
38(300 MHz, CD3OD) δ 3,12-to 3.35 (4H, m), 7,27 (1H, DDD), was 7.36 (2H, d), 7,47 (1H, d), 7,54 (1H, DD), 7,72 (1H, TD), 7,80-a 7.85 (3H, m), of 8.00 (1H, d) of 8.06 (1H, d), 8,32 (1H, d), 8,53 (1H, d), 8,83 (1H, DD)420

39(300 MHz, CDCl3) δ 4,07 (2H, s), is 6.61 (1H, DD), of 6.71 (1H, d), 6,77 (1H, m), 6,98-was 7.08 (2H, m), 7,21 (1H, m), 7,27 (1H, DD), 7,35 (1H, t), 7,74 (1H, d), to $ 7.91 (2H, d), 7,98 (1H, s), 8,35 (1H, m), 8,83 (1H, DD), 9,84 (1H, ush. C)10,90 (1H, ush. C)379
40(300 MHz, CD3OD) δ 4,06 (2H, s), 6,74 (2H, dt), 7,18 (2H, dt), 7,25 (1H, DDD), 7,46 (1H, d), 7,49 (1H, DD), to 7.68 (1H, DDD), of 7.82 (1H, DD), of 7.97 (1H, d), with 8.05 (1H, d), of 8.27 (1H, m), and 8.50 (1H, m), 8,80 (1H,DD)379

1. The compound of formula (I) or its pharmaceutically acceptable salt

where R1is a phenyl group optionally substituted by the Oh substituents, selected from a halogen atom, -O-C1-6-alkyl, or R1is a phenyl fused with an aromatic or non-aromatic 5-7 membered ring, where the said ring may optionally contain up to three heteroatoms, independently selected from N, O and S;

R2is hydrogen, -O-C1-6-alkyl, -C1-6-alkyl or a halogen atom;

R3is1-6-alkyl, -(CH2)P-NO2, -(CH2)P-NR4R5, -(CH2)P-CONHOH, -(CH2)P-CN, -(CH2)P-CO2H, -(CH2)P-CO2R4, -(CH2)P-CONR4R5, -(CH2)P-OR4, -(CH2)P-NHCOR4or -(CH2)P-NHSO2R4;

R4and R5are independently hydrogen or C1-6-alkyl;

p is 0, 1, 2, 3 or 4;

X is C1-10-alkalinous group;

one of the A1and a2is a nitrogen atom and the other is NR7; and

R7is a hydrogen atom or a group.

2. The compound according to claim 1, where R1is phenyl, optionally substituted with substituents selected from a halogen atom, -O-C1-6-alkyl; or R1is a phenyl fused with an aromatic or non-aromatic 5-7 membered ring, where the abovementioned ring optional is positive contains up to two heteroatoms, independently selected from N, O and S,

R2is a non-hydrogen substituent and is orthopaedie relative to the nitrogen atom peredelnogo cycle;

R3is -(CH2)P-CONHOH, -(CH2)P-CN, -(CH2)P-CO2H or -(CH2)P-CONR4R5;

R4and R5are independently hydrogen or C1-3-alkyl,

p is 0, 1 or 2;

X represents a C1-6-alkylenes group; and

one of the A1and a2is a nitrogen atom and the other is NR7where R7is a hydrogen atom.

3. The compound according to claim 1, chosen from:

4-((4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile;

4-((4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile;

3-((4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

4-(2-(4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)ethyl)benzonitrile;

4-(2-(4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

4-(3-(4-(benzo[1,3]dioxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)propyl)benzonitrile;

4-(3-(4-(benzo[1,3]d is oxol-5-yl)-5-(6-methylpyridin-2-yl)-1(3)H-imidazol-2-yl)propyl)benzamide;

4-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

4-((5-(6-ethylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

4-((5-(6-n-propylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

4-((5-(6-isopropylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

4-((5-(6-n-butylparaben-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzonitrile;

3-((5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((5-(6-ethylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((5-(6-n-propylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((5-(6-isopropylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

3-((5-(6-n-butylparaben-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)methyl)benzamide;

4-(2-(5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

4-(2-(5-(6-ethylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

4-(2-(5-(6-n-propylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

4-(2-(5-(6-isopropylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

4-(2-(5-(6-n-butyl ridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

3-(2-(5-(6-methylpyridin-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

3-(2-(5-(6-ethylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

3-(2-(5-(6-n-propylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

3-(2-(5-(6-isopropylpyridine-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide;

3-(2-(5-(6-n-butylparaben-2-yl)-4-(cinoxacin-6-yl)-1(3)H-imidazol-2-yl)ethyl)benzamide,

and their pharmaceutically acceptable salts.

4. The pharmaceutical composition which is capable of inhibiting the activity of receptors, ALK5 and/or ALK4, containing the compound of formula (I) according to claim 1, or its pharmaceutically acceptable salt, or MES, and a pharmaceutically acceptable diluent or carrier.

5. A method of inhibiting the transmission of signals of TGF-βand/or activin, or both in a mammal, comprising the administration to a mammal, in need of such treatment, a therapeutically effective amount of a compound according to claim 1, or its pharmaceutically acceptable salt, or MES.

6. A method of reducing the accumulation of excess extracellular matrix in mammals comprising the administration to a mammal, in need of such treatment, a therapeutically effective amount of a compound according to claim 1, or its pharmaceutically acceptable salt, or MES.

7. SPO is about inhibiting metastasis of tumor cells in mammals, including the introduction of a mammal in need of such treatment, a therapeutically effective amount of a compound according to claim 1, or its pharmaceutically acceptable salt, or MES.

8. The method of treatment of cancer, caused by the overexpression of TGF-β, by inhibiting the transmission signal of TGF-β in mammals comprising the administration to a mammal, in need of such treatment, a therapeutically effective amount of a compound according to claim 1, or its pharmaceutically acceptable salt, or MES.

9. The method of treatment of a disease selected from glomerulonephritis, diabetic nephropathy, lupus nephritis, nephropathy induced hypertension, renal interstitial fibrosis, renal fibrosis resulting from complications of drug use, HIV-related nephropathy, transplantati acrobatie, hepatic fibrosis all of etiology, liver dysfunction associated with various infections, hepatitis caused by alcohol, disorders of the bile ducts, pneumovirus, acute respiratory failure, respiratory distress syndrome in vzroslyh, idiopathic pneumovirus, chronic obstructive pulmonary syndrome, pulmonary disease due to infectious or toxic agents, post-infarction cardiac FIB the ose congestive heart failure, cardiomyopathy when dilatation, myocarditis, vascular stenosis, restenosis, atherosclerosis, and scarring of the lens, scarring of the cornea, proliferating vitreoretinopathy, education, excessive or hypertrophic scars or keloids on the skin in the healing process of wounds received in traumatic or surgical injuries, peritoneally and the subcutaneous spiek, scleroderma, tissue, progressive systemic sclerosis, dermatomyositis, polymyositis, arthritis, osteoporosis, ulcers, neurological dysfunction, erectile dysfunction in men, Alzheimer's, disease, Raynaud's disease, fibrocycstic cancers, the growth of tumor metastases, radiation-induced fibrosis any disease, in which fibrosis is a major component, and thrombosis, including the introduction of a mammal in need of such treatment, a therapeutically effective amount of a compound according to claim 1, or its pharmaceutically acceptable salt, or MES.

10. The method of claim 8, where the said mammal is a human.

11. The method according to claim 9, where the said mammal is a human.

12. The method according to claim 10, where the said mammal is a human.

13. The method according to claim 11, where the said mammal is a human.

14. The compound according to claim 2, R 2is C1-4-alkyl.

15. Method of inhibiting thrombosis in a mammal, comprising the administration to a mammal, in need of such treatment, a therapeutically effective amount of a compound according to claim 1, or its pharmaceutically acceptable salt, or MES.

16. The method according to clause 15, where the said mammal is a human.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: description is given of a piperidine derivative with general formula (I) , where L represents CH or N; M represents CH or N; under the condition that, L and M both do not represent CH; R1 represents phenyl (possibly substituted with a halogen or C1-4alkyl), S(O)2(C1-4alkyl), S(O)2(C1-4fluroalkyl), S(O)2phenyl (possibly substituted with CF3 or OCF3), benzyl, benzoyl (possibly substituted with a halogen) or C(O)NHphenyl (possibly substituted with a halogen); R2 represents phenyl, possibly substituted with a halogen; R3 represents hydrogen or C1-4alkyl; R4 represents methyl or ethyl; R5 represents phenyl-NH, phenyl (C1-2alkyl), phenyl(C1-C2)alkyl-NH or pyridyl(C1-2alkyl). The phenyl can be substituted with a halogen, cyano, C1-4alkyl, C1-4alkoxy, S(O)k(C1-4alkyl) or S(O)2NR8R9; k is equal to 2; R8 and R9 represent hydrogen or its pharmaceutical salts. The compound is a modulator of the activity of the CCR5 receptor. Description is given of the method of obtaining the compound, where L represents N, and the pharmaceutical composition based on a compound with formula (I).

EFFECT: design of a method of obtaining a compound, where L represents N, and a pharmaceutical composition based a compound with formula (I).

7 cl, 7 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns to new diamides of pyrimidine-4,6-dicarboxylic acid of I formula, selective inhibitors of collagenases possessing properties which concern to the metalloproteinase superfamily and the matrix metalloproteinases. The bonds render influence on hyperactivity of the matrix metalloproteinase-13 (MMP-13) and thus do not render influence on MMP-3 and MMP-8. In the formula I R1 means an atom of hydrogen, R2 means - (C1-C6)-alkyl where alkyl is unitary replaced by phenyl where phenyl is replaced 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 identical or different and independently from each other mean i) atom of hydrogen or ii) - (C1-C6)-alkyl or R9 and R10 together with atom of nitrogen to which they are bound, form 5, 6-links the sated cycle, and instead of one or two other atoms of carbon there can be also a heteroatom from an oxygen row, sulphur and nitrogen, and in case of nitrogen atoms of nitrogen independently from each other can be unsubstituted or substituted with (C1-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-SN, 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10) where R9 and R10 have the specified above value, 4) -(C0-C6)-alkyl-C(O)-N (R8)-(C0-C6)-alkyl-N(R9)-(R10) where R8 means hydrogen, R9 and R10 have the specified above value, 5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the specified above value, and Het means the sated or nonsaturated monocyclic heterocyclic system with number of links from 3 to 6 which contains in a cycle of 1 or 2 identical or different heteroatoms from a number nitrogen, oxygen and sulphur and unsubstituted or one-, two- or triple independently from each other is replaced by halogen, b) hydroxy,) -(C1-C6)-alkyl, and alkyl is unsubstituted or one-, two- or triple is substituted by halogen, d)=0,e)-Het, R4 and R5 or R5 and R6 together with atom of Carboneum to which they are bound, independently from each other form 5 or 6-unit cycle which is sated and contains one or two heteroatoms from an oxygen row.

EFFECT: obtaining of bonds which can find application for treatment of degenerate diseases of joints, such as osteoarthritis, rheumatic disease.

7 cl, 3 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula (I) , and their salts used in pharmacology, and their hydra as well as others, where W represents or and R3, R7, R16, R17, R20, R21 and R21 are identical or different and each of them represents a hydrogen atom or assumes other values, given in the formula of invention. The invention also relates to pharmaceutical compositions and medicinal preparations based on these compounds, cultures, used for obtaining them, methods of inhibition and treatment and use.

EFFECT: formula (I) can be used as medicinal preparations for curing solid malignant tumours.

43 cl, 4 tbl, 60 ex

FIELD: chemistry.

SUBSTANCE: present invention concerns new piperidinyl compounds of the formula (I) and (II) which are selectively binding integrine receptors, pharmaceutical compositions and application of the compositions for obtaining medication with antagonistic effect on integrine receptors, where W, R2, Z and q are described in the claim.

EFFECT: pharmaceutical composition for obtaining medication with antagonistic effect on integrine receptors.

33 cl, 1 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to 2-thio substituted derivatives of imidazole with formula I , where R1 represents aryl, which can be substituted by a halogen atom or halogen-C1-C6-alkyl; R2 is chosen from a group, containing a) aryl-C1-C4-alkyl, and b) C1-C6-alkyl; R3 is chosen from a group, containing (a) NR4R10, (b) NR7COR10, (c) OR10, (d) NH2; R4 represents H; R3 and R6, which can be the same or different, represent H, halogen, OH, C1-C6-alkoxy, C1-C6-alkyl or halogen-C1-C6-alkyl; R7 represents R4; R10 has one of the following values: (a) A-B, (b)-(e), (f) C1-C6-alkyl, which is substituted with 2 phenyl groups; A represents linear or branched C1-C6-alkylene; B is chosen from a group, containing (a) H, (b)-(e), (f) OC1-C6-alkyl, (g) OH; Hy represents 3-10-member non-aromatic, mono-, bi- or tricyclic carbocycle, which can be or not be condensed with a benzene ring; Ar represents 5- or 6- member aromatic heterocycle, which has 1 heteroatom, chosen from a group, consisting of O, S, and N, and which may not be condensed with a benzene ring, Het represents 5- or 6-member non-aromatic heterocycle, which has 1 heteroatom, which represents O, which may not be condensed with a benzene ring; m is 0,1 or 2; or its optical isomers or physiologically used salts. Compounds with formula I are used when making pharmaceutical compositions with inhibiting effect on release of cytokines.

EFFECT: obtaining of derivatives, which have inhibiting action to release of cytokine action.

13 cl, 4 tbl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of treatment, alleviation and/or prevention of neurological state, particularly neurodegenerative disorders, involving administration of effective quantity of compound with formula I: . Also invention concerns application of compound of the formula I as neurotherapeutical, neuroprotective or antimyloid agent, pharmaceutical or veterinary composition for treatment, alleviation and/or prevention of neurological states, and compounds of the formula I on the following additional terms: (b) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not ethyl or methyl; (c) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not hydrogen or ethyl; (d) if R3, R and R' are H, and R2 is NR11R12, then both R11 and R12 are not hydrogen; (e) if R3, R and R' are H, and R2 is COR6, then R6 is not H, OH or CH2Cl; (f) if R3, R and R' are H, and R2 is not CH3 or CH2Cl; (g) if R3, R and R' are H, and R2 is HCNN R9R10, then both R9 and R10 are not H.

EFFECT: efficient treatment, alleviation and prevention of neurological state.

24 cl, 14 tbl, 21 ex, 14 dwg

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to application of indazole derivatives of general formula (I) , in which: R stands for O; R3 stands for radical (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, said radicals being unsubstituted or substituted with one or several substitutes, given in item 1 of the formula; R4, R5, R6 and R7, independently on each other are selected from following radicals; hydrogen atom, halogen, CN, NO2, NH2, NHSO2R9, trifluoromethyl, trifluoromethoxygroup, (C1-C6)-alkyl, phenyl, phenyl-(C1-C6)-alkyl, pyridyl, possibly substituted with amino or hydroxygroup, thienyl, furanyl, morpholino, phenyl being unsubstituted or substituted with one or several substitutes, given in item 1 of the formula; R8, R9, R10, R11, independently on each other, stand for hydrogen atom, (C1-C6)-alkyl, phenyl possibly substituted with halogen; their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts for obtaining medication, inhibiting phosphorylation of Tau-protein. Invention also relates to novel compounds of formula (I), particular indazole derivatives, their racemates, enantiomers, tautomers and pharmaceutically acceptable salts, pharmaceutical composition and based on them medication which inhibits Tau-protein phosphorylation, as well as to method of obtaining compounds of formula (I).

EFFECT: obtaining medication based on indazole derivatives, inhibiting Tau-protein phosphorylation.

9 cl, 118 ex, 3 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention claims ethers of substituted 1H-indol-3-carboxylic acid of the general formula 1 or their pharmaceutically acceptable salts. Compounds can be applied as active substance for pharmaceutical compositions and for application of these compositions in production of medicine for virus disease prevention and treatment, especially for diseases caused by infection hepatitis viruses (HCV, HBV) and influenza A viruses. In the general formula 1 R1 is aminogroup substitute selected out of hydrogen, optionally substituted inferior alkyl, optionally substituted C3-6cycloalkyl, optionally substituted aryl selected out of phenyl, naphthyl or 5-6 member heteroaryl containing 1-2 heteroatoms selected out of nitrogen, oxygen and sulfur, and possibly condensed with benzene ring of optionally substituted heterocyclyl, which can be optionally substituted 5-6-member heterocyclyl with 1-2 heteroatoms in heterocyclic ring selected out of nitrogen and oxygen; R2 is alkyl substitute selected out of hydrogen, optionally substituted hydroxyl group, optionally substituted mercapto group, optionally substituted arylsulfinyl group; optionally substituted amino group, optionally substituted 5-6-member heterocyclyl containing 1-2 heteroatoms selected out of nitrogen, oxygen and sulfur; R3 is hydrogen or optionally substituted inferior alkyl; R14 and R24 are independently substitutes of cyclic system, selected out of hydrogen or halogen atom, cyano group, trifluoromethyl, optionally substituted phenyl or optionally substituted heterocyclyl which is an optionally substituted 5-6-member heterocyclyl with 1-2 heteroatoms in heterocyclic ring, selected out of nitrogen, oxygen or sulfur, possibly condensed with benzene ring.

EFFECT: improved efficiency of compositions.

15 cl, 3 tbl, 1 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to compounds of formula (I) or their pharmaceutically acceptable salts, where Q represents optionally substituted with 1-3 substituents, determined in formula, phenyl or pyridyl or pyrodazinyl; R2 represents C1-6alkyl or aminogroup, determined in item 1 of formula or C1-6alkyl, substituted with said aminogroup; bond between oxygen atom O* and adjacent carbon atom C1 or (i) is double bond, which determines carbonyl group [C(=O)], where R6 represents C1-6alkyl or cyclopropyl; or (ii) represents simple bond, where, in case of simple bond, said oxygen atom O*, is in addition bound to group R6 and, taken together with R6 and with adjacent nitrogen atom, determines optionally substituted with C1-6alkyl, oxadiazolyl ring, bond between C1 and adjacent nitrogen atom being double bond.

EFFECT: obtaining medications which are useful in obtaining medications for treatment of conditions connected with p38 kinase and/or in obtaining medications for treatment of inflammatory diseases or conditions in patient.

8 cl, 6 tbl, 88 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: medicine; pharmacology.

SUBSTANCE: compounds of this invention possess properties of protein kinase inhibitors. In the general formula p means integer within 0 to 2; R and R1 mean O; A1 and A2 mean single bond, (C1-C6)alkyl; B2 means monocyclic or bicyclic, saturated or unsaturated heterocyclic radical including 1 to several identical or different heteroatoms, chosen among O, S, N and NR7, probably substituted with one or several identical or different substitutes.

EFFECT: inhibiting effect on protein kinase, effective application of compounds of formula for medical products.

49 cl, 1 tbl, 6 dwg, 334 ex

FIELD: chemistry.

SUBSTANCE: described are novel compounds of series 2-propen-1-on of general formula or their tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, where Q stands for heteroaryl cycle, containing up to 2 nitrogen atoms. Compounds I induce HSP-70 and are useful in treatment of diseases accompanying pathologic process in organisms of mammals, including humans.

EFFECT: novel compounds possess useful biological properties.

26 cl, 7 tbl, 179 ex

FIELD: medicine; sexual pathology.

SUBSTANCE: prevention of cardiovascular by-effects induced by introduction of phosphodiesterase type 5 inhibitors for treatment of erectile dysfunction in men is ensured with introduction of one preparation from the specified group: Sildenafil citrate dosed 25-100 mg, or Vardenafil hydrochloride dosed 5-20 mg, or Tadalafil dosed 20 mg, combined with introduction of De-Nol dosed 1 tablet.

EFFECT: improved microcirculation due to higher synthesis of endogenous prostaglandins and prevented cardiovascular by-effects induced by introduction of specified preparations, improved erection in present category of patients.

1 ex

Up!