Derivatives of 6-amino quinazoline or 3-cyanoquinoline, methods of their production and their application as inhibitors of receptor tyrozine kinases egfr or her-2

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

 

The SCOPE of the INVENTION

The present invention relates to new derivatives of 6-aminoquinazolin or 3-cyanohydrin, to methods for their preparation, to pharmaceutical compositions containing such derivatives and to the use of such derivatives as therapeutic agents, in particular as inhibitors of protein kinases.

PRIOR art

Signal conversion is a fundamental mechanism by which extracellular stimuli are transferred into the cells. These signals regulate a wide variety of physical responses in the cell, including proliferation, differentiation and apoptosis. Many of these conversion processes the signal using the reversible phosphorylation of proteins, which involves specific protein kinases and phosphatases.

There are two classes of protein kinases (PK): the protein-tyrosine kinase (RTK) and serine-trionychinae (STK). RTC can fosforilirovanii the tyrosine residue in the protein. STK can fosforilirovanii residue serine and/or threonine. Tyrosine kinase can be divided into kinase or receptor type receptor tyrosinekinase, RTK) or precepting type (preceptory tyrosinekinase). At present in the human genome identified approximately 90 tyrosinekinase, of which about 60 belongs to the receptor type and about 30 prinadlejit preceptored type.

The family of receptor tyrosinekinase (RTK) includes: (1) the family of EGF receptor tyrosinekinase, such as EGFR, HER-2, HER-3 and HER-4; (2) insulin family of receptor tyrosinekinase, such as the insulin receptor (IR) and the receptor for insulin-like growth factor-I (IGF-IR) and the receptor, similar to the insulin receptor (IRR); (3) family of class III receptor tyrosinekinase, such as receptor tyrosine kinase platelet-derived growth factor (PDGF), receptor tyrosinekinase of stem cell factor (SCF) RTK (commonly known as c-Kit, receptor tyrosinekinase fms-like tyrosinekinase 3 (Flt3) receptor and tyrosinekinase colony-stimulating growth factor 1 (CSF-1R) and the like. Other tyrosine kinase, growth factor receptor of hepatocytes (HGFR) c-Met and growth factor vascular endothelial (VEGFR), belong to the family RTK. They play a critical role in the control of cell growth and differentiation and are key mediators of cellular signals leading to the production of cytokines such as growth factors (Schlessinger and Ullrich, Neuron 1992, 9, 383).

EGFR (ErbB, HER) plays a critical role in the regulation of cell proliferation and growth. These RTK consist of a glycosylated extracellular ligand-binding domain, a transmembrane domain and an intracellular cytoplasmic catalytic domain. The enzymatic activity of the receptor tyrosinekinase can STI is to wirawati by ligand-mediated homodimerization or heterodimerization. Dimerization results in the phosphorylation of tyrosine residues on the receptors in the catalytic domain, thus producing the next binding site. This is followed by activation of intracellular biochemical signal transduction pathways, such as a pathway involving protein kinase associated with microtubules (MAP kinase), and phosphatidylinositol-3-kinase (P13 kinase). It is shown that the activation of these biochemical pathways leading to cell proliferation and inhibition of apoptosis. Identified that such mutated or hyperexpression form tyrosinekinase, such as EGFR, HER-2, are present in a large fraction of common human cancers such as breast cancer, prostate cancer, non-small cell lung cancer, esophageal cancer, ovarian cancer and pancreatic cancer and the like. The prevalence and relevance of tyrosinekinase confirmed in carcinogenesis and cancer growth.

With regard to the family of class III receptor tyrosinekinase, a group of receptor platelet-derived growth factor (DERIVED), which includes c-Kit and Fms-like tyrosinekinase 3 (FLT-3), has the same structure and the activation method, as for the EGFR family. They transmit signals through dimerization, consistently regulate physical responses, consisting of cell proliferation, differentiation, motility, and growth of blood from the vessels. Thus, members of this family are closely associated with the initiation and development of cancer. The pattern of expression of C-Kit investigated, for example, under different primary solid tumors. High expression of c-Kit can be found, among other things, in small-cell bronchial carcinoma, testicular intraepithelial tumors, melanomas, carcinomas of the breast, Neoplatonic, particularly in gastrointestinal stromal tumors (GIST) [see Weber et al., J. Clin. Oncol. 22(148), 9642 (2004)]. The majority (50-80%) cases of GIST occurs through mutations of the gene C-Kit. Mutations can make c-Kit with a permanent activation of the receptor tyrosinekinase, leading to a high rate of cell division and possibly genomic instability. Thus, induced cancer.

Another important member of the receptor tyrosinekinase is a growth factor receptor vascular endothelial (VEGFR). VEGFR closely involved in angiogenesis. VEGF can activate related biochemical route of transmission of the signal for stimulation of angiogenesis through binding to VEGFR. Recent evidence indicates that VEGF can induce the proliferation and migration of endothelial cells, which subsequently leads to the formation of capillary tubes, which contribute to the formation of overpronates, immature vascular network, which fuels the growth of cancer. In addition to their ang is agenoy activity VEGFR and VEGF can directly stimulate tumor growth through effects that promote survival of tumor cells. Observed that VEGFR highly expressed in several solid malignancies, such as lung carcinoma, breast carcinoma, carcinoma of the ovary, pancreatic cancer and melanoma. Thus, the development of tumors can be inhibit by inhibiting the activation of VEGFR. This is useful in the treatment of cancer.

What affects one member of the RTK, receptor growth factor hepatocyte (HGF) (C-Met or HGFR), it is shown that in many cancers person he is involved in tumorigenesis, tumor invasion and metastasis, as well as in enhanced cell motility (see MA, R. C. et al. (2003b). Cancer Metastasis Rev, 22, 309-25; Maulik, G. et al. (2002b). Cytokine Growth Factor Rev, 13, 41-59).

As for the other members of the RTC, preceptories tyrosine kinase (abbreviated "NRTK" or "JCC") is a protein-tyrosine kinase in the cytoplasm. Compared to RTK, STK no functional extracellular domain and the transmembrane domain. Activation of tyrosine kinase STK is also closely involved in cancer. A more detailed description STK given in the article Bolen, 1993, Oncogen 8: 2025-2031.

The two main characteristics of cancer is genomic instability and uncontrolled biochemical pathway signal for cell cycle regulation and proliferation. Gene is MNA instability leads to a change or loss of the biological function of key regulatory proteins, then to intervene in the biochemical pathway of signal conversion or damage and aberrant biochemical pathway of signal conversion are unable to regulate and control the normal flow of the cell cycle and apoptosis, while cancer cells can continue to live and proliferate in genetic damage. As regards the basis of achieving these regulatory processes, RK, discussed above including RTK and cytoplasmic RTC (STC) is closely involved in carcinogenesis and cancer growth and become an important target for cancer treatment.

Expect to synthesize new compounds with antitumor activity against cell proliferation. Expect that these compounds inhibit one or more than one RTK, STK or STK, and are useful for the treatment or attenuation mediated by angiogenesis-mediated RTK, STK or STK, physiological disorders with hyperproliferating cells.

Up to the present time, there is a series of literary data on inhibitors of protein kinases, such as WO 00/18761 A1, WO 2003089439 A1, WO 2005028443 A1, WO 2007055514 A1. In them are disclosed derivatives of quinoline or hintline, their application and receipt. In article Hwei-Ru Tsou et al. in J. Med.Chem. 48, 1107-1131 (2005) also disclosed are quinoline derivatives as inhibitors of protein kinases.

Although some inhibitors of protein kinases for which ecene cancers disclosed, there is still a need to develop new compounds that have the best therapeutic effect and pharmacokinetic absorption. After long efforts, the inventor has developed new compounds of formula (I) in the present invention and disclosed that these compounds showed the best efficiency and function.

SUMMARY of the INVENTION

In order to overcome the disadvantages of the prior art, the present invention is directed to the development of new derivatives of 6-aminoquinazolin and 3-cyanohydrin formula (I) and their tautomers, enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts and metabolites, precursors or prodrugs,

where:

And selected from the group consisting of a carbon atom or a nitrogen atom;

when a represents a carbon atom, R1selected from the group consisting of a hydrogen atom or alkoxyl; where alkoxyl optionally additionally substituted by one or more than one group selected from the group consisting of a halogen atom or alkoxyl; R2represents cyano;

when a represents a nitrogen atom, R1selected from the group consisting of a hydrogen atom or alkoxyl; where alkoxyl optionally additionally substituted by one or more than one group selected from the group consisting of a halogen atom or alkoxyl; R2no;

R3represents a radical having the following formula:

or;

where:

D is selected from the group consisting of aryl or heteroaryl, where the aryl or heteroaryl each independently optionally additionally substituted by one or more than one group selected from the group consisting of halogen atom, alkyl or trifloromethyl;

T is selected from the group consisting of -(CH2)r-, -O(CH2)r-, -NH(CH2)r- or-S(O)r(CH2)r-;

L is selected from the group consisting of aryl or heteroaryl, where the aryl or heteroaryl each independently optionally additionally substituted by one or more than one group selected from the group consisting of a halogen atom, or alkyl;

R4and R5each independently selected from the group consisting of hydrogen atom, alkyl, alkoxyl, hydroxyl, hydroxyalkyl, halogen atom, carbonyl, amino, cyano, nitro, carboxy or ether carboxylic acids;

In selected from the group consisting of carbon atom, oxygen atom or S(O)r;

when is a carbon atom, R6and R7each independently selected from the group consisting of hydrogen atom, alkyl, alkoxyl, hydroxyl, hydroxyalkyl, and the Ohm halogen, carbonyl, amino, cyano, nitro, carboxy or ether carboxylic acids;

when is an oxygen atom or S(O)r, R6and R7no;

R8selected from the group consisting of a hydrogen atom or alkyl;

R9selected from the group consisting of hydrogen atom, alkyl, aryl, carboxy or ether carboxylic acids;

r is 0, 1 or 2; and

n is 1, 2, 3, 4 or 5.

Preferred compounds of formula (I) or their tautomers, the racemates, the enantiomers, the diastereomers and their mixtures and their pharmaceutically acceptable salts, where a represents a carbon atom, R1is alkoxyl; R2represents cyano.

Preferred compounds of formula (I) or their tautomers, the racemates, the enantiomers, the diastereomers and their mixtures and their pharmaceutically acceptable salts, where a represents a nitrogen atom, R1represents a hydrogen atom; R2is missing.

Preferred compounds of formula (I) or their tautomers, the racemates, the enantiomers, the diastereomers and their mixtures and their pharmaceutically acceptable salts, where n is equal to 2.

Preferably the compounds of formula (I) or their tautomers, the racemates, the enantiomers, the diastereomers and their mixtures and their pharmaceutically acceptable salts include the compounds of formula (II) or their tautomers, the racemates, the enantiomers, diaster the Windows and mixtures thereof, and their pharmaceutically acceptable salts:

where:

And selected from the group consisting of a carbon atom or a nitrogen atom;

when a represents a carbon atom, R1selected from the group consisting of a hydrogen atom or alkoxyl; where alkoxyl optionally additionally substituted by one or more than one group selected from the group consisting of a halogen atom or alkoxyl; R2represents cyano;

when a represents a nitrogen atom, R1selected from the group consisting of a hydrogen atom or alkoxyl; where alkoxyl optionally additionally substituted by one or more than one group selected from the group consisting of a halogen atom or alkoxyl; R2no;

R3represents a radical having the following formula:

or;

where:

D is selected from the group consisting of aryl or heteroaryl, where the aryl or heteroaryl each independently optionally additionally substituted by one or more than one group selected from the group consisting of halogen atom, alkyl and trifloromethyl;

T is selected from the group consisting of -(CH2)r-, -O(CH2)r-, -NH(CH2)r- or-S(O)r(CH2)r-;

L is selected from the group consisting of aryl or CGU is eroarea, where the aryl or heteroaryl each independently optionally additionally substituted by one or more than one group selected from the group consisting of a halogen atom, or alkyl;

R4and R5each independently selected from the group consisting of hydrogen atom, alkyl, alkoxyl, hydroxyl, hydroxyalkyl, halogen atom, carbonyl, amino, cyano, nitro, carboxy or ether carboxylic acids;

R8selected from the group consisting of a hydrogen atom or alkyl;

R9selected from the group consisting of hydrogen atom, alkyl, aryl, carboxy or complex ether carboxylic acids;

r is 0, 1 or 2; and

n is 1, 2, 3, 4 or 5.

Preferred compounds of formula (II) or their tautomers, the racemates, the enantiomers, the diastereomers and their mixtures and their pharmaceutically acceptable salts, where a represents a carbon atom, R1is alkoxyl; R2represents cyano.

Preferred compounds of formula (II) or their tautomers, the racemates, the enantiomers, the diastereomers and their mixtures and their pharmaceutically acceptable salts, where a represents a nitrogen atom, R1represents a hydrogen atom; R2is missing.

Preferred compounds of formula (II) or their tautomers, the racemates, the enantiomers, the diastereomers and their mixtures and their pharmaceutically acceptable salts, g the e n is 2.

Compounds of the present invention include, but are not limited to, the following.

Example No.The structure and name
1
(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(25)-1-methylpyrrolidine-2-yl]prop-2-ename
2
(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(25)-pyrrolidin-2-yl]prop-2-ename
3
(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2S,4R)-4-hydroxy-1-methylpyrrolidine-2-yl]prop-2-ename
4
(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]hinzelin-6-yl]-3-[(2S)-1-methylpyrrolidine-2-yl]prop-2-ename
5
(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2R)-1-methylpyrrolidine-2-yl]prop-2-ename
6
(E)-N-[-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-(1-methyl-2-piperidyl)prop-2-ename
7
(E)-N-[4-[(3-Chloro-4-forfinal)amino]-7-ethoxy-hinzelin-6-yl]-3-[(2S)-1-methylpyrrolidine-2-yl]prop-2-ename
8
(E)-N-[4-[(3-Chloro-4-forfinal)amino]-7-(2-methoxyethoxy)hinzelin-6-yl]-3-[(2R)-1-methylpyrrolidine-2-yl]prop-2-ename
9
(E)-N-[4-[(3-Chloro-4-forfinal)amino]-7-ethoxy-hinzelin-6-yl]-3-[(2R)-1-methylpyrrolidine-2-yl]prop-2-ename
10
(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-(1-methylpyrrolidine-2-yl)prop-2-ename

or their tautomers, the racemates, the enantiomers, the diastereomers and their mixtures and their pharmaceutically acceptable salts.

In another aspect this invention relates to compounds having the following formula (IA), as intermediates in the synthesis of compounds of formula (I):

where:

And selected from the group consisting of a carbon atom or a nitrogen atom;

when a represents a carbon atom, R1selected from the group consisting of a hydrogen atom or alkoxyl; where alkoxyl optional is optional substituted with one or more than one group, selected from the group consisting of a halogen atom or alkoxyl; R2represents cyano;

when a represents a nitrogen atom, R1selected from the group consisting of a hydrogen atom or alkoxyl; where alkoxyl optionally additionally substituted by one or more than one group selected from the group consisting of a halogen atom or alkoxyl; R2no;

R3represents a radical having the following formula:

or;

D is selected from the group consisting of aryl or heteroaryl, where the aryl or heteroaryl each independently optionally additionally substituted by one or more than one group selected from the group consisting of halogen atom, alkyl or trifloromethyl;

T is selected from the group consisting of -(CH2)r-, -O(CH2)r-, -NH(CH2)r- or-S(O)r(CH2)r-;

L is selected from the group consisting of aryl or heteroaryl, where the aryl or heteroaryl each independently optionally additionally substituted by one or more than one group selected from the group consisting of a halogen atom, or alkyl;

r is 0, 1 or 2.

In another aspect, the invention relates to a method for obtaining compounds of formula (IA), comprising the following stages:

the conversion of compounds of formula (IA_1) in the compounds of formula (IA), where A, R1, R2and R3defined as in formula (IA).

In another aspect, the invention relates to a method for producing compounds of formula (I) or their pharmaceutically acceptable salts, comprising the following stages:

the interaction of the phosphate compounds of the formula (IA) with compounds of formula (IB) to produce compounds of formula (I); where a, b, n, R1-R9defined as in formula (I).

In another aspect, the invention relates to a method for producing compounds of the formula (II) or their pharmaceutically acceptable salts, comprising the following stages:

the interaction of compounds of formula (IA) compounds of the formula (IIB) to obtain the compounds of formula (II); where A, n, R1-R5, R8and R9defined as in formula (II).

This invention relates to compounds of formula (I) or their tautomers, the racemates, the enantiomers, the diastereomers and their mixtures, and. their pharmaceutically acceptable salts for use as inhibitors of the receptor tyrosinekinase, inhibiting VEGFR, EGFR, HER-2, HER-3, HER-4, c-Met, Jak3, or mixtures thereof.

This invention relates to the use of compounds of formula (I) or their tautomers, racemates, enantiomers, GeoStereo the development and mixtures thereof, and their pharmaceutically acceptable salts upon receipt of inhibitors of receptor tyrosine kinase selected from the group consisting of VEGFR, EGFR, HER-2, HER-3, HER-4, c-Met, Jak3, or mixtures thereof.

This invention relates to the use of compounds of formula (I) or their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and their pharmaceutically acceptable salts to obtain drugs for treatment of diseases associated with protein kinases, where the protein kinase is selected from the group consisting of a receptor tyrosine kinase, preceptory tyrosine kinase or serine-trainingin; where receptor tyrosinekinase selected from the group consisting of VEGFR, EGFR, HER-2, HER-3, HER-4, c-Met, Jak3, or mixtures thereof.

In one another aspect, this invention relates to compounds of formula (I) or their tautomers, the racemates, the enantiomers, the diastereomers and their mixtures and their pharmaceutically acceptable salts for use as pharmaceuticals for the treatment of diseases associated with protein kinases, where the protein kinase is selected from the group consisting of a receptor tyrosine kinase, preceptory tyrosine kinase or serine-trainingin; where receptor tyrosinekinase selected from the group consisting of VEGFR, EGFR, HER-2, HER-3, HER-4, c-Met, Jak3, or mixtures thereof.

In one another aspect, the invention relates to the application is connected to the second formula (I) or their tautomers, the racemates, enantiomers, diastereomers and mixtures thereof, and their pharmaceutically acceptable salts to obtain drugs for the treatment of cancer, where the cancer is selected from the group consisting of lung cancer, breast cancer, squamous cell carcinoma or gastric cancer.

In one another aspect, this invention relates to compounds of formula (I) or their tautomers, the racemates, the enantiomers, the diastereomers and their mixtures and their pharmaceutically acceptable salts for use as pharmaceuticals for the treatment of cancer.

In one another aspect, the present invention relates to pharmaceutical compositions containing a therapeutically effective amount of compounds of formula (I) or their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and their pharmaceutically acceptable salts or prodrugs and pharmaceutically acceptable carriers or excipients. The present invention also relates to use of pharmaceutical compositions for obtaining a medicinal product for the treatment of diseases associated with protein kinases, where the protein kinase is selected from the group consisting of receptor tyrosinekinase selected from the group consisting of VEGFR, EGFR, HER-2, HER-3, HER-4, c-Met, Jak3, or mixtures thereof. Further, the present invention relates to the use of the pharmaceutical composition is to obtain drugs for the treatment of cancer, where the cancer is selected from the group consisting of lung cancer, breast cancer, squamous cell carcinoma or gastric cancer.

In another aspect this invention relates to a method for producing a pharmaceutical composition, comprising the stage of combining compounds of the formula (I) or their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and their pharmaceutically acceptable salts or prodrugs with pharmaceutically acceptable carriers or diluents.

In another aspect, the present invention relates to a method of regulating the catalytic activity of protein kinases, including bringing into contact of protein kinases with compounds of formula (I) or their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and their pharmaceutically acceptable salts; where protein kinases represent a receptor tyrosine kinase selected from the group consisting of VEGFR, EGFR, HER-2, HER-3, HER-4, c-Met, Jak3, or mixtures thereof.

In another aspect, the present invention relates to a method of treatment of cancer, comprising the introduction of a separate or co-administration with other drugs to a subject in need, a therapeutically effective amount of compounds of formula (I) or their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and their pharmaceutically acceptable salts, where together in the possible drugs are anticancer drugs, selected from the group consisting of trastuzumab, Herceptin, cetuximab, lapatinib, neratinib, letrozole, involving capecitabine, topotecan, docetaxel, and so on

DETAILED description of the INVENTION

Unless otherwise stated, the following terms used in the description and the claims, shall have the meanings discussed below.

"Alkyl" refers to saturated aliphatic hydrocarbon group, including C1-C20remotemachine and branched groups. Preferably the alkyl group is an alkyl having from 1 to 12 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-etylhexyl, 3-etylhexyl, 4-etylhexyl, 5-methylhexan, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylphenyl, 3-ethylphenyl, n-octyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2.5-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylphenyl 2-methyl-3-ethylphenyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylbutyl, n-decyl, 3,3 is di-ethylhexyl, 2,2 is di-ethylhexyl and their isomers branched chain. More preferably the alkyl group is a lower alkyl having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl etc., the Alkyl group may be substituted or unsubstituted. When she substituted group(s) Deputy preferably represents one or more than one group independently selected from the group consisting of alkyl, alkenyl, quinil, alkoxyl, alkylsulfate, alkylamino atom of halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkoxyl, cycloalkyl, heterocyclic, alkylthio, carbonyl, carboxy or ester of carboxylic acid.

"Cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic Ugledar the ne group and has from 3 to 20 carbon atoms. Preferably cycloalkyl group represents cycloalkyl having from 3 to 12 carbon atoms, cycloalkyl group represents cycloalkyl having from 3 to 10 carbon atoms. Representative examples of monocyclic alkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene, cyclooctyl etc. Polycyclic cycloalkyl includes cycloalkyl having a Spiro ring, a condensed ring and a ring with an internal bridge.

"Spiro-cycloalkyl" refers to a 5-20-membered polycyclic hydrocarbon group with rings connected through one common carbon atom (called Spiro-atom), where one or more than one ring may contain one or more than one double bond, but none of the rings has a completely conjugated PI-electron system. Preferably Spiro-cycloalkyl is a 6-14-membered, more preferably is 7 to 10 membered. In accordance with the total number of Spiro atoms Spiro-cycloalkyl divided into monocyclic Spiro-ring, bicyclic Spiro-ring or Spiro polycyclic ring, preferably it refers to monocyclic Spiro-ring or bicyclic Spiro-ring. More preferably Spiro-cycloalkyl is a 4-clenn the f/4-membered, 4-membered to 5-membered, 4-membered/6-membered, 5-membered to 5-membered or 5-membered/b-membered monocyclic Spiro-ring. Representative examples of Spiro-cycloalkyl include, but are not limited to, the following groups:

.

"Condensed cycloalkyl" refers to a 5-20-membered polycyclic hydrocarbon group, where each ring in the system contains a pair of adjacent carbon atoms with another ring, where one or more than one ring may contain one or more than one double bond, but none of the rings has a completely conjugated PI-electron system. Preferably condensed cycloalkyl group is a 6-14-membered, more preferably 7-10-membered. In accordance with the number of ring members condensed cycloalkyl divided into a condensed bicyclic ring, tricyclic ring, tetracyclic ring or polycyclic ring, preferably it refers to a condensed bicyclic or tricyclic ring. More preferably condensed cycloalkyl represents a 5-membered to 5-membered or 5-membered/6-membered condensed bicyclic ring. Representative examples kondensirovannoi is about cycloalkyl include, but not limited to, the following groups:

and.

"Cycloalkyl with internal bridge" refers to a 5-20-membered polycyclic hydrocarbon group, where every two rings in the system are of two General-decoupled carbon atoms. These rings may have one or more than one double bond, but do not have a completely conjugated PI-electron system. Preferably cycloalkyl with the internal bridge is a 6-14-membered, more preferably 7-10-membered. In accordance with the number of ring members cycloalkyl with the internal bridge is divided into a bicyclic ring, tricyclic ring, tetracyclic ring or polycyclic ring with the inner bridge, preferably it relates to bicyclic, tricyclic or tetracyclic to cycloalkyl with internal bridge, more preferably refers to a bicyclic or tricyclic cycloalkyl with the internal bridge. Representative examples of cycloalkyl with internal bridge include, but are not limited to, the following groups:

.

Cycloalkyl may be condensed with aryl, heteroaryl or heterocyclic-alkyl, where the ring is connected with the source structure is cycloalkyl. Representative examples of cycloalkyl with internal bridge include, but are not limited to, Indaselassie acid, tetrahydronaphthalene, 6,7,8,9-tetrahydro-5H-benzo[7]aniline and so on Cycloalkyl may be substituted or unsubstituted. When he substituted group(s) Deputy preferably represents one or more than one group independently selected from the group consisting of alkyl, alkenyl, quinil, alkoxyl, alkylsulfate, alkylamino atom of halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkoxyl, cycloalkyl, heterocyclic, alkylthio, carbonyl, carboxy or ester of carboxylic acid.

"Aryl" refers to 6-14-membered fully carbon monocyclic ring or polycyclic condensed ring ("condensed ring system means that each ring in the system contains a pair of adjacent carbon atoms with the other ring in the system) group and has a completely conjugated PI-electron system. Preferably aryl is 6-10-membered ring, such as phenyl and naphthyl. The aryl may be condensed with heteroaryl, heterocyclic-alkyl or cycloalkyl, where the ring is connected with the source structure is aryl. Representative examples of aryl include, but are not limited to, the following groups:

and.

The aryl may be substituted or unsubstituted. When he substituted group(s) Deputy preferably represents one or more than one group independently selected from the group consisting of alkyl, alkenyl, quinil, alkoxyl, alkylsulfate, alkylamino atom of halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkoxyl, cycloalkyl, heterocyclic, alkylthio, carbonyl, carboxy or ester of carboxylic acid.

"Heteroaryl" refers to a 5-14-membered aryl, having from 1 to 4 heteroatoms selected from the group consisting of O, S Is N, as ring atoms, where the remaining ring atoms are atoms C. Preferably the ring is a 6 - or 10-membered ring. Preferably heteroaryl represents a 5 - or 6-membered ring. Examples of heteroaryl groups are furan, thiophene, pyridine, pyrrole, N-acylpyrrole, pyrimidine, pyrazin, imidazole, tetrazole and so on Heteroaryl may be condensed with aryl, heterocyclic-alkyl or cycloalkyl, where the ring is connected with the source structure is heteroaryl. Representative examples of heteroaryl include, but are not limited to, the following groups:

and.

Heteroaryl may be substituted or unsubstituted. When he substituted group(s) Deputy preferably represents one or more than one group independently selected from the group consisting of alkyl, alkenyl, quinil, alkoxyl, alkylsulfate, alkylamino atom of halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkoxyl, cycloalkyl, GE is eroticlinks alkylthio, carbonyl, carboxy or ester of carboxylic acid.

"Heterocyclic alkyl" refers to a 3-20 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more than one heteroatom selected from the group consisting of N, O or S(O)p(where n is 0, 1 or 2), as ring atoms, but excluding-O-O-, -O-S - or-S-S - in the ring, where the remaining ring atoms are atoms C. Preferably heterocyclic alkyl is a 3-12-membered having from 1 to 4 of the above heteroatoms, more preferably 3-10-membered. Representative examples of monocyclic heterocyclic alkyl include, but are not limited to, pyrrolidyl, piperidyl, piperazinil, morpholinyl, sulfonatophenyl, homopiperazine etc. Floor and cyclic and heterocyclic alkyl includes heterocyclic alkyl having Spiro ring, a condensed ring and a ring with an internal bridge.

"Spiro-heterocyclic alkyl" refers to a 5-20-membered polycyclic heterocyclic alkyl group with rings connected through one common carbon atom (called Spiro-atom), where the rings have one or more than one heteroatom selected from the group consisting of N, O or S(O)p(where p is 0, 1 or 2) as ring atoms, where the rest of the ring atoms is the fast atoms, where one or more than one ring may contain one or more than one double bond, but none of the rings has a completely conjugated PI-electron system. Preferably Spiro-heterocyclic alkyl is a 6-14-membered, more preferably 7-10-membered. In accordance with the number of shared atoms Spiro-heterocyclic alkyl divided into monocyclic Spiro-heterocyclic alkyl, bicyclic Spiro-heterocyclic alkyl or Spiro polycyclic-heterocyclic alkyl, preferably it refers to monocyclic Spiro-heterocyclic alkyl or bicyclic Spiro-heterocyclic alkyl. More preferably Spiro-heterocyclic alkyl is a 4-membered or 4-membered, 4-membered to 5-membered, 4-membered/6-membered, 5-membered to 5-membered or 5-membered/6-membered monocyclic Spiro-heterocyclic alkyl. Representative examples of Spiro-heterocyclic alkyl include, but are not limited to, the following groups:

.

"Condensed heterocyclic alkyl" refers to a 5-20-membered polycyclic heterocyclic alkyl group, where each ring in the system contains a pair of adjacent carbon atoms with others what olicom, where one or more than one ring may contain one or more than one double bond, but none of the rings has a completely conjugated PI-electron system, and where the rings have one or more than one heteroatom selected from the group consisting of N, O or S(O)p(where p is 0, 1 or 2) as ring atoms, where the remaining ring atoms are atoms C. Preferably condensed heterocyclic alkyl is a 6-14-membered, more preferably 7-10-membered. In accordance with the number of ring members condensed heterocyclic alkyl divided into a condensed bicyclic ring, tricyclic ring, tetracyclic ring or polycyclic ring, preferably it refers to a condensed bicyclic or tricyclic ring. More preferably condensed heterocyclic alkyl represents a 5-membered to 5-membered or 5-membered/6-membered condensed bicyclic ring. Representative examples of the condensed heterocyclic alkyl include, but are not limited to, the following groups:

img src="https://img.russianpatents.com/1188/11887100-s.jpg" height="33" width="24" /> and.

"Heterocyclic alkyl with an internal bridge" refers to a 5-14-membered polycyclic heterocyclic alkyl group, where every two rings in the system are of two General-decoupled carbon atoms, the ring may have one or more than one double bond, but do not have a completely conjugated PI-electron system rings have one or more than one heteroatom selected from the group consisting of N, O or S(O)p(where p is 0, 1 or 2) as ring atoms, where the remaining ring atoms are atoms C. Preferably heterocyclic alkyl with an internal bridge is a 6-14-membered, more preferably 7-10-membered. In accordance with the number of ring members of the heterocyclic alkyl with an internal bridge is divided into a bicyclic ring, tricyclic ring, tetracyclic ring or polycyclic ring with the inner bridge, preferably it relates to bicyclic, tricyclic or tetracyclic heterocyclic alkyl with an internal bridge, more preferably refers to a bicyclic or tricyclic heterocyclic alkyl with an internal bridge. Representative examples of heterocyclic alkyl with an internal bridge include, but are not limited to,the following groups:

.

Heterocyclic alkyl may be condensed with aryl, heterocyclic-alkyl or cycloalkyl, where the ring is connected with the source structure is a heterocyclic alkyl. Representative examples of heterocyclic alkyl include, but are not limited to, the following groups:

and.

Heterocyclic alkyl may be substituted or unsubstituted. When he substituted group(s) Deputy preferably represents one or more than one group independently selected from the group consisting of alkyl, alkenyl, quinil, alkoxyl, alkylsulfate, alkylamino atom of halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkoxyl, cycloalkyl, heterocyclic, alkylthio, carbonyl, carboxy or ester of carboxylic acid.

"Alkoxyl" refers to the group-O-(alkyl), and to the group-O-(unsubstituted cycloalkyl), where alkyl is defined above. Representative instances include, but not limited to, methoxy, ethoxyl, propoxy, butoxy, cyclopropane, CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy and the like. Alkoxy may be substituted or unsubstituted. When he substituted group(s) Deputy preferably represent one or more than one group independently selected from the group consisting of alkyl, alkenyl, quinil, alkoxyl, alkylsulfate, alkylamino atom of halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkoxyl, cycloalkyl, heterocyclic, alkylthio, carbonyl, carboxy or ester of carboxylic acid.

"Hydroxyl" refers to-IT group.

"Hydroxyalkyl" refers to-alkyl-HE, where alkyl is defined above.

"Halogen" refers to a fluorescent, chloro, bromo or iodine, preferably with fluorescent or chloro.

"Carbonyl" refers to-C(=O)-.

"Nitro" refers to-NO2.

"Cyano" refers to-CN.

"Amino" refers to-NH2.

"Carboxy" refers to-C(=O)HE.

"Ether carboxylic acid" refers to-C(=O)O-alkyl.

"Optional" or "optionally" means that the described subsequently, the event or circumstance may occur or not occur, and that the description includes instances where the event or circumstance may occur or not occur. N the example, "heterocyclic group optionally additionally substituted alkyl group" means that the alkyl may be present or absent, and the description includes situations where the heterocyclic group is substituted by an alkyl group and situations where the heterocyclic group is not substituted by an alkyl group.

"Pharmaceutical composition" refers to a mixture of one or more than one of the compounds described in this application or their physiologically/pharmaceutically acceptable salts or prodrugs with other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the introduction of compounds into the body, where the benefit is more efficient reception of the active ingredient.

The METHOD of SYNTHESIS of the COMPOUNDS ACCORDING to the INVENTION

To fulfill the purpose of the invention, the invention is applied to the following technical solution:

The method of obtaining the compounds of formula (I) or its pharmaceutically acceptable salts in accordance with this invention, comprising the following stages:

The interaction of the compounds of formula (IA-1) with diethylphosphonate acid to obtain the compounds of formula (IA) in the presence of a condensing agent; in the bath with dry ice, the interaction with the unity of formula (IA) with bis(trimethylsilyl)amidon lithium heating of the reaction solution to room temperature and its interaction with the compound of the formula (IB) by Wittig reaction to obtain compounds of formula (I);

where a, b, n and R1-R9are as defined in formula (I). The method of obtaining the compounds of formula (II) or its pharmaceutically acceptable salts in accordance with this invention, comprising the following stages:

The interaction of compounds of formula (IA) with bis(trimethylsilyl)amidon lithium in the bath with dry ice, and then heating the reaction solution to room temperature and its interaction with the compound of the formula (IV) by means of a Wittig reaction to obtain compounds of formula (II);

where A, n, R1~R5and R8-R9are as defined in formula (II).

SPECIFIC WAYS to IMPLEMENT

Further, the present invention is described below by Examples, which are not intended to limit the scope of the invention.

EXAMPLES

Structures of all compounds were identified by nuclear magnetic resonance (1H NMR and/or mass spectrometry (MS). Chemical shifts1H NMR recorded in million-1(10-6).1H NMR was performed on a spectrometer Bruker AVANCE-400. Appropriate solvents include deuterated methanol (CD33) and deuterated dimethylsulfoxide (DMSO-d6) with tetramethylsilane was (TMS) as internal standard.

MS was determined by mass spectrometer FINNIGAN LCQ Ad (IER) (Thermo, model: Finnigan LCQ advantage MAX).

HPLC was determined on the spectrometer, liquid chromatography high pressure Agilent 1200DAD (chromatographic column Sunfire C18 150×4.6 mm) and spectrometer liquid chromatography high-pressure Waters 2695-2996 (chromatographic column Gimini C18 150×4.6 mm).

IC50was determined on NovoStar ELISA (BMG Co. German).

As a thin-layer silica gel used a plate of silica gel Yantai Huanghai HSGF254 or Qingdao GF254. The size of the plates used in TLC, ranged from 0.15 mm to 0.2 mm, and the size of the plates used for the purification of the product ranged from 0.4 mm to 0.5 mm

When column chromatography as a carrier, as a rule, used silica gel Yantai Huanghai with a cell size of from 200 to 300 mesh.

When column chromatography on basic alumina as a carrier, usually used alkaline alumina GuoYao FCP 200 to 300 mesh.

The original substance of the present invention are known or acquired firms ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Finechemical Co., Ltd and so on, or you may receive a common synthesis methods of the prior art.

If not specified in the e, following the reaction mixture was placed in a nitrogen atmosphere or argon atmosphere.

The term "atmosphere of argon or nitrogen atmosphere" refers to the fact that reaction flask equipped with a balloon filled with approximately 1 l of nitrogen.

The term "atmosphere of hydrogen" refers to the fact that reaction flask equipped with a balloon filled with approximately 1 liter of hydrogen.

Of the hydrogenation reaction under pressure were performed using a spectrometer Parr hydrogenation 3916EKX and hydrogen generator QL-500 or spectrometer hydrogenation HC2-SS.

When the reactions of hydrogenation reaction system is usually placed in a vacuum and filled with hydrogen, by repeating the above operation three times.

Unless otherwise stated, the solution used in the examples, refers to aqueous solution.

Unless otherwise stated, the temperature of the reaction is at room temperature.

Room temperature is the high temperature environment, which is 20ºC-30ºC.

Over the course of the reactions of examples was monitored using thin-layer chromatography (TLC). Chromatographic solvent system consisted of a system of dichloromethane and methanol, hexane and ethyl acetate, the system of petroleum ether and ethyl acetate and acetone. The volume ratio of the solvents is regulated in accordance with the polarity of the connections.

The system e is lirovaniya column chromatography and chromatographic solvent system thin-layer chromatography included: a: a system of dichloromethane and methanol, In: system of hexane and ethyl acetate, With: the system of dichloromethane and acetone. The volume ratio of the solvents is regulated in accordance with the polarity of the connections, and sometimes also added a basic agent such as triethylamine, or an acid agent, such as acetic acid.

Example 1

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2S)-1-methylpyrrolidine-2-yl]prop-2-ename

Stage 1

(2S)-1-Methylpyrrolidine-2-carbaldehyde

Oxalicacid (1.1 ml, 13,02 mmol) was dissolved in dimethyl sulfoxide (1.9 ml, to 26.04 mmol) in a bath with dry ice. After 30 minutes, was added dropwise a solution of [(25)-1-methylpyrrolidine-2-yl]methanol 1A (1 g, 8,68 mmol) in dichloromethane (25 ml). Then the mixture was stirred at -30 º C for 45 minutes, followed by adding dropwise triethylamine (x 6.15 g, 60,77 mmol). The mixture was heated to room temperature and was stirred for 12 hours. To the reaction mixture was added 250 ml of dichloromethane, then washed with saturated sodium bicarbonate (100 ml), saturated ammonium chloride (100 ml) and saturated brine (100 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatograph is she on alkaline alumina with elution with connection, specified in the header, (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (308 mg, yield of 31.4%) as a pale yellow oil.

Stage 2

N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-2-diethoxyphosphoryl

N,N'-Carbonyldiimidazole (487 mg, 3 mmol) was dissolved in 4 ml of tetrahydrofuran. The mixture was heated to 40 º C in an oil bath, to the mixture was added dropwise a solution of diethylphosphonate acid (588 mg, 3 mmol) in tetrahydrofuran (4 ml) and was stirred for 30 minutes before the next stage.

6-Amino-4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-7-ethoxyquinoline-3-carbonitril 1C (446 mg, 1 mmol, obtained by a well-known method: the patent application WO 2005028443) was dissolved in 4 ml of tetrahydrofuran at -40 ° C, followed by adding dropwise the above reaction solution. After stirring for 12 hours the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, N-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin-2-diethoxymethylsilane 1d (624 mg, the output of 99.9%) as a pale yellow solid.

MS m/z (IER): 624 [M+1]

Stage 3

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(25)-1-methylpyrrolidine-2-yl]prop-2-ename

N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-2-diethoxyphosphoryl 1d (50 mg, 0.08 mmol) was dissolved in 2 ml of tetrahydrofuran at-78º followed by the addition dropwise of a solution of bis(trimethylsilyl)amide lithium (1 M) in toluene (80 μl, 0.08 mmol). After the mixture was stirred for 45 minutes, was added (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (20 mg, 0,17 mmol). After stirring for 1 hour the reaction mixture was heated to room temperature and was stirred for 12 hours. To the reaction mixture were added 1 ml water and 1 ml of methanol, then the organic extracts were extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, (E)-N-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2S)-1 methylpyrrolidine-2-yl]prop-2-enamide 1 (25 mg, yield of 53.5%) as a yellow solid is th substance.

MS m/z (IER): 583 [M+1]

1H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 2H), 8.95 (s, 1H), 8.60 (d, 1H), 8.48 (s, 1H), 7.89 (t, 1H), 7.59 (d, 1H), 7.37 (m, 3H), 7.27-7.20 (m, 2H), 6.80-6.60 (m, 2H), 5.29 (s, 2H), 4.34 (dd, 2H), 2.33-2.24 (m, 3H), 2.23-2.15 (m, 2H), 1.99-1.88 (m, 3H), 1.80-1.78 (m, 2H), 1.49 (t, 3H).

Example 2

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2S)-pyrrolidin-2-yl]prop-2-ename

Stage 1

Tert-butyl(2S)-2-(hydroxymethyl)pyrrolidin-1-carboxylate

[(2S)-Pyrrolidin-2-yl]methanol 2A (of 5.06 g, 0.05 mmol) and triethylamine (10,12 g, 0.10 mmol) was dissolved in 100 ml of dichloromethane in a bath of ice-water. To the reaction mixture was added di-tert-butylpyrocatechol (16,37 g, 0.08 mmol) in portions and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate (50 ml×3). The combined organic extracts were washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the connection specified in the header, tert-butyl(2S)-2-(hydroxymethyl)pyrrolidin-1-carboxylate 2b (10 g, yield of 99.9%) as a pale yellow oil.

Stage 2

Tert-butyl(2S)-2-formylpyridine-1-carboxylate

Oxalicacid (3.2 ml, 0.04 mol) and dimethylsulfoxide (4.3 ml, 0.06 mol) was dissolved in 100 ml dichlormid is on in the bath with dry ice. After stirring for 30 minutes was added dropwise a solution of tert-butyl(2S)-2-(hydroxymethyl)pyrrolidin-1-carboxylate 2b (2 g, 0.01 mol) in 20 ml of dichloromethane. The reaction mixture was stirred for 45 minutes and was added drop wise addition of triethylamine (7,08 g, 0.07 mol). After stirring for 1 hour at 0 ° C to the reaction mixture was added 500 ml of dichloromethane. The combined organic layers were washed with saturated brine (100 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, tert-butyl(2S)-2-formylpyridine-1-carboxylate 2 (1.10 g, yield of 55.4%) as a pale yellow oil.

Stage 3

Tert-butyl(2S)-2-[(E)-3-[[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]amino]-3-oxoprop-1-enyl]pyrrolidine-1-carboxylate

N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-2-diethoxyphosphoryl 1d (156 mg, 0.25 mmol) was dissolved in 3 ml of tetrahydrofuran in a bath with dry ice followed by the addition dropwise of a solution of bis(trimethylsilyl)amide lithium (1 M) in toluene (375 μl, 0.38 mmol). After the reaction mixture was stirred for 45 minutes, the solution was added tert-butyl(2S)-2-formhelper ridin-1-carboxylate 2C (100 mg, 0.50 mmol) in 2 ml of tetrahydrofuran. The reaction mixture was stirred for 1 hour, then warmed to room temperature and was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, tert-butyl(2S)-2-[(E)-3-[[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]amino]-3-oxoprop-1-enyl]pyrrolidine-1-carboxylate 2d (161 mg, the yield of 96.2%) as a pale yellow solid.

MS m/z (IER): 669 [M+1]

Stage 4

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2S)-pyrrolidin-2-yl]prop-2-ename

Tert-butyl(2S)-2-[(E)-3-[[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]amino]-3-oxoprop-1-enyl]pyrrolidine-1-carboxylate 2d (161 mg, 0.24 mmol) was dissolved in a solution of hydrogen chloride (2 M) in 25 ml of 1,4-dioxane. After stirring for 12 hours the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column of chromatographie the on silica gel with elution system And obtaining compounds specified in the header, (E)-N-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2S)-pyrrolidin-2-yl]prop-2-enamide 2 (20 mg, yield of 14.6%) as a yellow solid.

MS m/z (IER): 569,4 [M+1]

1H NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.76 (s, 1H), 9.71 (s, 2H), 9.40 (s, 1H), 8.92 (s, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 7.90 (t, 1H), 7.60 (d, 1H), 7.58-7.41 (s, 2H), 7.39-7.38 (m, 2H), 6.95 (dd, 1H), 6.79 (d, 1H), 5.29 (s, 1H), 4.35 (t, 2H), 4.21-4.20 (m, 1H), 3.23-3.22 (m, 3H), 2.21-2.20 (m, 1H), 2.039-1.94 (m, 1H), 1.84-1.76 (m, 1H),1.49 (t, 3H).

Example 3

(E)-N-[4-[[3-Hor-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]prop-2-ename

Stage 1

Methyl(2S,4R)-4-hydroxy-1-methylpyrrolidine-2-carboxylate

Methyl(2S,4R)-4-hydroxypyrrolidine-2-carboxylate 3A (5.53 g, 38 mmol) was dissolved in 80 ml of methanol in a bath of ice-water followed by the addition of 40% formaldehyde solution (31 ml, 380 mmol) and cyanoborohydride sodium (12 g, 190 mmol) in portions. The reaction mixture was stirred for 0.5 hour, then warmed to room temperature and was stirred for 3 hours. The mixture is extinguished 40 ml of water, concentrated under reduced pressure and extracted with dichloromethane (80 ml×3). The combined organic extracts were washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate and filtered. The filtrate koncentrira is whether under reduced pressure to obtain compound, specified in the header, the crude product of methyl-(2S,4R)-4-hydroxy-1-methylpyrrolidine-2-carboxylate 3b in the form of a colorless oil which was used directly in the next stage.

Stage 2

Methyl(2S,4R)-4-(tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-carboxylate

Methyl(2S,4R)-4-hydroxy-1-methylpyrrolidine-2-carboxylate 3b (6 g, 37 mmol) was dissolved in 100 ml of dichloromethane followed by the addition of imidazole (of 7.70 g, 113 mmol) and tert-butyldimethylchlorosilane (6,80 g, 45 mmol) sequentially. After stirring for 12 hours the reaction mixture was diluted with 100 ml dichloromethane, then washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, the crude product of methyl-(2S,4R)-4-(tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-carboxylate 3C in the form of a colorless oil, which was used directly in the next stage without purification.

MS m/z (IER): 274 [M+1]

Stage 3

[(2S,4R)-4-(Tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-yl]methanol

Methyl(2S,4R)-4-(tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-carboxylate 3 (2.50 g, 9,10 mmol) was dissolved in 50 ml dig armeana in a bath of ice-water. Diisobutylaluminum (18 ml, 18 mmol) was slowly added dropwise, and the mixture was stirred for 6 hours. The reaction mixture is extinguished 1 ml of methanol, diluted with 200 ml dichloromethane, was added anhydrous sodium sulfate and was stirred for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on basic alumina with elution system And obtaining the connection specified in the header, [(2S,4R)-4-(tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-yl]methanol 3d (570 mg, yield 50,0%) as a yellow oil.

MS m/z (IER): 246 [M+1]

Stage 4

(2S,4R)-4-(Tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-carbaldehyde

Dimethyl sulfoxide (174 μl, 2.45 mmol) was dissolved in 20 ml of dichloromethane in a bath with dry ice. After the temperature stabilized, was slowly added dropwise oxalicacid (156 μl, of 1.80 mmol). After stirring for 30 minutes was added dropwise a solution of [(2S,4R)-4-(tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-yl]methanol 3d (300 mg, 1.20 mmol) in 2 ml of dichloromethane. After stirring for 45 minutes to the reaction mixture were added triethylamine (510 μl, to 3.67 mmol) and was stirred for 10 minutes, then warmed to room temperature and was stirred for 1 hour. The reaction mixture rasba the Lyali 100 ml of dichloromethane, then washed with saturated sodium bicarbonate (20 ml), saturated ammonium chloride (20 ml) and saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the connection specified in the header, a crude product of (2S,4R)-4-(tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-carbaldehyde 3E (320 mg) as a yellow oil which was used directly in the next stage.

Stage 5

(E)-3-[(2S,4R)-4-(Tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-yl]-M-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]prop-2-ename

N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-2-diethoxyphosphoryl 1d (418 mg, 0.67 mmol) was dissolved in 2.5 ml of tetrahydrofuran in a bath with dry ice followed by the addition dropwise of a solution of bis(trimethylsilyl)amide lithium (1 M) in toluene (1 ml, 1 mmol). After the mixture was stirred for 45 minutes, was added a solution of (2S,4R)-4-(tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-carbaldehyde 3E (326 mg, of 1.34 mmol) in 2.5 ml of tetrahydrofuran and stirred for 1 hour, then warmed to room temperature and was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified column of chromatographie the on silica gel with elution system And obtaining compounds specified in the header, (E)-3-[(2S,4R)-4-(tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-yl]-N-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]prop-2-enamide 3f (292 mg, yield of 61.2%) as a yellow solid.

MS m/z (IER): 713 [M+1]

Stage 6

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(25,4 I)-4-hydroxy-1-methylpyrrolidine-2-yl]prop-2-ename

(E)-3-[(2S,4R)-4-(Tert-butyl(dimethyl)silyl)hydroxy-1-methylpyrrolidine-2-yl]-N-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]prop-2-UNAMID 3f (50 mg, 0.07 mmol) and tetrabutylammonium fluoride (51 mg, 0.21 mmol) was dissolved in 5 ml of tetrahydrofuran, and the mixture was stirred for 12 hours. To the reaction mixture were added 1 ml of water, concentrated under reduced pressure and extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, (E)-N-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2S,4R)-4-hydroxy-1-methylpyrrolidine-2-yl]prop-2-enamide 3 (17 mg, yield of 40.4%) as a yellow solid.

MS m/z (IER): 599,4 [M+1]

1H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 9.52 (s, 1H), 8.97 (s, 1H), 8.61-8.60 (m, 1H), 8.48 (s, 1H), 7.904-7.862 (m, 1H), 7.60 (d, 1H), 7.41-7.36 (m, 3H), 7.28-7.20 (m, 2H), 6.76 (dd, 1H), 6.61 (d, 1H), 5.29 (s, 2H), 4.82 (s, 1H), 4.35-4.29 (m, 2H), 4.21 (d, 1H), 3.42-3.38 (m, 2H), 3.36-3.33 (m, 3H), 2.93 (d, 1H), 2.41-2.37 (m, 1H), 2.20-2.18 (m, 1H), 1.49 (t, 3H).

Example 4

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]hinzelin-6-yl]-3-[(25)-1-methylpyrrolidine-2-yl]prop-2-ename

Stage 1

4-Chloro-6-nitroquinazoline

6-Nitro-3H-hinzelin-4-one 4a (18,88 g, 99,40 mmol) was dissolved in chloride phosphorus (31,03 g, 149 mmol). The mixture was heated to 160º and was stirred for 3 hours. To the reaction mixture while hot was added 250 ml of n-hexane, stirred, and from the solution deposited a lot of solid, which was filtered, the filter cake was washed with n-hexane, dried under vacuum to obtain the connection specified in the header, 4-chloro-6-nitroquinazoline 4b (18,14 g, yield 87,2%) as a yellow solid.

Stage 2

N-[3-Chloro-4-(2-pyridyloxy)phenyl]-6-nitroquinazoline-4-amine Crude product 4-chloro-6-nitroquinazoline 4b (6,06 g, 28,90 mmol) was dissolved in 100 ml of isopropanol followed by the addition of 3-chloro-4-(2-pyridyloxy)aniline 4c (7.47 g, of 31.8 mmol). The reaction mixture was heated up to the formation of phlegmy for 5 hours. The mixture was cooled to room temperature, the solid was besieged, filtered the filter cake is then washed with ethyl acetate, saturated brine (50 ml) and water (150 ml), dried in vacuum, obtaining the connection specified in the header, N-[3-chloro-4-(2-pyridyloxy)phenyl]-6-nitroquinazoline-4-amine 4d (scored 8.38 g, yield 74,8%) as a yellow solid.

MS m/z (IER): 319 [M+1]

Stage 3

N4-[3-Chloro-4-(2-pyridyloxy)phenyl]hinzelin-4,6-diamine

N-[3-Chloro-4-(2-pyridyloxy)phenyl]-6-nitroquinazoline-4-amine 4d (4,07 g, 10 mmol) and concentrated hydrochloric acid (2 ml, 24 mmol) was dissolved in 130 ml of a solvent mixture of 95% ethanol and water (V/V=10/3) followed by the addition of iron powder (11,17 g, 200 mmol). The reaction mixture was heated up to the formation of phlegmy for 2 hours, filtered hot and the filtrate was concentrated under reduced pressure to remove ethanol. The resulting residue was brought to pH>7 with ammonium hydroxide, filtered and the filter cake was dried in vacuo, was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, N4-[3-chloro-4-(2-pyridyloxy)phenyl]hinzelin-4,6-diamine 4E (2,04 g, the output of 54.1%) as a white solid.

MS m/z (IER): 378 [M+1]

Stage 4

N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]hinzelin-6-yl]-2-diethoxyphosphoryl

Diethylphosphonoacetate acid (1.04 g, and 5.30 mmol) was dissolved in 10 ml dichloromethane in a bath of ice-water to follow what they add oxalicacid (1,34 g, 10 mmol) and 1 drop of N,N-dimethylformamide. After stirring for 1 hour the mixture was heated to room temperature and stirred for 1 hour, concentrated under reduced pressure and added 10 ml of tetrahydrofuran for the next stage.

N4-[3-Chloro-4-(2-pyridyloxy)phenyl]hinzelin-4,6-diamine 4E (1 g, to 2.65 mmol) was dissolved in N,N-diisopropylethylamine (1,03 g, 7,94 mmol), followed by adding dropwise the above reaction solution. The mixture was heated to room temperature and was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, N-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]hinzelin-6-yl]-2-diethoxymethylsilane 4f (671 mg, yield of 45.7%) as a white solid.

MS m/z (IER): 556 [M+1]

Stage 5

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]hinzelin-6-yl]-3-[(25)-1-methylpyrrolidine-2-yl]prop-2-ename

N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]hinzelin-6-yl]-2-diethoxyphosphoryl the ndimethylacetamide 4f (277 mg, 0.50 mmol) was dissolved in 2.5 ml of tetrahydrofuran in a bath with dry ice followed by the addition dropwise of a solution of bis(trimethylsilyl)amide lithium (1 M) in toluene (750 μl, 0.75 mmol). After stirring for 45 minutes to the reaction mixture was added (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (113 mg, 2 mmol) and was stirred for 1 hour, then warmed to room temperature and was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, (E)-N-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]hinzelin-6-yl]-3-[(25)-1-methylpyrrolidine-2-yl]prop-2-enamide 4 (85 mg, yield 33,0%) as a yellow solid.

MS m/z (IER): 515,3 [M+1]

1H NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.82 (s, 1H), 8.79 (s,1H), 8.61 (d, 1H), 8.52 (s, 1H), 8.00 (s, 1H), 7.91-7.89 (t, 2H), 7.78-7.69 (m, 2H), 7.61 (d, 1H), 7.38 (d, 1H), 7.28 (d, 1H), 6.78-6.72 (t, 1H), 6.47 (d, 1H), 5.30 (s, 2H), 3.14-3.00 (t, 2H), 3.001 (s, 1H), 2.31 (t, 4H), 2.10-2.07 (m, 1H), 1.81 (t, 2H), 1.63 (t, 1H)

Example 5

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2E)-1-methylpyrrolidine-2-yl]prop-2-ename

Stage 1

[(2R)-1-Methylpyrrolidine-2-yl]methanol

Alumoweld lithium (230 mg, 6 mmol) and N-tert-butoxycarbonyl-L-p is ainol 5A (400 mg, 2 mmol) was dissolved in 10 ml dry tetrahydrofuran in a bath of ice-water portions. After visible gas is no longer allocated, the reaction mixture was heated up to the formation of phlegmy within 2 hours. To the reaction mixture was added dropwise 5 ml of methanol in a bath of ice-water, followed by adding 5 ml of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to get the connection specified in the header, [(2R)-1-methylpyrrolidine-2-yl]methanol 5b (221 mg, yield 77,0%) as a colourless oil.

MS m/z (IER): 116 [M+1]

Stage 2

(2R)-1-Methylpyrrolidine-2-carbaldehyde

Dimethyl sulfoxide (820 μl, 11,46 mmol) was dissolved in 5 ml of dichloromethane in a bath with dry ice, followed by slow addition dropwise of oxalicacid (968 mg, of 7.64 mmol). After stirring for 45 minutes to this solution was added a solution of [(2R)-1-methylpyrrolidine-2-yl]methanol 5b (220 mg, at 1.91 mmol) in 2 ml of dichloromethane. The reaction mixture was stirred for 45 minutes and was added triethylamine (1.9 ml, 13,37 mmol). The reaction mixture was stirred for 10 minutes, then warmed to room temperature and was stirred for 1 hour. The reaction mixture is then washed with water (20 ml) and saturated brine (10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and which has centriole under reduced pressure, and the resulting residue was purified column chromatography on basic alumina with elution system And obtaining the connection specified in the header, (2R)-1-methylpyrrolidine-2-carbaldehyde 5 (300 mg) as a yellow solid, which was used directly in the next stage without purification.

Stage 3

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2R)-1-methylpyrrolidine-2-yl]prop-2-ename

N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-2-diethoxyphosphoryl 1d (250 mg, 0.40 mmol) was dissolved in 10 ml dry tetrahydrofuran in a bath with dry ice followed by the addition dropwise of a solution of bis(trimethylsilyl)amide lithium (1 M) in toluene (440 μl, 0.44 mmol). The reaction mixture was stirred for 30 minutes, was added dropwise a solution of (2R)-1-methylpyrrolidine-2-carbaldehyde 5 (90 mg, 0.80 mmol) in 5 ml of tetrahydrofuran and stirred for 30 minutes, then warmed to room temperature and was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, (E)-N-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-[(2R)-1-methylpyrrolidine-2-yl]the p-2-enamide 5 (46 mg, the output of 19.7%) as a yellow solid.

MC m/z (IER): 583,4 [M+1]

1H NMR (400 MHz, DMSO-d6): S 9.16 (s, 1H), 8.63 (d, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 7.83-7.80 (dd, 1H), 7.76-7.50 (m, 2H), 7.57-7.56 (m,1H), 7.40 (s, 1H), 7.38(s, 1H), 7.19 (d, 1H), 7.06-7.03 (m, 2H), 6.34-6.31 (d, 1H), 5.35 (s, 2H), 4.39 (m, 2H), 4.27-4.26 (m, 1H), 3.32 (m, 1H), 3.10 (m, 1H), 2.73 (s, MN), 2.37-2.36 (m, 2H), 2.07-2.01 (m, 2H), 1.64 (t, 3H)

Example 6

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-(1-methyl-2-piperidyl)prop-2-ename

Stage 1

1 Methylpiperidin-2-carbaldehyde

Dimethyl sulfoxide (3,3 ml, 46 mmol) was dissolved in 15 ml of dichloromethane in a bath with dry ice, followed by slow addition dropwise of oxalicacid (2,6 ml, 31 mmol). After stirring for 45 minutes to this solution was added dropwise a solution of (1-methyl-2-piperidyl)methanol 6A (1 g, 7,74 mmol) in 5 ml of dichloromethane. The reaction mixture was stirred for 45 minutes, then was added triethylamine (7.2 ml, 52 mmol) and was stirred for 10 minutes, then warmed to room temperature and was stirred for 1 hour. The reaction mixture is then washed with water (20 ml) and saturated brine (20 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then the resulting residue was purified count the night chromatography on basic alumina with elution with connection, specified in the header, 1 methylpiperidin-2-carbaldehyde 6b (300 mg, yield 31,0%) as a brown oil which was used directly in the next stage without purification.

Stage 2

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-(1-methyl-2-piperidyl)prop-2-ename

N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-2-diethoxyphosphoryl 1d (300 mg, 0.48 mmol) was dissolved in 10 ml of tetrahydrofuran in a bath with dry ice followed by the addition dropwise of a solution of bis(trimethylsilyl)amide lithium (1 M) in toluene (530 μl, of 0.53 mmol). After stirring for 30 minutes was added dropwise a solution of 1-methylpiperidin-2-carbaldehyde 6b (120 mg, 0.96 mmol) in 5 ml of tetrahydrofuran. The reaction mixture was stirred for 30 minutes, then warmed to room temperature and was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, (E)-N-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-(1-methyl-2-piperidyl)prop-2-enamide 6 (14 mg, yield of 4.9%) as a yellow solid.

MS m/z (IER): 597,3 [M+1]

1H NMR (400 MHz, DMSO-d6): δ 9.09 (s, 1H), 8.63 (d, 1H), 8.51 (s, 1H), 7.83-7.79 (m, 2H), 7.587.56 (t, 1H), 7.30-7.27 (t, ZN), 7.14-7.12 (t, 2H), 7.04 (d, 1H), 6.69-6.66 (t, 1H), 5.32 (s, 2H), 4.32-4.29 (t, 2H), 4.27-4.24 (t, 2H), 3.60-3.40 (t, 2H), 2.71 (s, 3H), 2.05-1.72(m, 6H),1.62(t, 3H)

Example 7

(E)-N-[4-[(3-Chloro-4-forfinal)amino]-7-ethoxyquinoline-6-yl]-3-[(2S)-1-methylpyrrolidine-2-yl]prop-2-ename

Stage 1

N-[4-[(3-Chloro-4-forfinal)amino]-7-ethoxyquinoline-6-yl]-2-diethoxyphosphoryl

N,N'-Carbonyldiimidazole (292 mg, of 1.80 mmol) was dissolved in 4 ml of tetrahydrofuran. The mixture was heated to 50 º C in an oil bath, was added dropwise a solution of diethylphosphonate acid (353 mg, 1.8 mmol) in 3 ml of tetrahydrofuran and stirred for 1.5 hours until the next stage.

N4-(3-Chloro-4-forfinal)-7-ethoxyquinoline-4,6-diamine 7a (200 mg, of 0.60 mmol, obtained by a well-known method: the patent application WO 2005028443) was dissolved in 10 ml of tetrahydrofuran, followed by adding dropwise the above reaction solution at 50'C. After stirring for 3 hours at -40 ° C the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel by rendering elution And getting connection specified in the header, N-[4-[(3-chloro-4-forfinal)amino]-7-ethoxyquinoline-6-yl]-2-diethoxymethylsilane 7b (100 mg, yield 33,3%) as a pale yellow solid.

MS m/z (IER): 511,1 [M+1]

Stage 2

(E)-N-[4-[(3-Chloro-4-forfinal)amino]-7-ethoxyquinoline-6-yl]-3-[(28)-1-methylpyrrolidine-2-yl]prop-2-ename

N-[4-[(3-Chloro-4-forfinal)amino]-7-ethoxyquinoline-6-yl]-2-diethoxyphosphoryl 7b (100 mg, 0.20 mmol) was dissolved in 10 ml of tetrahydrofuran. The mixture was cooled to-78º in the bath with dry ice followed by the addition dropwise of a solution of bis(trimethylsilyl)amide lithium (1 M) in toluene (400 μl, 0.40 mmol) and the mixture was stirred for 45 minutes, was added to (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (100 mg, 0.85 mmol). After stirring for 1 hour the reaction mixture was heated to room temperature and was stirred for 12 hours. To the reaction mixture were added water (1 ml) and methanol (1 ml), was extracted with dichloromethane (100 ml×3). The combined organic extracts were washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and then the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, (E)-N-[4-[(3-chloro-4-forfinal)amino]-7-ethoxyquinoline-6�]-3-[(28)-1-methylpyrrolidine-2-yl]prop-2-enamide 7 (60 mg, the yield of 65.2%) as a yellow solid.

MS m/z (IER): 470,2 [M+1]

1H NMR (400 MHz, DMSO-d6): δ 9.78 (s, 1H), 9.53 (s, 1H), 8.91 (s, 1H), 8.52 (s, 1H), 8.13-8.15 (m, 1H), 7.79-7.81 (m, 1H), 7.39-7.43 (m, 1H), 7.26 (s, 1H), 6.67-6.69 (m, 2H), 4.26-4.31 (m, 2H), 4.09-4.10 (m, 1H), 3.17-3.15 (m, 2H), 3.08-3.04 (m, 1H), 2.77-2.79 (m, 1H), 2.87-2.82 (m, 1H), 2.23 (s,3H), 1.74-1.76 (m,1H), 1.47 (m, 3H).

Example 8

(E)-N-[4-[(3-Chloro-4-forfinal)amino]-7-(2-methoxyethoxy)hinzelin-6-yl]-3-[(2R)-1-methylpyrrolidine-2-yl]prop-2-ename

Stage 1

N-(3-Chloro-4-forfinal)-7-(2-methoxyethoxy)-6-nitroquinazoline-4-amine 2-Methoxyethanol (152 mg, 2 mmol) was dissolved in 30 ml of dimethyl sulfoxide in a bath of ice-water, followed by addition of 60% sodium hydride (80 mg, 2 mmol). The mixture was heated to 40 º C and was stirred for 2 hours, then was added N-(3-chloro-4-forfinal)-7-fluoro-6-nitroquinazoline-4-amine 8a (336 mg, 1 mmol). The reaction mixture was stirred for 4 hours at -40 ° C, then warmed up to 50 º C and was stirred for 12 hours. To the reaction mixture were added water (20 ml), filtered and the filter cake washed with water (50 ml), dried in vacuum, obtaining the connection specified in the header, N-(3-chloro-4-forfinal)-7-(2-methoxyethoxy)-6-nitroquinazoline-4-amine 8b (392 mg, yield 100%) as a yellow solid, which was used directly in the next stage.

MS m/z (IER): 393,0 [M+1]

Stage 2

N4-(3-Chloro-4-forfinal)-7-(2-methoxyethoxy)hinzelin~4,6-diamine

N-(3-Chloro-4-forfinal)-7-(2-methoxyethoxy)-6-nitroquinazoline-4-amine 8b (392 mg, 1 mmol) and iron powder (392 mg, 7 mmol) was dissolved in 20 ml of acetic acid. The reaction mixture was heated up to the formation of phlegmy for 4 hours, concentrated under reduced pressure. To the residue was added 100 ml of saturated sodium bicarbonate, extracted with dichloromethane (100 ml×3). The combined organic extracts were washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the connection specified in the header, N4-(3-chloro-4-forfinal)-7-(2-methoxyethoxy)hinzelin-4,6-diamine 8 (200 mg, yield of 55.2%) as a pale yellow solid.

MS m/z (IER): 363,1 [M+1]

Stage 3

N-[4-[(3-Chloro-4-forfinal)amino]-7-(2-methoxyethoxy)hinzelin-6-yl]-2-diethoxyphosphoryl

N,N'-Carbonyldiimidazole (292 mg, of 1.80 mmol) was dissolved in 4 ml of tetrahydrofuran. The mixture was heated to 50 º C in an oil bath, was added dropwise a solution of diethylphosphonate acid (353 mg, 1.8 mmol) in 3 ml of tetrahydrofuran and stirred for 1.5 hours until the next stage.

N4-(3-Chloro-4-forfinal)-7-(2-methoxyethoxy)hinzelin-4,6-diamine 8 (200 mg, 0.55 mmol) was dissolved in 10 ml of tetrahydrofuran, followed by adding dropwise receive the frame above reaction solution at 50'C. After stirring for 3 hours at -40 ° C the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, N-[4-[(3-chloro-4-forfinal)amino]-7-(2-methoxyethoxy)hinzelin-6-yl]-2-diethoxymethylsilane 8d (150 mg, yield a 50.5%) as a pale yellow solid.

MS m/z (IER): 541,2 [M+1]

Stage 4

(E)-N-[4-[(3-Chloro-4-forfinal)amino]-7-(2-methoxyethoxy)hinzelin-6-yl]-3-[(2R)-1-methylpyrrolidine-2-yl]prop-2-ename

N-[4-[(3-Chloro-4-forfinal)amino]-7-(2-methoxyethoxy)hinzelin-6-yl]-2-diethoxyphosphoryl 8d (200 mg, and 0.37 mmol) was dissolved in 10 ml of tetrahydrofuran. The mixture was cooled to-78º in the bath with dry ice. In an argon atmosphere was added dropwise a solution of bis(trimethylsilyl)amide lithium (1 M) in toluene (740 μl, of 0.74 mmol). After stirring for 30 minutes to the reaction solution was added (2R)-1-methylpyrrolidine-2-carbaldehyde 5 (84 mg, of 0.74 mmol). The reaction mixture was stirred for 1 hour, then warmed to room temperature and was stirred tip is of 12 hours. The reaction mixture was concentrated, added to it 10 ml of water, was extracted with dichloromethane (25 ml×3). The combined organic extracts were washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, (E)-N-[4-[(3-chloro-4-forfinal)amino]-7-(2-methoxyethoxy)hinzelin-6-yl]-3-[(2R)-1-methylpyrrolidine-2-yl]prop-2-enamide 8 (100 mg, yield 54,2%) as a yellow solid.

MS m/z (IER): 500,2 [M+1]

1H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 9.58 (s, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 8.12-8.13 (m, 1H), 7.79-7.81 (m, 1H), 7.40-7.44 (m, 1H), 7.32 (s, 1H), 6.57-6.75 (m, 2H), 4.36-4.37 (m, 2H), 3.80-3.81 (m, 2H), 3.35-3.32 (m, 4H), 3.15-3.13 (m, 1H), 2.5(s, 3H), 2.40-2.31 (m, 2H), 2.08 (m, 1H), 1.90-1.81(m, 1H), 1.70-1.64 (m, 1H)

Example 9

(E)-N-[4-[(3-Chloro-4-forfinal)amino]-7-ethoxyquinoline-6-yl]-3-[(2R)-1-methylpyrrolidine-2-yl]prop-2-ename

Stage 1

(E)-N-[4-[(3-Chloro-4-forfinal)amino]-7-ethoxyquinoline-6-yl]-3-[(2R)-1-methylpyrrolidine-2-yl]prop-2-ename

N-[4-[(3-Chloro-4-forfinal)amino]-7-ethoxyquinoline-6-yl]-2-diethoxyphosphoryl 7b (300 mg, 0.59 mmol) was dissolved in 10 ml of Tetra hydrofera on. The mixture was cooled to-78º in the bath with dry ice. In an argon atmosphere was added the drop wise addition of a solution of bis(trimethylsilyl)amide lithium (1 M) in toluene (1.2 ml, 1.18 mmol). After the mixture was stirred for 30 minutes, was added (2R)-1-methylpyrrolidine-2-carbaldehyde 5 (133 mg, 1.18 mmol) and the mixture was stirred for 1 hour, then warmed to room temperature and was stirred for 12 hours. The reaction mixture was concentrated, added 10 ml of water, was extracted with dichloromethane (25 ml×3). The combined organic extracts were washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, (E)-N-[4-[(3-chloro-4-forfinal)amino]-7-ethoxyquinoline-6-yl]-3-[(2R)-1-methylpyrrolidine-2-yl]prop-2-enamide 9 (130 mg, yield of 47.3%) as a yellow solid.

MS m/z (IER): 470,2 [M+1]

1H NMR (400 MHz, DMSO-d6): δ 9.79 (s, 1H), 9.53 (s, 1H), 8.93 (s, 1H), 8.53 (s, 1H), 8.12-8.15 (m, 1H), 7.79-7.83 (m, 1H), 7.40-7.45 (m, 1H), 7.27 (s, 1H), 6.67-6.73 (m, 1H), 6.56-6.60 (m, 1H), 4.27-4.32 (m, 2H), 4.09-4.10 (m, 1H), 3.17 (m, 2H), 3.04 (m, 1H), 2.77-2.79 (m, 1H), 2.18-2.16 (m, 1H), 2.21 (s, 3H), 1.74-1.76 (m, 1H), 1.47 (t, 3H)

Example 10

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-(1-methylpyrrolidine-2-yl)prop-2-ename

Stage 1

Methylpyrrolidine-2-carboxylate

7 ml of thionyl chloride was dissolved in 50 ml of methanol in a bath of ice-water and then adding pyrrolidin-2-carboxylic acid 10A (5 g, 43,40 mmol). The mixture was heated to room temperature and was stirred for 24 hours. The mixture was concentrated under reduced pressure to get crude product, methylpyrrolidine-2-carboxylate 10b (10 g) as a white solid, which was used directly in the next stage without purification.

MC m/z (IER): to 130.1 [M+1]

Stage 2

Methyl-1-methylpyrrolidine-2-carboxylate

The crude product methylpyrrolidine-2-carboxylate 10b (5 g) was dissolved in 100 ml of methanol. The solution was cooled to 0-5 º C in a bath of ice-water, followed by addition of 13 ml of 40% formaldehyde. The reaction mixture was heated to room temperature and was stirred for 2 hours, then was cooled to 0-5 º C in a bath of ice-water was added in portions cyanoborohydride sodium (the 5.45 g, 87,20 mmol). The reaction mixture was heated to room temperature and was stirred for 24 hours. The mixture was concentrated under reduced pressure and added 5 ml of water, was extracted with dichloromethane (5 ml×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude product methyl-1-methylpyrrolidine-2-carboxylate 10 (4.7 g, yield 70,1) korichnevaya.

MS m/z (IER): 144,1 [M+1]

Stage 3

(1 Methylpyrrolidine-2-yl)methanol

Diisobutylaluminum (60 ml, 66 mmol) was added dropwise to a solution of methyl-1-methylpyrrolidine-2-carboxylate 10 (4.7 g, 33 mmol) in 50 ml of dichloromethane. The reaction mixture was stirred for 6 hours in a bath of ice-water, followed by adding 10 ml of methanol. The reaction mixture was concentrated under reduced pressure to get the connection specified in the header, (1 methylpyrrolidine-2-yl)methanol 10d (1.8 g, yield 47,4%) as a brown oil.

Stage 4

1 Methylpyrrolidine-2-carbaldehyde

Dimethyl sulfoxide (2.2 ml, 31,20 mmol) was dissolved in 20 ml of dichloromethane in a bath of dry ice - acetone followed by the addition of oxalicacid (2 ml, 23,40 mmol). After stirring for 45 minutes at-18º was added (1 methylpyrrolidine-2-yl)methanol 10d (1.8 g, 15,60 mmol). After stirring for 45 minutes, was added triethylamine (6.5 ml, 46,80 mmol). The reaction mixture was heated to room temperature and was stirred for 1 hour. The reaction mixture was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified column chromatography on basic alumina with elution system And obtaining 1 methylpyrrolidine-2-carbaldehyde 10th (1 g, in the course of 56,8%) as a brown oil.

Stage 5

(E)-N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-(1-methylpyrrolidine-2-yl)prop-2-ename

N-[4-[[3-Chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-2-diethoxyphosphoryl 1d (3 g, 4.40 mmol) was dissolved in 30 ml of tetrahydrofuran in a bath with dry ice followed by the addition dropwise of a solution of bis(trimethylsilyl)amide lithium (1 M) in toluene (9.6 ml, 8,80 mmol). After the mixture was stirred for 30 minutes, was added dropwise a solution of 1-methylpyrrolidine-2-carbaldehyde 10th (1 g 8,80 mmol) in 5 ml of tetrahydrofuran. The reaction mixture was stirred for 30 minutes, then warmed to room temperature and was stirred for 24 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified column chromatography on silica gel with elution system And obtaining the connection specified in the header, (E)-N-[4-[[3-chloro-4-(2-pyridyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-chinolin]-3-(1-methylpyrrolidine-2-yl)prop-2-enamide 10 (500 mg, yield 20,8%) as a yellow solid.

MS m/z (IER): 583,2 [M+1]

1H NMR (400 MHz, DMSO-d6): δ 11.59 (s, 1H), 11.28 (s, 1H), 9.19 (s,1H), 9.05 (s, 1H), 8.71 (d, 1H), 8.09-8.07 (m, 1H), 7.74-7.68 (m, MN), 7.56-7.55 (m, 1H), 7.45-7.37 (m, 2H), 7.04-7.00 (m, 1H), 6.88-6.84 (m, 1H), 5.43 (s, 2H), 4.38 (dd, 2H), 4.10 (m, 2H), 3.63-3.60 (m, 1H), 3.13-3.08 (m, 1H), 2.73-2.72 (m, MN), 2.31-2.29 (m, 1H), 2.08-2.02 (m, 2H), 1.53(t, 3H).

TEST cases

BIOLOGICAL ASSAYS

EXAMPLE 1: analysis of the inhibition of cell proliferation in EGFR

The following in vitro assays designed to determine the activity of the compounds according to the invention for the inhibition of cell proliferation epidermoid carcinoma human A431, which have high expression of EGFR.

The following in vitro assays designed to determine the activity of the test compounds on the inhibition of proliferation of cancer cells that have high expression of EGFR. This activity is presented in the form of values SBO. Common methods for this analysis are the following: cancer A431 cells with high expression of EGFR (Institute of biochemistry and cell biology), were selected and sown in 96-well plate for cell culture at a suitable concentration (for example, 5000 cells/ml of medium). The cells are then incubated in an incubator with carbon dioxide (CO2) before they reach 85% of confluently. Then the cell culture medium was replaced with fresh medium with the test compounds added in serial dilutions (usually from 6 to 7 concentrations). Then the cells were placed back in the incubator and cultured continuously. After 72 hours the activity of the test compounds on the inhibition of cell proliferation was determined by using the method of sulforhodamine In (SRB). The value of the IC 50on the test cells is calculated according to the levels of inhibition of serial concentrations of the test compounds.

The active compounds according to the invention.

The biological activity of the compounds according to the invention was tested by using the analysis described above. The values of the IC50measured and presented in the table below.

Example No.IC50(EGFR/A431)(MKM)
10,022
20,003
3being 0.036
50,045
90,008

Conclusion: the compounds of the present invention have significant activity in inhibiting the proliferation of A431 cells.

EXAMPLE 2: analysis of the activity of the EGFR kinase

Analysis of the activity of the EGFR kinase in vitro were tested using analysis below.

The analysis below is used to determine the activity of the compounds according to the invention for inhibition of kinase activity of EGFR. Half-maximal inhibitory concentration (IC50(the concentration of test compounds proabley the 50% inhibition of enzyme activity) of each compound was determined by incubation of several different concentrations of the test compounds with a specific enzyme and substrate. The EGFR kinase used in this analysis, is a recombinant protein of human origin (Cell signaling technology, #7908), which was subjected to interaction with a peptide substrate and various concentrations of test compounds in a buffer solution containing 60 mm HEPES (pH 7.5), 5 mm MgCl2, 5 mm MnCl2, 3 μm Na3VO4, 1,25 M DTT (1000 x) and 20 μm ATP at 25 º C for 45 minutes. The kinase activity of EGFR was determined by using the time-of-flight fluorescence.

The active compounds according to the invention.

The biological activity of the compounds according to the invention was tested by using the above analysis. The values of the IC50measured and presented in the table below.

Example No.IC50(EGFR/BIO) (mm)
10,048
20,006
30,059
50,013
70,004
80,002
90,002

The output is: compounds of the present invention have significant activity in inhibiting the kinase activity of EGFR.

PHARMACOKINETIC ANALYSIS

Test Example 1: pharmacokinetic analysis of compounds of Example 1 and Example 5 of the present invention

1. Short description

Compounds of Example 1 and Example 5 of the present invention was administered intragastrically to rats to determine the concentration of drug in plasma at different time points by LC/MS/MS. Pharmacokinetic properties of the compounds of the present invention researched and evaluated in rats.

2. Protocol

2.1 Samples

Compounds of Example 1 and Example 5

2.2 Experimental animals

8 healthy adult SD rats, half male and half female, bought the firm SINO-BRITSH SIPPR/BK LAB. ANIMAL LTD., CO, license number: SCXK (Shanghai) 2003-0002

2.3 Preparation of test compounds

The exact number of compounds were weighed and uniformly crushed with 0.5% sodium salt of carboxymethyl cellulose, suspended with 1% tween 80 to 2.5 mg/ml suspension before use.

2.4 Introduction

8 healthy adult SD rats, half male and half female, after fasting overnight were injected compounds intragastrically at a dose of 25.0 mg/kg, in a volume of 10 ml/kg

2.5 sample Collection

8 healthy adult SD rats, half male and half female, were divided into 2 groups. After fasting during the night the rats were injected compounds intragastrically at a dose of 25.0 mg/kg of blood Samples (0.2 m is) was taken from the orbital sinus before the introduction and after 0.5, 1,0, 2,0, 3,0, 4,0, 5,0, 7,0, 9,0, 12,0, 24,0 and 30,0 hours after administration, and kept them in heparinised tubes and centrifuged for 10 minutes at 3500 rpm plasma Samples were stored at-20ºC until analysis. Rats fed 2 hours after injection.

3. Work

50 μl of plasma of rats taken at different time points after injection, was mixed with 50 ál of standard solution series to obtain the concentration in plasma 50,0,100, 200, 500, 1000, 2000, 5000 ng/ml was Added 150 μl of methanol, and then the mixture was stirred for 3 minutes using a vortex, and centrifuged for 10 minutes at 13500 rpm 10 μl of the supernatant was analyzed using LC-MS/MS. Average pharmacokinetic parameters were calculated using the software DAS 2.0.

4. Results pharmacokinetic parameters

Pharmacokinetic parameters of the compounds of the present invention is shown below.

RoomPharmacokinetic analysis (25 mg/kg)
Conc. plasmaThe area under the curveThe half-lifeAverage duration of stayClearanceThe apparent volume of distribution
Cmax(ág/ml)AUC (μg/ml*h)t1/2(h)MRT (h)CL/F (l/h/kg)Vz/F (l/kg)
Example 14,48±1,8852,58±38,96Android 4.04±1,397,78±1,890,76±0,533,71±1,68
Example 56,47±1,8152,81±23,593,4±0,457,66±0,750,53±0,182,6±0,94

Conclusion: the compounds of the present invention have good absorption in the pharmacokinetics and obviously improved pharmacokinetic characteristics.

Therapeutic effects against lung cancer xenografts of human Calu-3 in Nude mice

1. Short description

Evaluated therapeutic effect of the compound of Example 1 against lung cancer xenografts of human Calu-3 in Nude mice. The compound of Example 1 significantly inhibited growth of human lung cancer Calu-3, and test mice were well tolerated.

2. Purpose

Evaluated and compared therapeutic effects of the compounds of Examples is 1 and Example 5 against lung cancer xenografts of human Calu-3 in Nude mice.

3. The tested drugs

The name of the drug and party drugs: compounds of Example 1 and Example 5

Method of preparation: the Compound of Example 1 and Example 5 were prepared up to the appropriate concentration by using distilled water containing 0.1% tween-80.

4. Experimental animals

Nude mice BALB/cA aged 6 to 7 weeks, $, bought the company Slaccas Experimental Animal LTD., CO.

Certificate number: SCXK 2007 - 0005. Environment: the level of SPF (free of specific pathogens).

5. Experimental Protocol

Nude mice were inoculable subcutaneously cell lung cancer human Calu-3. After tumors grew to 150-250 mm3mice are randomly divided into groups (d0).

The volume of tumors and weight of mice was measured and recorded 2-3 times per week.

The formula tumor volume (V): V=1/2×a×b2and: length of the tumor, b: width of the tumor.

6. Short description

The compound of Example 1 significantly inhibited growth of human lung cancer Calu-3. Low dose (100 mg/kg) compound of Example 1 was reduced tumor volume on 2/6, high dose (200 mg/kg) compound of Example 1 was reduced tumor volume on 1/6 and completely destroyed another 1/6 of the tumor. Low dose (100 mg/kg) compound of Example 5 was reduced tumor volume by 3/6, high dose (200 mg/kg) compound of Example 5 was reduced tumor volume on 4/6. Also what about the, mouse had good tolerance to compounds of Example 1 and Example 5 in accordance with this Protocol introduction.

1. The compounds of formula (I) or their racemates, the enantiomers, diastereoisomers and their mixtures and their pharmaceutically acceptable salts:

where:
A is selected from the group consisting of a carbon atom or a nitrogen atom;
when A is a carbon atom, R1represents a C1-C6-alkoxyl; R2represents cyano;
when A represents a nitrogen atom, R1represents a hydrogen atom or a C1-C6-alkoxyl; where the specified C1-C6-alkoxyl optionally additionally substituted by one group C1-C6-alkoxyl; R2no;
R3represents a radical having the following formula:
or;
where:
D represents phenyl, where phenyl optionally additionally substituted by one or two halogen atoms;
T represents-O(CH2)r-;
L represents a pyridyl;
R4and R5each represents a hydrogen atom;
Represents a carbon atom;
R6and R7each independently selected from a hydrogen atom, or hydroxyl;
R8represents a hydrogen atom;
R 9represents a hydrogen atom or a C1-C6-alkyl;
r is 1; and
n is 2 or 3.

2. Connection on p. 1 or their racemates, the enantiomers, diastereoisomers and their mixtures and their pharmaceutically acceptable salts, where A represents a carbon atom, R1represents a C1-C6-alkoxyl; R2represents cyano.

3. Connection on p. 1 or their racemates, the enantiomers, diastereoisomers and their mixtures and their pharmaceutically acceptable salts, where A represents a nitrogen atom, R1represents a hydrogen atom; R2is missing.

4. Compounds according to any one of paragraphs.1-3 or their racemates, the enantiomers, diastereoisomers and their mixtures and their pharmaceutically acceptable salts, where n is equal to 2.

5. Connection on p. 1 or their racemates, the enantiomers, diastereoisomers and their mixtures and their pharmaceutically acceptable salts, include compounds having the following formula (II), and their racemates, the enantiomers, the diastereomers and their mixtures and their pharmaceutically acceptable salts:

where:
A is selected from the group consisting of a carbon atom or a nitrogen atom;
when A is a carbon atom, R1represents a C1-C6-alkoxyl; R2represents cyano;
when a represents a nitrogen atom, R1not only is em a hydrogen atom or a C 1-C6-alkoxyl; where the specified C1-C6-alkoxyl optionally additionally substituted by one group C1-C6-alkoxyl; R2no;
R3represents a radical having the following formula:
or;
where:
D represents phenyl, where phenyl optionally additionally substituted by one or two halogen atoms;
T represents-O(CH2)r-;
L represents a pyridyl;
R4and R5each represents a hydrogen atom;
R8represents a hydrogen atom;
R9represents a hydrogen atom or a C1-C6-alkyl;
r is 1; and
n is 2 or 3.

6. Connection on p. 5 or their racemates, the enantiomers, diastereoisomers and their mixtures and their pharmaceutically acceptable salts, where a represents a carbon atom; R1represents a C1-C6-alkoxyl; R2represents cyano.

7. Connection on p. 5 or their racemates, the enantiomers, diastereoisomers and their mixtures and their pharmaceutically acceptable salts, where A represents a nitrogen atom; R1represents a hydrogen atom; R2is missing.

8. Compounds according to any one of paragraphs.5-7 or their racemates, the enantiomers, diastereoisomers and their mixtures and their pharmaceutically priemel the appropriate salt, where n is equal to 2.

9. Connection on p. 1 or their racemates, the enantiomers, diastereoisomers and their mixtures and their pharmaceutically acceptable salts, where the compound is selected from the group consisting of:
and

10. The compounds of formula (IA),

where:
A is selected from the group consisting of a carbon atom or a nitrogen atom;
when A is a carbon atom, R1represents a C1-C6-alkoxyl; R2represents cyano;
when a represents a nitrogen atom, R1represents a hydrogen atom or a C1-C6-alkoxyl; where the specified C1-C6-alkoxyl optionally additionally substituted by one or more than one group C1-C6-alkoxyl; R2no;
R3represents a radical having the following formula:

where:
D represents phenyl, where phenyl optionally additionally substituted by one or two halogen atoms;
T represents-O(CH2)r-;
L represents a pyridyl; and
r is 1.

11. The method of obtaining compounds of formula (IA) under item 10, including:

the conversion of compounds of formula (IA_1) to obtain the compounds of formula (IA); where A, R1, R2and R3are as defined is prohibited in paragraph 10.

12. The method of obtaining compounds of formula (I) under item 1, including:

the interaction of compounds of formula (IA) with compounds of formula (IB) to produce compounds of formula (I); where A, B, n and R1-R9are as defined in paragraph 1.

13. The method of obtaining compounds of formula (II) under item 5, including:

the interaction of compounds of formula (IA) compounds of the formula (IIB) to obtain the compounds of formula (II); where A, n, R1-R5, R8and R9are as defined in paragraph 5.

14. The pharmaceutical composition having inhibitory activity against receptor tyrosinekinase EGFR or receptor tyrosinekinase HER-2 containing a therapeutically effective amount of the compounds according to any one of paragraphs.1-9 or their racemates, enantiomers, diastereomers and mixtures thereof, and their pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

15. A method of obtaining a pharmaceutical composition according to p. 14, including the Association of compounds of formula (I) under item 1 or their racemates, enantiomers, diastereomers and mixtures thereof, and their pharmaceutically acceptable salts, with pharmaceutically acceptable carriers or diluents.

16. The use of compounds of formula (I) according to any one of paragraphs.1-9 or their racemates, enantiomers, diastereomers and mixtures thereof, and the e their pharmaceutically acceptable salts, or use of the pharmaceutical composition according to p. 14 for obtaining a medicinal product for the treatment of diseases associated with protein kinases, where the protein kinase is selected from the group consisting of receptor tyrosinekinase EGFR or receptor tyrosinekinase HER-2.

17. The use of compounds of formula (I) according to any one of paragraphs.1-9 or their racemates, enantiomers, diastereomers and mixtures thereof, and their pharmaceutically acceptable salts, or use of a pharmaceutical composition for p. 14 for receiving the inhibitor receptor tyrosinekinase EGFR or an inhibitor of the receptor tyrosinekinase HER-2.

18. The use of compounds of formula (I) according to any one of paragraphs.1-9 or their racemates, enantiomers, diastereomers and mixtures thereof, and their pharmaceutically acceptable salts, or use of a pharmaceutical composition for p. 14 for obtaining a medicinal product for the treatment of cancer, where the cancer is selected from the group consisting of lung cancer, breast cancer, squamous cell carcinoma or gastric cancer.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1 or their stereoisomers or pharmaceutically acceptable salts possessing the properties of inhibitors of RNA polymerase HCV NS5B, and to methods for producing them. In general formula 1 R1 represents C1-C4alkyl; R2 and R3 represents fluorine, or R2 represents fluorine, while R3 represents methyl; one of R4 and R5 represents hydrogen, and the other of R4 and R5 represents C1-C6acyl optionally substituted by α-aminoacyl specified in a group containing (dimethylamino)acetyl, 1-tert-butoxycarbonylamino-2-methyl-propylcarbonyl, 1-methylpyrrolidine-2-carbonyl, 1-methylpiperidine-3-carbonyl and 1-methylpiperidine-4-carbonyl, R6 represents hydrogen, methyl, methoxy and halogen.

EFFECT: compounds can be used for treating and preventing viral infections, including hepatitis C, optionally with additional agents specified in an inhibitor of inosin-5-monophosphate dehydrogenase, eg Ribamidine, an inhibitor of hepatitis C protease C NS3, eg Asunaprevir (BMS-650032), an inhibitor of hepatitis C protease C NS3/4A, eg Sofosbuvir (TMC435), an inhibitor of RNA-polymerase NS5A, eg Daclatasvir (BMS-790052) or Ledipasvir (GS-5885).

18 cl, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 2-amino-1-((phosphonoxy)methyl)-3-(3-((4-((2-pyridinyloxy)methyl)phenyl)methyl)-5-isoxazolyl)pyridinium of formula: and salts thereof effective as an antimycotic agent, and to pharmaceutical compositions and therapeutic agents based on it and the use thereof in treating mycotic diseases.

EFFECT: what is presented is the new effective antimycotic agent with improved water solubility and safety.

6 cl, 16 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to derivatives of Ice formula and the use thereof in treating the diseases associated with thrombocyte aggregation ICE', wherein P(O)R5R8 is specified in R1 is specified in phenyl; W is specified in a bond, -O-, -NR3-; R2 is specified in alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, phenyl, heterocyclyl, or heteroaryl, alkoxycarbonyl alkyl, carboxyalkyl or phenyl alkyl; R3 is specified in hydrogen or alkyl; or R2 and R3 form a ring together with a nitrogen atom; Ra is specified in hydrogen or methyl; R4 is specified in alkoxy; n is from 0 to 3; m is from 0 to 1; V is specified in a bond and phenyl; R5 and R8 are specified in hydroxyl, phenyloxy, benzyloxy, -O-(CHR6)-O-C(=O)-R7, -O-(CHR6)-O-C(=O)-O-R7, -O-(CHR6)-C(=O)-O-R9, -NH-(CHR10)-C(=O)-O-R9, -NH-C(CH3)2-C(=O)-O-R9; q is equal to 2; R6 is specified in hydrogen and alkyl; R7 is specified in alkyl or cycloalkyl; R9 is specified in alkyl; R10 is specified in hydrogen, alkyl, phenyl or benzyl; and R11 is specified in hydrogen, alkyl or alkoxy.

EFFECT: new P2Y12 receptor antagonists are produced.

25 cl, 126 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.

EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

FIELD: chemistry.

SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).

EFFECT: obtaining of new biologically active substances.

184 cl, 52 tbl, 62 ex

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

The invention relates to organic chemistry, specifically to methods of producing phosphoric esters of thiamine, which (namely fosfotiamina and cocarboxylase hydrochloride) is used in medicine as drugs

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new isatin-5-sulphonamide derivatives of general formula or their physiologically acceptable salts, wherein R represents phenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, tetrahydropyranyl, diazine or triazolyl methyl optionally substituted by one C1-6alkyl, which can be additionally substituted by one halogen; R' represents phenyl optionally substituted by one or two halogens, or triazolyl optionally substituted by one C1-6alkyl which can be additionally substituted by one halogen; provided R means phenyl, R' represents optionally substituted triazolyl, pharmaceutical compositions containing the above derivatives, using them as molecular imaging agents, using them in diagnosing or treating diseases or disorders related to apoptosis dysregulation, methods for synthesis of the above derivatives, methods for molecular imaging of caspase activity and apoptosis, and methods for assessing the therapeutic exposure of the analysed compound on caspase activity.

EFFECT: new isatin-5-sulphonamide derivatives are described.

27 cl, 26 dwg, 4 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a heterocyclic compound of formula I and its pharmaceutically acceptable salt, wherein if a chemical valency permits, i represents 1 or 2, R1 represents H; a linear (C1-C4) alkyl group, R2 represents H, Cl or F, X represents either N, or CR3, R3 represents H; halogen; a linear (C1-C4) alkyl or (C1-C4) alkoxyl group, Y represents Z represents O or NRx, Rx represents H or a linear or branched (C1-C4) alkyl, k is equal to 2, 3 or 4, n and p independently represents 2, and a sum of n+p cannot exceed 4, T represents H or a linear (C1-C4) alkyl group; T′ represents a linear C1-C3 alkyl chain substituted by either (C1-C6)-dialkylaminogroup, or a 5-6-merous saturated heterocycle containing one nitrogen atom and optionally containing the second heteroatom specified in O, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; or a 5-merous saturated heterocycle containing one nitrogen atom, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; r represents zero, 1; R′ represents di(C1-C4)alkylamino, (C1-C4)alkoxy; except for the compounds specified in the clause. The invention also refers to a pharmaceutical composition based on the compound of formula (I), using the compound of formula (I) and to a method of treating diseases, in which the hedgehog signalling pathway modulation is effective.

EFFECT: there are prepared new heterocyclic compounds possessing t effective biological properties.

20 cl, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the derivatives of pyrimidine with formula I, where Z is a carbon atom or a nitrogen atom; Y is a carbon atom or a nitrogen atom, where one of the Z and Y is a nitrogen atom; A, D and E are chosen from the carbon atom and nitrogen atom; R1 is hydrogen or methyl, when D is a carbon atom; R2 is hydrogen or an amine group; R3 is hydrogen, methyl, trifluoromethyl or (C0-C1) alkylaryl; R5 is hydrogen or methyl; L-R4 is chosen from: and R6 is chosen from hydrogen and methyl; R7 is chosen from hydrogen, methyl, (C1-C4)alkyl-OH and (CO)OCH3, R7a and R7b are independently chosen from hydrogen and methyl; R8 is chosen from halogen, hydrogen, hydroxy, (CO)OH, (CO)OCH3, O(C1-C4) alkyl, O(C1-C4)alkyl(C6-C10)aryl, O(C1-C4)alkyl(C2-C9)heterocyclyl, O(EtO)1-3(C1-C4)alkyl and OCF3; and R11 is chosen from hydrogen, methyl and O(C1-C4) alkyl. The invention also relates to a pharmaceutical formulation for curing of cancer which contains the compounds with the formula I, to the usage of the compounds with the formula I to produce a medicinal agent and pharmaceutical formulation and to the cancer curing method.

EFFECT: compounds with the formula I aimed at cancer curing.

20 cl, 3 tbl, 109 ex

Diaryl ethers // 2528231

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), to its possible stereoisomers, or to its pharmaceutically acceptable salts, where R and R1, independently on each other, represent benzoyl, substituted with one substituent, each of which is independently selected from halogen or -C(=O)-Het, where Het is optionally substituted with two substituents, independently selected from C1-4alkyl, or a group of formula -C(=O)-CH(Rx)-R6, C1-6alkyloxycarbonyl, a group of formula R8-O-C(=O)-HN-CH(R7)-C(=O)- or -C(=O)-C(=O)-phenyl; R6 represents C1-4alkyl, C3-6cycloalkyl, benzyl or phenyl, where phenyl can be optionally substituted with one, two or three substituents, each of which is independently selected from halogen, C1-6alkyl, methoxy, trifluoromethoxy, or two substituents at adjacent atoms of the ring together with a phenyl ring form benzodioxol, and where C1-4alkyl is substituted with diC1-6alkylamino, phenylsulphonyl, Het, and where benzyl is substituted with one substituent, each of which is independently selected from halogen, methoxy; Rx is selected from hydrogen, hydroxyl, diC1-6alkylamino, imidazolyl, Het represents a heterocyclic group, containing one or two heteroatoms, selected from O and N, and containing 5-6 atoms in a ring, where the said heterocyclic ring is bound with the carbonyl carbon atom through the ring carbon atom and where at least one of the said heteroatoms is adjacent to the said ring carbon atom, R2 and R3, independently on each other represent hydrogen; R4 and R5, independently on each other represent hydrogen or methoxy; each R7 independently represents phenyl or C1-4alkyl optionally substituted with methoxy; and R8 represents C1-4alkyl. The invention also relates to particular compounds and a pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel compounds, useful as HCV inhibitors.

11 cl, 4 tbl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to application of bis(2,4,7,8,9-pentamethyldipyrrolylmethen-3-yl)methane dihydrobromide as fluorescent zinc (ii) cation sensor.

EFFECT: invention will make it possible to increase fluorescent activity of heterocyclic organic compound with respect to zinc (II) ion in presence of other ions of metals.

1 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula or to its therapeutically acceptable salt, where A1 represents N or C(A2); A2 represents H; B1 represents H, OR1 or NHR1; D1 represents H; E1 represents H; Y1 represents CN, NO2, F, Cl, Br, I, R17 or SO2R17; R1 represents R4 or R5; Z1 represents R26 or R27; Z2 represents R30; Z1A and Z2A both are absent; L1 represents R37; R26 represents phenylene; R27 represents indolyl; R30 represents piperasinyl; R37 represents R37A; R37A represents C2-C4 alkylene; Z3 represents R38, R39 or R40; R38 represents phenyl; R39 represents benzodioxilyl; R40 represents C4-C7cycloalkenyl, heterocycloalkyl, which represents monocyclic six- or seven-member ring, containing one heteroatom, selected from O, and zero of double bonds, or azaspiro[5.5]undec-8-ene; the remaining values of radicals are given in i.1 of invention formula. Invention also relates to pharmaceutical composition, based on claimed compound.

EFFECT: novel compounds, which can be applied in medicine for treatment of diseases, in the process of which anti-apoptotic Bcl-2 protein is expressed, are obtained.

8 cl, 2 tbl, 411 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1.0:

,

where Q represents tetrahydropyridinyl ring substituted. R5, R1 are selected from: (1) pyridyl, substituted with substituent, selected from group, consisting of: -O-CH3, -O-C2H5, -O-CH(CH3)2, and -O-(CH2)2-O-CH3, R2 is selected from group, consisting of: -OCH3 and -SCH3; and R5 is selected from (a) substituted triazolylphenyl-, where triazolyl is substituted with one or two alkyl groups, selected from group, consisting of: -C1-C4alkyl, (b) substituted triazolylpheenyl-, wheretriazolyl is substituted on nitrogen atom with -C1-C4alkyl, (c) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2alkylene-O-C1-C2alkyl, (d) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2-C4alkylene-O-CH3, and (e) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with hydroxy-substituted -C1-C4alkyl, and where phenyl is optionally substituted with from 1 to 3 substituents, independently selected from group, consisting of halogen; and their pharmaceutically acceptable salts and solvates, which are claimed as ERK inhibitors.

EFFECT: obtaining pharmaceutically acceptable salts and solvates, claimed as ERK inhibitors.

15 cl, 2 tbl, 32 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new isatin-5-sulphonamide derivatives of general formula or their physiologically acceptable salts, wherein R represents phenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, tetrahydropyranyl, diazine or triazolyl methyl optionally substituted by one C1-6alkyl, which can be additionally substituted by one halogen; R' represents phenyl optionally substituted by one or two halogens, or triazolyl optionally substituted by one C1-6alkyl which can be additionally substituted by one halogen; provided R means phenyl, R' represents optionally substituted triazolyl, pharmaceutical compositions containing the above derivatives, using them as molecular imaging agents, using them in diagnosing or treating diseases or disorders related to apoptosis dysregulation, methods for synthesis of the above derivatives, methods for molecular imaging of caspase activity and apoptosis, and methods for assessing the therapeutic exposure of the analysed compound on caspase activity.

EFFECT: new isatin-5-sulphonamide derivatives are described.

27 cl, 26 dwg, 4 tbl, 11 ex

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