Naphthalene carboxamide derivatives as protein kinase and histone deacetylase inhibitors, methods for preparing and using them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to naphthalene carboxamide derivatives of general formula I which possess the properties of protein kinase or histone deacetylase inhibitors. The compounds can find application for preparing a drug for treating inflammatory diseases, autoimmune diseases, oncological disease, diseases of the nervous system and neurodegenerative diseases, allergies, asthma, cardiovascular diseases and metabolic diseases or disease related to hormonal diseases. In general formula I: , Z represents CH or N; each of the groups R1, R2 and R3 represents hydrogen, halogen, alkyl, alkoxy or trifluoromethyl; R4 represents or X represents a benzene ring or a pyridine ring; R5 represents one or more substitutes specified in a group consisting of hydrogen, halogen, alkyl, alkoxy or trifluoromethyl. The invention also refers to a method for preparing the above compounds, a pharmaceutical preparation and using them.

EFFECT: preparing the compounds which possess the properties of protein kinase or histone deacetylase inhibitors.

13 cl, 10 tbl, 6 dwg

 

The scope to which the invention relates

The present invention relates to a derivative naphthaleneboronic (naphthalide), which have activity of inhibiting protein kinases and inhibition of orally bioavailable, to methods for their preparation and their clinical application in the treatment of diseases associated with impaired activity of protein kinases and violation activity discontiuation.

Prior art

Protein kinases represent a family of enzymes that catalyze the phosphorylation of proteins, in particular, hydroxy-group specific residues of tyrosine, serine and threonine in proteins. Protein kinases play a key role in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell differentiation, survival of the cells, the response of the host organism to environmental factors, immune response and angiogenesis. Many diseases are associated with abnormal cellular responses triggered by a regulation of the protein kinase. These diseases include inflammatory diseases, autoimmune diseases, cancer, diseases of the nervous system and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, allergies, asthma, and diseases associated with hormonal what archenemy (Tan, S-L., 2006,J. Immunol., 176: 2872-2879; Healy, A. et al., 2006,J. Immunol., 177: 1886-1893; Salek-Ardakani, S. et al., 2005,J. Immunol., 175: 7635-7641; Kim, J. et al., 2004,J. Clin. Invest., 114: 823-827). Therefore, considerable efforts have been made to identify inhibitors of protein kinases, which are effective as therapeutic agents against these diseases.

Protein kinases can generally be divided into two classes: proteincontaining (PTK) and the serine-trionychinae (STK).

Proteincontaining (PTK) can be divided into two classes: retransmission tyrosine kinase and has tyrosinekinase activity transmembrane receptors of growth factors (RTK). Currently identified at least 19 distinct RTK subfamilies, such as the receptor for epidermal growth factor (EGFR), a receptor for vascular endothelial growth factor (VEGFR), the receptor for platelet-derived growth factor (DERIVED) and the receptor fibroblast growth factor (FGFR).

The family of the receptor for epidermal growth factor (EGFR) includes four have tyrosinekinase activity of transmembrane receptors of growth factors: HER1, HER2, her3, and HER4. Linking specific set of ligands of the receptor promotes the dimerization of EGFR leads to receptor autophosphorylation on tyrosine residues (Arteaga, C-L., 2001,Curr. Opin. Oncol., 6: 491-498). After autophosphorylated receptor, become activated and W which are located below in the course of transcription pathways of EGFR signaling. Path signaling EGFR was associated with neoplastic processes, including development, cell cycle, inhibition of apoptosis, motility, invasion and metastasis of tumor cells. Activation of EGFR stimulates vascular endothelial growth factor (VEGF), which is a primary inducer of angiogenesis (Petit, A-M. et al., 1997,Am. J. Pathol., 151: 1523-1530). In experimental models, rasagulla mediated EGFR transmission signals associated with oncogenesis (Wikstrand, C-J. et al., 1998,J Natl Cancer Inst., 90: 799-800). Mutations leading to continuous activation, amplification, and excess expression of EGFR protein, observed in many human tumors, including tumors of the breast, lung, ovary and kidney. These mutations are determining the aggressiveness of tumors (Wikstrand, C-J. et al.,1998,J Natl Cancer Inst., 90: 799-800). Overexpression of EGFR is often observed in non-small cell lung cancer (NSCLC). The EGFR activity can also be inhibited or blocked extracellular binding domain of the ligand with the use of anti-EGFR antibodies, or by the use of small molecules that inhibit tyrosinekinase EGFR, thus leading to inhibition below during transcription of path components of EGFR (Mendelsohn, J., 1997,Clin. Can. Res., 3: 2707-2707).

Vascular endothelial growth factor (VEGF) secreted by almost all Suli is different tumors and is associated with the tumor stroma in response to hypoxia. He is highly specific for vascular endothelium and regulates proliferation and vascular permeability. Overexpression of VEGF levels correlated with increased microvascular density, recurrence of cancer and decreased survival (Parikh, A-A., 2004;,Hematol. Oncol. Clin. N. Am., 18:951-971). There are 6 different ligands of the receptor for VEGF, VEGF-A through-E and placental growth factor. The ligands bind with specific receptors on endothelial cells, mainly VEGFR-2. The binding of VEGF-A, VEGFR-1 induces migration of endothelial cells. Binding to VEGFR-2 induces proliferation, permeability, and survival of endothelial cells. It is believed that VEGFR-3 mediates lymphangiogenesis. Binding with VEGF receptors VEGFR-2 leads to activation and autophosphorylation of the intracellular tyrosine kinase domains, which then trigger other intracellular cascades that transmit signals (Parikh, A-A., 2004,Hematol. Oncol. Clin. N. Am., 18:951-971).

Serine-trionychinae (STK) are predominantly intracellular, although there are several receptor kinases type STK. STK represent the most common forms of cytosolic kinases that perform their function in part of the cytoplasm, distinct from cytoplasmic organelles and the cytoskeleton.

Glycogen synthase-kinase-3 (GSK-3) is a serine-treanonretain is the nae, consisting of α - and β-isoforms, each of which are encoded by specific genes. It was found that GSK-3 phosphorylates and modulates the activity of a number of regulatory proteins. GSK-3 was associated with the development of various diseases, including diabetes, Alzheimer's disease, Central nervous system disorders, such as manic-depressive disorder and neurodegenerative diseases, and hypertrophy of cardiomyocytes (Haq, et al., 2000,J. Cell Biol., 151: 117).

Aurora-2 is a serine-trainingtraining, which was associated with cancer in humans, such as cancer of the colon, breast cancer and other solidne tumors. Believe that this kinase is involved in the phosphorylation of proteins that regulate the cell cycle. In particular, Aurora-2 may play a role in the regulation of the accurate segregation of chromosomes during mitosis.

Dysregulation of the cell cycle can lead to cell proliferation and other pathological processes. It was found that in the tissue of the colon cancer human protein Aurora-2 redundantly expressed (Schumacher, et al., 1998,J. Cell Biol., 143: 1635-1646; Kimura et al., 1997,J. Biol. Chem., 272: 13766-13771).

Cyclin-dependent kinases (cdks) are serine-trainingtraining, which regulates the division of mammalian cells. To date, were identified 9 subunits of the kinase (CDK 1-9). Each is inasa is associated with certain regulatory partner together and is active catalytic part. Uncontrolled proliferation is a hallmark of malignant cells, and impaired regulation of CDK function occurs with high frequency in many important solidnyh tumors. CDK2 and CDK4 are of special interest, because their activity is often violated when a wide variety of cancer people.

Raf-kinase below during transcription effector of oncoproteinrasthat is a key mediator of the transduction of signals from the cell surface to the cell nucleus. Inhibition of raf-kinase is correlatedin vitroandin vivowith the inhibition of growth of various types of human cancers (Monia et al., 1996,Nat. Med., 2: 668-675).

Other serine-trionychinae include protein kinase A, B and C. These kinases, known as PKA, PKB and PKC play a key role in the transduction of signals.

There have been many attempts to identify small molecules that act as inhibitors of protein kinases, which can be used in the treatment of diseases associated with abnormal activity of protein kinases. For example, the cyclic compounds (U.S. patent No. 7151096), bicyclic compounds (U.S. patent No. 7189721), tricyclic compounds (U.S. patent No. 7132533), (2-oxindol-3-methylidene), derivatives of acetic acid (U.S. patent No. 7214700), derivatives of 3-(4-aminopyrrolo--Ilmarinen)-2-indolinone (U.S. patent No. 7179910), condensed pyrazole derivatives (U.S. patent No. 7166597), compounds aminopyrazine (U.S. patent No. 7157476), pyrrole substituted 2-indole compounds (U.S. patent No. 7125905), triazole compounds (U.S. patent No. 7115739), pyrazoline-substituted hintline compounds (U.S. patent No. 7098330) and indazol compounds (U.S. patent No. 7041687) - all have been described as inhibitors of protein kinases. Several inhibitors of protein kinases, such as Gleevec, Sten and sorafenib, have been successfully approved by the FDA (the food and drug USA) for anti-cancer therapy. Their clinical use has demonstrated clear advantages over existing types of chemotherapy treatment, stimulating the continued interest in innovation based on the mechanisms of treatment and the improvement of chemical frames to identify new compounds with excellent oral bioavailability, better antitumor activity and lower toxicity.

Summary of the invention

One purpose of the present invention is the obtaining of certain derivative naftalina, which is capable of selectively inhibit protein kinase and discontiuation. Another objective of the present invention is to develop methods for obtaining such compounds.

<> Another purpose of this invention is the provision of clinical application of these compounds in the treatment of diseases associated with abnormal activity of protein kinases and abnormal activity of orally bioavailable.

Brief description of drawings

Figure 1 graphically illustrates the antitumor activity of compound 31 in naked mice with transplanted tumor of human lung cancer A549, where the Vehicle is media, Sutent is an existing drug sunitinib and comp 31 represents the connection 31.

Figure 2 graphically illustrates the antitumor activity of compound 31 in naked mice with transplanted tumor of colon cancer human HCT-8, where the Vehicle is media, Sutent is an existing drug sunitinib and comp 31 represents the connection 31.

Figure 3 graphically illustrates the antitumor activity of compound 31 in naked mice with transplanted tumor of liver cancer man SSMC7721 where the Vehicle is media, Sutent is an existing drug sunitinib and comp 31 represents the connection 31.

Figure 4 graphically illustrates the antitumor activity of compound 33 and compound 34 in naked mice with transplanted tumor of colon cancer human HCT-8, where the Vehicle is media, utent represents an existing drug sunitinib, comp 33 represents the connection 33, and 34 com is the connection 34.

Figure 5 graphically illustrates the antitumor activity of compound 33 and compound 37 in naked mice with transplanted tumor of colon cancer human HCT-8, where the Vehicle is media, Sutent is an existing drug sunitinib, comp 33 represents the connection 33, and com 37 represents a connection 37.

6 graphically illustrates the antitumor activity of compound 33 and compound 37 in naked mice with transplanted tumor of liver cancer man SSMC7721 where the Vehicle is media, Sutent is an existing drug sunitinib, comp 33 represents the connection 33, and com 37 represents a connection 37.

A detailed description of the invention

Proteins discontiuation (HDAC) play a key role in the regulation of gene expressionin vivoby changing the accessibility of transcription factors to genomic DNA. In particular, proteins HDAC removes the acetyl group balances acetylglycine on the histones, which can lead to nucleosomal the remodeling (Grunstein, M., 1997,Nature, 389: 349-352). HDAC proteins, because of their leadership role in gene expression associated with various cellular phenomena, including cell cycle regulation, cell proliferation, differentiation, reprogramming Genn is th expression and the development of cancer (Ruijter, A-J-M., 2003, Biochem. J., 370: 737-749; Grignani, F., 1998, Nature, 391: 815-818; Lin, R-J., 1998, 391: 811-814; Marks, P-A., 2001, Nature Reviews Cancer, 1: 194). Pathological deacetylation caused by dysregulation of the deacetylation of histones associated with various diseases such as syndrome Rubinstein-Taybi syndrome fragile X-chromosome, neurodegenerative diseases, cardiovascular and metabolic disease, rheumatoid disease, leukemia and other cancers (Langley B et al., 2005, Current Drug Targets-CNS &Neurological Disorders, 4: 41-50). In experiments it has been demonstrated that humans and animals HDAC inhibitors reduce the growth of tumors, including lung cancer, stomach cancer, breast cancer, prostate cancer, lymphoma and the like (Dokmanovic, M.,2005, J. Cell Biochenm., 96: 293-304).

HDAC mammals can be divided into three classes according to sequence homology. Class I consists of a protein similar to yeast Rpd3 (HDAC 1, 2, 3, 8 and 11). Class II consists of proteins that are similar to yeast HDA1 (HDAC 4, 5, 6, 7, 9 and 10). Class III consists of proteins that are similar to yeast SIR2 (SIRT 1, 2, 3, 4, 5, 6 and 7).

The activity of HDAC1 is associated with cell proliferation that is characteristic of cancer. In particular, mammalian cells with knockdown of the expression of HDAC1 using siRNAs (small interfering RNA) had antiproliferative action (Glaser, K-B., 2003,Biochem. Biphys. Res. Comm., 310: 529-536). Although mice with knockdown of HDAC1 was embryonic lethal mutation derived stem cells showed altered cell growth (Lagger, G., 2002,EMBO J., 21: 2672-2681). Mouse cells, excessively expressing HDAC1 showed elongation phase G2and M and reduced growth rate (Bartl. S., 1997, Mol. Cell Biol., 17: 5033-5043). Therefore, published data imply the involvement of HDAC1 in cell cycle regulation and cell proliferation.

HDAC2 regulates the expression of many fetal myocardial protein isoforms. Failure HDAC2 or chemical inhibition discontiuation can prevent re-expression of fetal genes and attenuate cardiac hypertrophy. Resistance to hypertrophy is associated with increased expression of the gene encoding Inositol polyphosphate-5-phosphatase f (Inpp5f), leading to activation of glycogen synthase kinase 3β (Gsk3β) by inactivation of the proto-oncogene thymoma (Akt) and 3-phosphoinositide-dependent protein kinase-1 (Pdk1). In contrast, HDAC2 transgenic mice had enhanced hypertrophy associated with inactivated Gsk3β. Chemical inhibition of activated Gsk3β has allowed adults with HDAC2 deficiency become susceptible to hypertrophic stimulation. These results suggest that HDAC2 is an important molecular target of HDAC inhibitors in heart is that HDAC2, and Gsk3β are components of the regulatory path, providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure (Trivedi, C-M., 2007,Nat. Med,.13: 324-331).

HDAC3 is maximally expressed in proliferating cells of the crypts in a healthy gut. Silencing of HDAC3 expression in cell lines colon cancer resulted in inhibition of cell growth, reduced survival and increased apoptosis. Similar results were observed for HDAC2 and, to a lesser extent, for HDAC1. The silencing of HDAC3 gene also selectively caused the expression of alkaline phosphatase, a marker of maturation of cells of the colon. Overexpression of HDAC3 inhibited basal and induced by butyrate transcription of p21, whereas the silencing of HDAC3 stimulated promoter activity and expression of p21. These data identify HDAC3 as gene regulation which is disrupted in cancer of the colon of a person and as a new regulator of maturation of cells of the colon and expression of p21 (Wilson, A-J., 2006,J. Biol. Chem., 281: 13548-13558).

HDAC6 is a subtype of the HDAC family, which will deacetylase alpha-tubulin and increases the mobility of cells. Using quantitative polymerase chain reaction with reverse transcription and Western blotting in nine cell lines derived from p is oracletool carcinoma of the oral cavity (OSCC) and normal keratinocytes of the oral cavity (NOK), HDAC6 mRNA and protein expression is usually stimulated in all cell lines, compared with NOK. The immunofluorescence analysis revealed HDAC6 protein in the cytoplasm of OSCC cell lines. Like OSCC cell lines, stimulation of HDAC6 was evident by the level and mRNA (74%), and protein (51%) of primary tumors OSCC person. Among the analyzed clinical variables was found that the clinical stage of the tumor is associated with States of expression of HDAC6. The analysis indicated a significant difference between the level of expression of HDAC6 between tumors at an early stage (stages I and II) and late stages (stage III and IV) (P=0,014). These results suggest that the expression of HDAC6 may correlate with aggressiveness of the tumor, and provide keys for the planning of new treatments (Sakuma, T., 2006,Int. J. Oncol., 29: 117-124).

Epigenetic silencing of functional chromosomes HDAC represents one of the main mechanisms that occur in many pathological processes, which are associated with the function of the genes repressed or reprogrammed HDAC activity that leads to loss of phenotypes in the final regulation of the differentiation, maturation and growth and loss of functional activity of the tissues. For example, genes suppressor tumors are often subjected to silencing during development of cancer, and the HDAC inhibitor can suppress e is cpressey these genes suppression tumors, leading to growth inhibition and cell differentiation (Glaros S, et al., 2007, Oncogene June 4, in press; Mai, A, et al., 2007, Int J Biochem Cell Bio., April 4, in press; Vincent A. et al., 2007, Oncogene, April 30, in press; unpublished data of the applicants). The repression of the structural genes, such as FXN with Friedrich's ataxia and SMN in spinal muscular atrophy, can be removed by HDAC inhibitors, which leads to reexpress FXN gene and SMN and resume their functions in tissues (Herman D et al., 2006, Nature Chemical Biology, 2(10): 551-8; Avila AM, et al., 2007, J Clinic Investigation, 117(3): 659-71; de Bore J, 2006, Tissue Eng. 12(10): 2927-37). Induction of expression of the entire gene family of MHC class II by reprogramming "hot spots" HDAC in chromosome 6p21-22 HDAC inhibitor further expands epigenetic modulation of immune recognition and immune response (Gialitakis M et al., 2007, Nucleic Acids Res., 34(1);765-72).

Identified several classes of HDAC inhibitors, including (1) short-chain fatty acids, such as butyrate and phenylbutyrate; (2) organic hydroxamic acids, for example, suberoylanilide acid (SAHA), trichostatin A (TSA); (3) cyclic tetrapeptide containing portion in the form of 2-amino-8-oxo-9,10-expositional (AOE), for example, trioxin and HC-toxin; (4) cyclic tetrapeptide no part in the form of AOE, for example, apicidin and FK228; and (5) benzamide, for example, MS-275 (EP0847992A1, US2002/0103192A1, WO02/26696A1, WO01/70675A2, WO01/18171A2). Although HDAC inherited is very promising biological role as a drug target the success of the drug SAHA, manufactured by Merck, currently limited to the treatment of cutaneous T-cell lymphoma, while there were no reports of high efficiency of this treatment when the main solidnyh tumors. Therefore there is a need in the discovery of new compounds with higher inhibitory activity against HDAC and activity against cancer, with a more selective inhibition of different subtypes of HDAC and lower toxicity.

Favorite metaphor developers medicines against cancer for a long time was targeted therapy. The hope was to create drugs that can kill tumor cells as a specific target and destroy tumor cells, at the same time leaving normal cells undamaged. However, malignant cells may use multiple biological triggers and ways to grow and spread throughout the body. Defeat them in the form of one target will also cause their rearrangement and redistribution of new ways of growth. This realization has led to the development of methods of combination targeted therapy, which become the new paradigm for cancer treatment. Currently razrabatyvaut the several kinase inhibitors, with multiple targets, and two of them - sorafenib, Sutin, already approved in the United States. For example, sorafenib, developed by Bayer Pharmaceuticals, is the first drug aimed on the way RAF/MEK/ERK (involved in cell proliferation) and the cascade of signaling VEGFR2/PDGFRβ (participating in angiogenesis). This drug was first approved in December 2005, regarding the running of cancer of the kidney. However, the data targeted therapy, while effective against some solidnyh tumors, but far from satisfying from the point of view of achieving the best efficiency while maintaining acceptable side effects related to treatment against other solidnyh tumors.

The present invention relates to new chemical compounds which combine antiangiogenic and antiproliferative activity of RTK inhibitors together with inducing differentiation, immunomodulatory, stopping the cell cycle and inducing apoptosis activity of HDAC inhibitors to achieve the best efficacy against solidnyh tumors, while simultaneously overcoming side effects such as hypertension, QT prolongation in the EKG, the regression of the thyroid gland, skin rashes and discoloration of the skin and pain associated with currently available on the market RTK inhibitors.

Often the spine, the present invention relates to a compound having a structure represented by formula (I):

including its free form, salt form, enantiomer, diastereoisomer or a hydrate

where

Z represents CH or N;

each of the groups R1, R2and R3represents hydrogen, halogen, alkyl, alkoxy or trifluoromethyl;

R4is

or

X represents a benzene ring or a pyridine ring;

R5represents one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and trifloromethyl.

In a preferred embodiment, the compounds of the present invention are compounds of formula (I), where

Z represents CH;

each of the groups R1, R2and R3represents hydrogen, halogen, alkyl, alkoxy or trifluoromethyl;

R4is

or

X represents a benzene ring or a pyridine ring;

R5represents one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and trifloromethyl.

In another preferred embodiment, compounds according to the present invention with the battle of the compounds of formula (I), where

Z represents CH;

each of the groups R1, R2and R3represents hydrogen or alkoxy;

R4is

or

X represents a benzene ring or a pyridine ring;

R5represents one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and trifloromethyl.

In another preferred embodiment, compounds according to the invention are compounds of formula (I), where

Z represents CH;

each of the groups R1and R2represents hydrogen or methoxy;

R3represents H;

R4is

or

X represents a benzene ring or a pyridine ring;

R5represents one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and trifloromethyl.

In another preferred embodiment, compounds according to the invention are compounds of formula (I), where

Z represents CH;

each of the groups R1and R2represents hydrogen or methoxy;

R3represents H;

R4is

or

X represents the be the ash ring or pyridine ring;

R5represents H or F.

Used in the present description, the term "halogen" means fluorine, chlorine, bromine or iodine.

Used in the present description, the term "alkyl" includes linear, branched or cyclic alkali, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Used in the present description, the term "alkoxy" means a group formed by attaching alkyl radical to the oxygen atom, where the oxygen atom has the ability to free associate. Its examples include methoxy, ethoxy, propoxy, butoxy, pentox, isopropoxy, tert-butoxy, cyclopropane, cyclohexyloxy and the like.

Compounds of the present invention can be obtained in the following way:

The compound of formula (II) is condensed with the compound of formula (III) to obtain the compound (I). The condensation reaction is carried out by use of a peptide condensing agent as catalyst, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole (CDI) and so the Reaction can be conducted at temperatures from 0 to 80°C for 4 to 72 hours. Solvents that can magalismontanum, represent normal solvents, such as benzene, toluene, tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N-dimethylformamide, etc. If necessary, a base such as sodium hydroxide, triethylamine or pyridine may be added to the reaction system.

The compounds of formula (II) can be obtained as follows:

Commercially available 6-hydroxynaphthoic acid is heated in the presence of cesium carbonate and appropriately substituted 4-chlorhydrin (IV) in DMSO (dimethylsulfoxide) to obtain naftowych acids (II). The reaction may be conducted at a temperature of from 130 to 140°C for 3-24 hours.

The compounds of formula (III) are commercially available or are obtained as follows:

Commercially available compound (V) is condensed with commercially available compound (VI) to obtain compound (VII). The condensation reaction is carried out using a peptide condensing agent as catalyst, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole (CDI) and so the Reaction can be conducted at temperatures from 0 to 60°C for 2-72 hours. Solvents that can be used are normal is these solvents, such as benzene, toluene, tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N-dimethylformamide, etc. If necessary, a base such as sodium hydroxide, triethylamine or pyridine, may be added to the reaction system.

The compound (VII) is dissolved in methanol and hereroense using 5% palladium on charcoal as catalyst to yield compound (IIIa). The reaction may be conducted at room temperature. If necessary, the reaction system may be added acid, such as sulphuric acid.

Compounds represented by formula (I)can be purified by conventional means of separation, such as extraction, recrystallization, column chromatography and the like.

Compounds represented by formula (I), is able to inhibit protein kinases and discontiuation, and therefore can be used in the treatment of diseases associated with abnormal activity of protein kinase and abnormal activities discontiuation. In particular, they are highly effective against hematologic malignancies and solidnyh tumors.

Compounds represented by formula (I)may be formulated in conventional pharmaceutical preparations such as tablets, capsules, powders, syrups, solutions, suspensions, injectable preparations, ointments, and things under the major. The preparations may contain the compound of formula (I) as an active ingredient together with pharmaceutically acceptable carriers, excipients and diluents. This product usually contains from 0.5 to 70%, preferably from 1 to 20 wt%. the active ingredient.

In the present invention, pharmaceutically acceptable carriers, excipients and diluents include, without limitation those listed in "Hubook of Pharmaceutical Excipients" (American Pharmaceutical Association, October, 1986).

The compounds presented in the present description by the formula (I)can clinically be introduced mammals, including humans, orally or by injection. Preferably ingested by. Enter the dosage is in the range from 0.0001 to 200 mg/kg of body weight per day, preferably in the range from 0.01 to 100 mg/kg of body weight per day and most preferably in the range from 0.1 to 50 mg/kg of body weight per day. However, the optimum dosage varies among different treatment of individuals, in General, initially introduced a smaller dose, and then made her speed increased.

Representative compounds of the present invention are shown below in table 1. The numbers of the compounds correspond to the numbers of examples in the" Examples "section. That is, the synthesis of compound 1, as shown in table 1, described in "Example 1", and the synthesis of the value 44, as shown in table 1, described in Example 44".

Table 1
Representative compounds of the present invention
ExampleStructureName
16N-(2-AMINOPHENYL)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
17N-(2-amino-4-forfinal)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
18N-(2-amino-4-were)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
19N-(2-amino-4-methoxyphenyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
20N-(2-amino-4-chlorophenyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime

tr>
21N-(2-amino-4-bromophenyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
22N-(2-amino-4-triptoreline)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
23N-(4-((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
24N-(4-((2-amino-4-forfinal)-carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
25N-(2-AMINOPHENYL)-6-((2-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide)methyl) nicotinamide

26N-(2-amino-4-forfinal)-6-((2-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide)methyl) nicotinamide
27 N-(3-((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
28N-(4-((2-amino-4-were)-carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
29N-(4-((2-amino-4-methoxyphenyl)-carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
30N-(4-((2-amino-4-triptoreline) carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime

31N-(2-AMINOPHENYL)-6-(7-methoxyquinoline-4-yloxy)-1-naptime
32N-(2-amino-4-forfinal)-6-(7-methoxyquinoline-4-yloxy)-1-naptime
33N-(4-((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(7-methoxyquinoline-4-yloxy)-1-naptime
34N-(2-AMINOPHENYL)-6-((2-(7-methoxyquinoline-4-yloxy)-1-naphthalide)methyl) nicotinamide
35N-(2-AMINOPHENYL)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
36N-(2-amino-4-forfinal)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime

37N-(4-((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naptime
38N-(2-AMINOPHENYL)-6-((2-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide)methyl) nicotinamide
39N-(2-AMINOPHENYL)-6-(quinoline-4-yloxy)-1-naptime
40N-(2-AMINOPHENYL)-6-(8-methylinosine-4-yloxy)-1-naptime
41 N-(2-AMINOPHENYL)-6-(7-chlorhydrin-4-yloxy)-1-naptime

42N-(2-AMINOPHENYL)-6-(8-(trifluoromethyl)quinoline-4-yloxy)-1-naptime
43N-(4-((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(7-chlorhydrin-4-yloxy)-1-naptime
44N-(4-((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(8-(trifluoromethyl)quinoline-4-yloxy)-1-naptime

Hereinafter the present invention will be illustrated in combination with the following examples, but the scope of protection of the present invention is not limited to the given examples. Further, while not otherwise defined in the present description the percentages are given in weight. Any range given in the description of the numbers, such as units of measure, conditions of reaction, physical connection state or a percentage, are intended to provide a literal and specific reference. Specialists in this field in the implementation of the present invention, using temperatures, concentrations, if the esta, the number of carbon atoms and the like, which fall out of the range or different from a single value, achieved the desired result.

Example 1

Getting 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid

6-Hydroxy-1-Naftowy acid (1,43 g, 7.6 mmol) was dissolved in 38 ml of DMSO was then added cesium carbonate (7.5 g, is 22.9 mmol) and 4-chloro-6,7-dimethoxyquinazoline (2,05 g, 9,14 mmol). The mixture was heated at 140°C for 3 hours. When the reaction was completed, the mixture was cooled to room temperature and diluted with 40 ml of H2O. the Mixture was neutralized 2 N. HCl to pH=6,5. Precipitated solids were filtered, washed with H2O, dried and recrystallized from methanol to obtain specified in the title compound (1.68 g, yield 59%) as a solid brown color. LC-MS (liquid chromatography-mass spectrometry) (m/z 377 (M+1).

Example 2

Getting 6-(7-methoxyquinoline-4-yloxy)-1-Naftowy acid

Specified in the title compound (1.73 g, yield 66%) was obtained in the form of a solid brown color of 6-hydroxy-1-Naftowy acid (1,43 g, 7.6 mmol) and 4-chloro-7-methoxyquinoline (1.77 g, 9,14 mmol) by a procedure similar to that described in example 1. LC-MS (m/z 346 (M+1).

Example 3

Getting 6-(6,7-dimethoxyquinazolin-4-yloxy-1-Naftowy acid

Specified in the header connection (1,95 g, yield 68%) was obtained in the form of a solid brown color of 6-hydroxy-1-Naftowy acid (1,43 g, 7.6 mmol) and 4-chloro-6,7-dimethoxyaniline (2,04 g, 9,14 mmol) by a procedure similar to that described in example 1. LC-MS (m/z 376 (M+1).

Example 4

Getting 6-(quinoline-4-yloxy)-1-Naftowy acid

Specified in the title compound (1.24 g, yield 52%) was obtained in the form of a solid brown color of 6-hydroxy-1-Naftowy acid (1,43 g, 7.6 mmol) and 4-chlorhydrin (1,49 g, 9,14 mmol) by a procedure similar to that described in example 1. LC-MS (m/z 316 (M+1).

Example 5

Getting 6-(8-methylinosine-4-yloxy)-1-Naftowy acid

Specified in the title compound (1.25 g, yield 55%) was obtained in the form of a solid brown color of 6-hydroxy-1-Naftowy acid (1,43 g, 7.6 mmol) and 4-chloro-8-methylinosine (1,62 g, 9,14 mmol) by a procedure similar to that described in example 1. LC-MS (m/z 330 (M+1).

Example 6

Getting 6-(7-chlorhydrin-4-yloxy)-1-Naftowy acid

Specified in the header of the connection (of 1.57 g, yield 59%) was obtained in the form of a solid brown color of 6-hydroxy-1-Naftowy acid (1,43 g, 7.6 mmol) and 4,7-dichloro is inoline (1,81 g, 9,14 mmol) by a procedure similar to that described in example 1. LC-MS (m/z 350 (M+1).

Example 7

Getting 6-(8-(trifluoromethyl)quinoline-4-yloxy)-1-Naftowy acid

Specified in the header connection (1,43 g, yield 49%) was obtained in the form of a solid brown color of 6-hydroxy-1-Naftowy acid (1,43 g, 7.6 mmol) and 4-chloro-8-(trifluoromethyl)quinoline (2,12 g, 9,14 mmol) by a procedure similar to that described in example 1. LC-MS (m/z 384 (M+1).

Example 8

Getting 4-(aminomethyl)-N-(2-AMINOPHENYL)benzamide

4-Cyanobenzoic acid (294 mg, 2 mmol) was dissolved in 8 ml of DMF, was then added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (768 mg, 4 mmol), 1-hydroxybenzotriazole (324 mg, 2.4 mmol), triethylamine (808 mg, 8 mmol) and o-phenylenediamine (432 mg, 4 mmol). The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml of concentrated salt solution. The solids were collected by vacuum filtration, washed with water and dried in vacuum to obtain N-(2-AMINOPHENYL)-4-cyanobenzene (364 mg, 77%) as a solid gray color. LC-MS (m/z 238 (M+1).

N-(2-AMINOPHENYL)-4-cyanobenzene (237 mg, 1 mmol) was dissolved in methanol (40 ml), then was added sulfuric acid (196 mg, 1 mmol) and 5% palladium on charcoal (0.20 g). A mixture of p is remedial in an atmosphere of hydrogen until the reaction. The mixture was filtered through celite and the filtrate was neutralized 1 N. NaOH solution (2 ml). The resulting mixture was filtered, and the filtrate was concentrated in vacuum to obtain specified in the title compound (232 mg, yield 96%) as a solid gray color.LC-MS (m/z 242 (M+1).

Example 9

Getting 4-(aminomethyl)-N-(2-amino-4-forfinal)benzamide

Specified in the title compound (186 mg, yield 72%) was obtained in the form of a solid brown color of the 4-cyanobenzoic acid (294 mg, 2 mmol) and 4-fluoro-o-phenylenediamine (302 mg, 2.4 mmol) by a procedure similar to that described in example 8. LC-MS (m/z 260 (M+1).

Example 10

Getting 4-(aminomethyl)-N-(2-amino-4-were)benzamide

Specified in the title compound (173 mg, yield 68%) was obtained as solid gray 4-cyanobenzoic acid (294 mg, 2 mmol) and 4-methyl-o-phenylenediamine (293 mg, 2.4 mmol) by a procedure similar to that described in example 8. LC-MS (m/z 256 (M+1).

Example 11

Getting 4-(aminomethyl)-N-(2-amino-4-methoxyphenyl)benzamide

Specified in the title compound (192 mg, 71%yield) was obtained as solid gray 4-cyanobenzoic acid (294 mg, 2 mmol) and 4-methoxy-o-phenylenediamine (331 mg, 2.4 mmol) what ROCEDURES, similar to the procedure described in example 8. LC-MS (m/z 272 (M+1).

Example 12

Getting 4-(aminomethyl)-N-(2-amino-4-triptoreline)benzamide

Specified in the title compound (195 mg, yield 63%) was obtained as solid gray 4-cyanobenzoic acid (294 mg, 2 mmol) and 4-trifluoromethyl-o-phenylenediamine (422 mg, 2.4 mmol) by a procedure similar to that described in example 8. LC-MS (m/z 310 (M+1).

Example 13

Obtaining 3-(aminomethyl)-N-(2-AMINOPHENYL)benzamide

Specified in the title compound (140 mg, yield 58%) was obtained in the form of a solid gray color of the 3-cyanobenzoic acid (294 mg, 2 mmol) and o-phenylenediamine (432 mg, 4 mmol) by a procedure similar to that described in example 8. LC-MS (m/z 242 (M+1).

Example 14

Getting 6-(aminomethyl)-N-(2-AMINOPHENYL)nicotinamide

Specified in the title compound (157 mg, yield 65%) was obtained as solid gray 6-canonicalname acid (296 mg, 2 mmol) and o-phenylenediamine (864 mg, 8 mmol) by a procedure similar to that described in example 8. LC-MS (m/z 243 (M+1).

Example 15

Getting 6-(aminomethyl)-N-(2-amino-4-forfinal)nicotinamide

Specified in the title compound (135 is g, yield 52%) was obtained as solid gray 6-canonicalname acid (296 mg, 2 mmol) and 4-fluoro-o-phenylenediamine (302 mg, 2.4 mmol) by a procedure similar to that described in example 8. LC-MS (m/z 261 (M+1).

Example 16

Obtaining N-(2-AMINOPHENYL)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

6-(6,7-Dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) was dissolved in 4 ml of DMF, was then added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (of 38.4 mg, 0.2 mmol), 1-hydroxybenzotriazole (16.2 mg, 0.12 mmol), triethylamine (40,4 mg, 0.4 mmol) and o-phenylenediamine (to 43.2 mg, 0.4 mmol). The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 200 ml of concentrated salt solution. The solids were collected by vacuum filtration, washed with water and dried in vacuum to obtain specified in the connection header (39,1 mg, 84%) as a solid brown color.1H-NMR (DMSO-d6) δ 4,01 (s, 6H, 2×OCH3), equal to 4.97 (s, 2H, benzene-NH2), of 6.65 (t, J=7.2 Hz, 1H, Ar-H), PC 6.82 (d, J=7,0 Hz, 1H, Ar-H), 7,00 (t, J=7,1 Hz, 1H, Ar-H), 7,38 (d, J=7,1 Hz, 1H, Ar-H), 7,42 (s, 1H, Ar-H), 7,60 (DD, J=2.4 and 9.2 Hz, 1H, Ar-H), to 7.64-7.68 per (m, 2H, Ar-H), 7,87 (d, J=6,7 Hz, 1H, Ar-H), of 7.97 (d, J=2.3 Hz, 1H, Ar-H), of 8.09 (d, J=8,2 Hz, 1H, Ar-H), scored 8.38 (d, J=9,2 Hz, 1H, Ar-H), 8,54 (s, 1H, Ar-H), 9,85 (s, 1H, benzene-NH). LC-MS (m/z 467 (M+1).

Example 17

Obtaining N-(2-amino-4-forfinal)-6-(6,7-dimethoxy azolin-4-yloxy)-1-naphthalide

Specified in the header connection (to 43.1 mg, yield 89%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 4-fluoro-o-phenylenediamine (15.1 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ 4,01 (s, 6H, 2×och3), 5,28 (s, 2H, benzene-NH2), 6,41 (TD, J=2.6 and 8.5 Hz, 1H, Ar-H), 6,59 (DD, J=2.6 and 11.2 Hz, 1H, Ar-H), 7,35 (TD, J=1.8 and 7.5 Hz, 1H, Ar-H), 7,41 (s, 1H, Ar-H), to 7.59 (DD, J=2.2 and an 8.4 Hz, 1H, Ar-H), 7,63-to 7.67 (m, 2H, Ar-H), 7,89 (d, J=6,9 Hz, 1H, Ar-H), of 7.96 (d, J=1.9 Hz, 1H, Ar-H), 8,08 (d, J=8,2 Hz, 1H, Ar-H), scored 8.38 (d, J=9,2 Hz, 1H, Ar-H), 8,54 (s, 1H, Ar-H), made up 9.77 (s, 1H, benzene-NH). LC-MS (m/z 485 (M+1).

Example 18

Obtaining N-(2-amino-4-were)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header connection (to 39.4 mg, yield 82%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 4-methyl-o-phenylenediamine (14.6 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) (ratio of isomers 0,77/0,23) δ of 2.21 (s, 1H, Ar-CH3), to 4.01 (s, 6H, 2×och3), of 4.77 (s, 0,23×2H, benzene-NH2), 4,89 (with, of 0.77×2H, benzene-NH2), 6,46 (d, J=7,6 Hz, 0,77×1H, Ar-H), 6,64 (with, of 0.77×1H, Ar-H), 6.73 x (d, J=7.9 Hz, 0,23×1H, Ar-H), for 6.81 (s, 0,23×1H, Ar-H), 7,24 (d, J=8,1 Hz, 1H, Ar-H), 7,41 (s, 1H, Ar-H), 7,58-7,66 (m, 3H, Ar(H)a 7.85 (d, J=6,7 Hz, 1H, Ar-H), of 7.97 (s, 1H, Ar-H), 8,08 (d, J=7.9 Hz, 1H, Ar-H), scored 8.38 (d, J=9.0 Hz, 1H, Ar-H), 8,54 (s, 1H, Ar-H), made up 9.77 (s, 1H, benzene-NH). LC-MS (m/z 481 (M+1).

Example 19

Obtaining N-(2-amino-4-methoxyphenyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header connection (to 43.2 mg, yield 87%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 4-methoxy-o-phenylenediamine (16.5 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ 3,70 (s, 3H, -och3), to 4.01 (s, 6H, 2×och3), to 5.00 (s, 2H, benzene-NH2), 6,23 (DD, J=2.6 and 8.6 Hz, 1H, Ar-H), 6,40 (d, J=2.6 Hz, 1H, Ar-H), 7,22 (d, J=8.6 Hz, 1H, Ar-H), 7,41 (s, 1H, Ar-H), to 7.59 (DD, J=2.2 and 9.1 Hz, 1H, Ar-H), 7,62-7,66 (m, 2H, Ar-H), 7,86 (d, J=6,9 Hz, 1H, Ar-H), of 7.96 (d, J=2.0 Hz, 1H, Ar-H), 8,07 (d, J=8,2 Hz, 1H, Ar-H), scored 8.38 (d, J=9,2 Hz, 1H, Ar-H), 8,54 (s, 1H, Ar-H), to 9.70 (s, 1H, benzene-NH). LC-MS (m/z 497 (M+1).

Example 20

Obtaining N-(2-amino-4-chlorophenyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header connection (42.9 mg, yield 83%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 4-chloro-o-phenylenediamine (17,1 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ 4,01 (s, 6H, 2×och3), 5,31 (s, 2H, benzene-NH2), and 6.5 (d, J=8,3 Hz, 1H, Ar-H), 6,86 (d, J=1.9 Hz, 1H, Ar-H), 7,41 (s, 1H, Ar-H), 7,58-to 7.67 (m, 4H, Ar-H), 7,89 (d, J=6,8 Hz, 1H, Ar-H), 8,01 (s, 1H, Ar-H), of 8.09 (d, J=8,1 Hz, 1H, Ar-H), of 8.37 (d, J=9,2 Hz, 1H, Ar-H), 8,55 (s, 1H, Ar-H), 9,84 (s, 1H, benzene-NH). LC-MS (m/z 501 (M+1).

Example 21

Obtaining N-(2-amino-4-bromophenyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header connection (42,0 mg, yield 77%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 4-bromo-o-phenylenediamine (of 22.4 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ 4,01 (s, 6H, 2×och3), 5,31 (s, 2H, benzene-NH2), 6,77 (d, J=8,3 Hz, 1H, Ar-H), 7,01 (s, 1H, Ar-H), 7,41 (s, 1H, Ar-H), 7,58-the 7.65 (m, 5H, Ar-H), 7,89 (d, J=7,0 Hz, 1H, Ar-H), of 8.00 (s, 1H, Ar-H), to 8.14 (d, J=10,2 Hz, 1H, Ar-H), of 8.37 (d, J=9.1 Hz, 1H, Ar-H), 8,54 (s, 1H, Ar-H), 9,84 (s, 1H, benzene-NH). LC-MS (m/z 545 (M+1).

Example 22

Obtaining N-(2-amino-4-triptoreline)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header of the connection (of 42.3 mg, yield 79%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 4-trifluoromethyl-o-phenylenediamine (21.1 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ 4,01 (s, 6H, 2×och3), 5,72 (s, 2H, benzene-NH2/sub> ), 6,92 (d, J=8.5 Hz, 1H, Ar-H), 7,42 (s, 1H, Ar-H), to 7.59-the 7.65 (m, 3H, Ar-H), of 7.90-of 7.96 (m, 2H, Ar-H), 7,98 (s, 1H, Ar-H), 8,10 (d, J=8,3 Hz, 1H, Ar-H), 8,17 (d, J=7,3 Hz, 1H, Ar-H), 8,39 (d, J=9,2 Hz, 1H, Ar-H), 8,54 (s, 1H, Ar-H), to 9.90 (s, 1H, benzene-NH). LC-MS (m/z 535 (M+1).

Example 23

Obtaining N-(4-((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header connection (to 43.1 mg, yield 72%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-AMINOPHENYL)benzamide (of 28.9 mg, 0.12 mmol) by a procedure similar to that described in example 16. LC-MS (m/z 600 (M+1).

Example 24

Obtaining N-(4-((2-amino-4-forfinal)carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header connection (46,3 mg, 75%yield) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-amino-4-forfinal)benzamide (31,1 mg, 0.12 mmol) by a procedure similar to that described in example 16. LC-MS (m/z 618 (M+1).

Example 25

Obtaining N-(2-AMINOPHENYL)-6-((2-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide)methyl)nicotinamide

Specified in the header connection (41,4 mg, yield 69%) was obtained in the form of Targovishte brown from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 6-(aminomethyl)-N-(2-AMINOPHENYL)nicotinamide (29.0 mg, 0.12 mmol) by a procedure similar to that described in example 16. LC-MS (m/z 601 (M+1).

Example 26

Obtaining N-(2-amino-4-forfinal)-6-((2-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide)methyl)nicotinamide

Specified in the header connection (to 43.3 mg, yield 77%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 6-(aminomethyl)-N-(2-amino-4-forfinal)nicotinamide (31,2 mg, 0.12 mmol) by a procedure similar to that described in example 16. LC-MS (m/z 619 (M+1).

Example 27

Obtaining N-(3-((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header connection (to 48.5 mg, yield 81%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 3-(aminomethyl)-N-(2-AMINOPHENYL)benzamide (of 28.9 mg, 0.12 mmol) by a procedure similar to that described in example 16. LC-MS (m/z 600 (M+1).

Example 28

Obtaining N-(4-((2-amino-4-were)carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header of the connection (and 52.7 mg, yield 86%) was obtained in the form of a solid brown, the CSOs color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-amino-4-were)benzamide (30,6 mg, 0.12 mmol) by a procedure similar to that described in example 16. LC-MS (m/z 614 (M+1).

Example 29

Obtaining N-(4-((2-amino-4-methoxyphenyl)carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header of the connection (of 51.6 mg, yield 82%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-amino-4-methoxyphenyl)benzamide (32,5 mg, 0.12 mmol) by a procedure similar to that described in example 16. LC-MS (m/z 630 (M+1).

Example 30

Obtaining N-(4-((2-amino-4-triptoreline)carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header connection (to 46.7 mg, yield 70%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-amino-4-triptoreline)benzamide (37,1 mg, 0.12 mmol) by a procedure similar to that described in example 16. LC-MS (m/z 668 (M+1).

Example 31

Obtaining N-(2-AMINOPHENYL)-6-(7-methoxyquinoline-4-yloxy)-1-naphthalide

Specified in the header connection (to 39.6 mg, yield 91%) was obtained in the form of a solid substance coric is avago colors of 6-(7-methoxyquinoline-4-yloxy)-1-Naftowy acid (34,5 mg, 0.1 mmol) and o-phenylenediamine (to 43.2 mg, 0.4 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ of 3.95 (s, 3H, -OCH3), equal to 4.97 (s, 2H, benzene-NH2), 6,60 (d, J=5,2 Hz, 1H, Ar-H), only 6.64 (t, J=7,6 Hz, 1H, Ar-H), PC 6.82 (d, J=7.8 Hz, 1H, Ar-H), of 6.99 (t, J=7,4 Hz, 1H, Ar-H), 7,31 (DD, J=2.5 and 9.1 Hz, 1H, Ar-H), 7,38 (d, J=7,6 Hz, 1H, Ar-H), was 7.45 (d, J=2.4 Hz, 1H, Ar-H), EUR 7.57 (DD, J=2.4 and 9.2 Hz, 1H, Ar-H), the 7.65 (t, J=7.8 Hz, 1H, Ar-H), 7,87-7,88 (m, 2H, Ar-H), 8,07 (d, J=8,2 Hz, 1H, Ar-H), to 8.25 (d, J=9,2 Hz, 1H, Ar-H), 8,43 (d, J=9,2 Hz, 1H, Ar-H), 8,65 (d, J=5,2 Hz, 1H, Ar-H), 9,84 (s, 1H, benzene-NH). LC-MS (m/z 436 (M+1).

Example 32

Obtaining N-(2-amino-4-forfinal)-6-(7-methoxyquinoline-4-yloxy)-1-naphthalide

Specified in the header connection (up 33.1 mg, yield 73%) was obtained in the form of a solid brown color of 6-(7-methoxyquinoline-4-yloxy)-1-Naftowy acid (34,5 mg, 0.1 mmol) and 4-fluoro-o-phenylenediamine (15.1 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ of 3.95 (s, 3H, -och3), at 5.27 (s, 2H, benzene-NH2), 6,41 (TD, J=2,5 and 8.4 Hz, 1H, Ar-H), 6,57-of 6.61 (m, 2H, Ar-H), 7,30 and 7.36 (m, 2H, Ar-H), was 7.45 (d, J=2.2 Hz, 1H, Ar-H), 7,56 (DD, J=2.2 and a 9.2 Hz, 1H, Ar-H), the 7.65 (t, J=7,6 Hz, 1H, Ar-H), 7,87-to $ 7.91 (m, 2H, Ar-H), 8,07 (d, J=8,3 Hz, 1H, Ar-H), 8,24 (d, J=9.1 Hz, 1H, Ar-H), 8,43 (d, J=9,2 Hz, 1H, Ar-H), 8,65 (d, J=5,1 Hz, 1H, Ar-H), of 9.75 (s, 1H, benzene-NH). LC-MS (m/z 454 (M+1).

Example 33

Obtaining N-(4-((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(7-methoxyquinoline-4-yloxy)-1-naphthalide

<> Specified in the header connection (to 48.3 mg, yield 85%) was obtained in the form of a solid brown color of 6-(7-methoxyquinoline-4-yloxy)-1-Naftowy acid (34,5 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-AMINOPHENYL)benzamide (of 28.9 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ of 3.95 (s, 3H, -och3), with 4.64 (d, J=5.6 Hz, 2H, -CH2), to 4.87 (s, 2H, benzene-NH2), to 6.58-6,62 (t, 2H, Ar-H), 6,78 (DD, J=1.2 and 7.8 Hz, 1H, Ar-H), 6,97 (dt, J=1.4 and 8.1 Hz, 1H, Ar-H), 7,18 (d, J=7,0 Hz, 1H, Ar-H), 7,31 (DD, J=2.5 and 9.2 Hz, 1H, Ar-H), 7,44 (d, J=2.4 Hz, 1H, Ar-H), 7,53-7,56 (m, 3H, Ar-H), a 7.62 (t, J=8.0 Hz, 1H, Ar-H), 7,72 (d, J=6,1 Hz, 1H, Ar-H), 7,86 (d, J=2.5 Hz, 1H, Ar-H), 7,98-of 8.06 (m, 3H, Ar-H), 8,24 (d, J=9.1 Hz, 1H, Ar-H), 8,39 (d, J=9,2 Hz, 1H, Ar-H), 8,64 (d, J=5,2 Hz, 1H, Ar-H), of 9.21 (t, J=6.0 Hz, 1H, -CONH), being 9.61 (s, 1H, benzene-NH). LC-MS (m/z 569 (M+1).

Example 34

Obtaining N-(2-AMINOPHENYL)-6-((2-(7-methoxyquinoline-4-yloxy)-1-naphthalide)methyl)nicotinamide

Specified in the title compound (46.6 mg, yield 82%) was obtained in the form of a solid brown color of 6-(7-methoxyquinoline-4-yloxy)-1-Naftowy acid (34,5 mg, 0.1 mmol) and 6-(aminomethyl)-N-(2-AMINOPHENYL)nicotinamide (29.0 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ of 3.95 (s, 3H, -OCH3), 4,74 (s, 2H, -CH2), of 4.95 (s, 2H, benzene-NH2), 6,60 (m, 2H, Ar-H), 6,79 (s, 1H, Ar-H), 6,98 (s, 1H, Ar-H), 7,17 (s, 1H, Ar-H), 7,31 (d, J=8.6 Hz, 1H, Ar-H), 7,44 (s, 1H, Ar-H), 7,58-7,63 (m, 3H, Ar-H), to 7.77 (s, 1H, A-H), 7,87 (s, 1H, Ar-H), with 8.05 (d, J=5.6 Hz, 1H, Ar-H), 8,24 (d, J=8,3 Hz, 1H, Ar-H), with 8.33 (s, 1H, Ar-H), of 8.47 (d, J=7.5 Hz, 1H, Ar-H), 9,13 (s, 1H, Ar-H), a 9.25 (s, 1H, -CONH), made up 9.77 (s, 1H, benzene-NH). LC-MS (m/z 570 (M+1).

Example 35

Obtaining N-(2-AMINOPHENYL)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header connection (40,0 mg, yield 86%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.5 mg, 0.1 mmol) and o-phenylenediamine (to 43.2 mg, 0.4 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ 3,93 (s, 3H, -och3), of 3.95 (s, 3H, -och3), at 4.99 (s, 2H, benzene-NH2), 6,56 (d, J=5,2 Hz, 1H, Ar-H), 6,63 (t, J=7,6 Hz, 1H, Ar-H), for 6.81 (d, J=7,6 Hz, 1H, Ar-H), 6,98 (t, J=7.2 Hz, 1H, Ar-H), was 7.36 (d, J=7,6 Hz, 1H, Ar-H), the 7.43 (s, 1H, Ar-H), 7,56-7,58 (m, 2H,, Ar-H), the 7.65 (t, J=7,6 Hz, 1H, Ar-H), 7,87-of 7.90 (m, 2H, Ar-H), 8,08 (d, J=8.0 Hz, 1H, Ar-H), 8,43 (d, J=9,2 Hz, 1H, Ar-H), 8,49 (d, J=5,2 Hz, 1H, Ar-H), 9,87 (s, 1H, benzene-NH). LC-MS (m/z 466 (M+1).

Example 36

Obtaining N-(2-amino-4-forfinal)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header connection (39,1 mg, yield 81%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.5 mg, 0.1 mmol) and 4-fluoro-o-phenylenediamine (15.1 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ 3,93 (s, 3H, -och3), and 3.5 (s, 3H, -och3), 5,31 (s, 2H, benzene-NH2), 6,40 (s, 1H, Ar-H), 6,55-6,59 (t, 2H, Ar-H), 7,30 (d, J=7,6 Hz, 1H, Ar-H), 7,42 (s, 1H, Ar-H), 7,54-EUR 7.57 (m, 2H, Ar-H), to 7.64 (t, J=8.0 Hz, 1H, Ar-H), 7,89-to $ 7.91 (m, 2H, Ar-H), 8,07 (d, J=8.0 Hz, 1H, Ar-H), 8,42 (d, J=9,2 Hz, 1H, Ar-H), 8,49 (d, J=5,2 Hz, 1H, Ar-H), 9,79 (s, 1H, benzene-NH). LC-MS (m/z 484 (M+1).

Example 37

Obtaining N-(4-((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide

Specified in the header connection (49,0 mg, yield 82%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-Naftowy acid (37.5 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-AMINOPHENYL)benzamide (of 28.9 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ 3,93 (s, 3H, -OCH3), of 3.95 (s, 3H, -OCH3), 4,63 (d, J=5.6 Hz, 2H, -CH2), the 4.90 (s, 2H, benzene-NH2), 6,56-6,59 (m, 2H, Ar-H), 6,78 (d, J=7,6 Hz, 1H, Ar-H), of 6.96 (t, J=8,1 Hz, 1H, Ar-H), 7,17 (d, J=7,6 Hz, 1H, Ar-H), 7,42 (s, 1H, Ar-H), 7,53-of 7.55 (m, 4H, Ar-H), a 7.62 (t, J=8.0 Hz, 1H, Ar-H), 7,71 (d, J=6,8 Hz, 1H, Ar-H), 7,87 (s, 1H, Ar-H), 7,98-of 8.06 (m, 3H, Ar-H), 8,39 (d, J=9,2 Hz, 1H, Ar-H), 8,49 (d, J=5,2 Hz, 1H, Ar-H), 9,26 (t, J=6.0 Hz, 1H, -CONH), to 9.66 (s, 1H, benzene-NH). LC-MS (m/z 599 (M+1).

Example 38

Obtaining N-(2-AMINOPHENYL)-6-((2-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthalide)methyl)nicotinamide

Specified in the header of the connection (or 47.9 mg, yield 80%) was obtained in the form of a solid brown color from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-n is freeway acid (37.5 mg, 0.1 mmol) and 6-(aminomethyl)-N-(2-AMINOPHENYL)nicotinamide (29.0 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ 3,93 (s, 3H, -OCH3), of 3.95 (s, 3H, -OCH3), to 4.73 (d, J=5.6 Hz, 2H, -CH2), equal to 4.97 (s, 2H, benzene-NH2), to 6.57 (m, 2H, Ar-H), 6,77 (d, J=6,4 Hz, 1H, Ar-H), 6,98 (t, J=8,1 Hz, 1H, Ar-H), 7,16 (d, J=5.6 Hz, 1H, Ar-H), 7,42 (s, 1H, Ar-H), 7,55-7,63 (m, 4H, Ar-H), a 7.62 (t, J=8.0 Hz, 1H, Ar-H), 7,76 (d, J=6,8 Hz, 1H, Ar-H), 7,88 (s, 1H, Ar-H), of 8.06 (s, 1H, Ar-H), with 8.33 (s, 1H, Ar-H), 8,45-8,48 (m, 2H, Ar-H), 9,12 (s, 1H, Ar-H), of 9.30 (t, J=6.0 Hz, 1H, -CONH), 9,80 (s, 1H, benzene-NH). LC-MS (m/z 600 (M+1).

Example 39

Obtaining N-(2-AMINOPHENYL)-6-(quinoline-4-yloxy)-1-naphthalide

Specified in the title compound (35.6 mg, yield 88%) was obtained in the form of a solid brown color of 6-(quinoline-4-yloxy)-1-Naftowy acid (31.5 mg, 0.1 mmol) and o-phenylenediamine (to 43.2 mg, 0.4 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ equal to 4.97 (s, 2H, benzene-NH2), of 6.65 (t, J=7,3 Hz, 1H, Ar-H), to 6.75 (d, J=5,1 Hz, 1H, Ar-H), PC 6.82 (d, J=7.8 Hz, 1H, Ar-H), 7,00 (t, J=7,1 Hz, 1H, Ar-H), 7,38 (d, J=7.5 Hz, 1H, Ar-H), to 7.59 (DD, J=2,3 and 9.2 Hz, 1H, Ar-H), of 7.64-7,71 (m, 2H, Ar-H), 7,83-a 7.92 (m, 3H, Ar-H), 8,08 (d, J=8,4 Hz, 2H, Ar-H), of 8.37 (d, J=7.9 Hz, 1H, Ar-H), to 8.45 (d, J=9,2 Hz, 1H, Ar-H), 8,73 (d, J=5,1 Hz, 1H, Ar-H), 9,85 (s, 1H, benzene-NH). LC-MS (m/z 406 (M+1).

Example 40

Obtaining N-(2-AMINOPHENYL)-6-(8-methylinosine-4-yloxy)-1-naphthalide

Specified in the header of the connection (of 37.7 mg, yield 90%) was obtained in the form of a solid brown color of 6-(8-methylinosine-4-yloxy)-1-Naftowy acid (32,9 mg, 0.1 mmol) and o-phenylenediamine (to 43.2 mg, 0.4 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ was 2.76 (s, 3H, Ar-CH3), equal to 4.97 (s, 2H, benzene-NH2), only 6.64 (t, J=7,1 Hz, 1H, Ar-H), 6,78 (d, J=5.0 Hz, 1H, Ar-H), PC 6.82 (d, J=7.8 Hz, 1H, Ar-H), of 6.99 (t, J=7,3 Hz, 1H, Ar-H), 7,38 (d, J=7.5 Hz, 1H, Ar-H), 7,55-7,58 (m, 2H, Ar-H), the 7.65 (t, J=7,6 Hz, 1H, Ar-H), 7,71 (d, J=7,0 Hz, 1H, Ar-H), 7,87-7,89 (m, 2H, Ar-H), 8,07 (d, J=8,2 Hz, 1H, Ar-H), to 8.20 (d, J=7.9 Hz, 1H, Ar-H), 8,44 (d, J=9,2 Hz, 1H, Ar-H), 8,76 (d, J=5.0 Hz, 1H, Ar(H)9,84 (s, 1H, benzene-NH). LC-MS (m/z 420 (M+1).

Example 41

Obtaining N-(2-AMINOPHENYL)-6-(7-chlorhydrin-4-yloxy)-1-naphthalide

Specified in the header connection (33,2 mg, yield 83%) was obtained in the form of a solid brown color of 6-(7-chlorhydrin-4-yloxy)-1-Naftowy acid (35,0 mg, 0.1 mmol) and o-phenylenediamine (to 43.2 mg, 0.4 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ equal to 4.97 (s, 2H, benzene-NH2), of 6.65 (t, J=7,4 Hz, Ar-H), 6,77 (d, J=5.5 Hz, 1H, Ar-H), PC 6.82 (d, J=7.2 Hz, 1H, Ar-H), 7,00 (t, J=7,0 Hz, 1H, Ar-H), 7,38 (d, J=7.2 Hz, 1H, Ar-H), 7,60 (DD, J=2,6 and 9.2 Hz, 1H, Ar-H), to 7.67-7,74 (m, 2H, Ar-H), 7,89 (d, J=7,4 Hz, 1H, Ar-H), 7,94 (d, J=2.4 Hz, 1H, Ar-H), of 8.09 (d, J=8,2 Hz, 1H, Ar-H), 8,13 (d, J=2.1 Hz, 1H, Ar-H), to 8.41 (d, J=9.0 Hz, 1H, Ar-H), 8,46 (d, J=9.6 Hz, 1H, Ar-H), 8,76 (d, J=5,2 Hz, 1H, Ar-H), 9,85 (s, 1H, benzene-NH). LC-MS (m/z 440 (M+1).

Example 42

Obtaining N-(2-AMINOPHENYL)-6-(8-trifloromethyl-4-yloxy)-1-naphthalide

Specified in the header connect the tion (to 38.3 mg, yield 81%) was obtained in the form of a solid brown color of 6-(8-trifloromethyl-4-yloxy)-1-Naftowy acid or 39.8 mg, 0.1 mmol) and o-phenylenediamine (to 43.2 mg, 0.4 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ to 4.98 (s, 2H, benzene-NH2), of 6.65 (t, J=7,3 Hz, 1H, Ar-H), 6,83 (d, J=7,6 Hz, 1H, Ar-H), 6.89 in (d, J=5,2 Hz, 1H, Ar-H), 7,00 (t, J=7.2 Hz, 1H, Ar-H), 7,38 (d, J=7.5 Hz, 1H, Ar-H), a 7.62 (DD, J=2.4 and 9.2 Hz, 1H, Ar-H), to 7.68 (t, J=7.7 Hz, 1H, Ar-H), 7,83 (t, J=7.9 Hz, 1H, Ar-H), of 7.90 (d, J=7,0 Hz, 1H, Ar-H), of 7.97 (d, J=2.3 Hz, 1H, Ar-H), 8,10 (d, J=8,3 Hz, 1H, Ar-H), 8,29 (d, J=7,1 Hz, 1H, Ar-H), of 8.47 (d, J=9,2 Hz, 1H, Ar-H), to 8.70 (d, J=7.8 Hz, 1H, Ar-H), 8,87 (d, J=5,2 Hz, 1H, Ar-H), 9,86 (s, 1H, benzene-NH). LC-MS (m/z 474 (M+1).

Example 43

Obtaining N-(4-((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(7-chlorhydrin-4-yloxy)-1-naphthalide

Specified in the header connection (42,4 mg, yield 74%) was obtained in the form of a solid brown color of 6-(7-chlorhydrin-4-yloxy)-1-Naftowy acid (35,0 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-AMINOPHENYL)benzamide (of 28.9 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ with 4.64 (d, J=5.8 Hz, 2H, -CH2), to 4.87 (s, 2H, benzene-NH2), 6,60 (t, J=7,0 Hz, 1H, Ar-H), 6.75 in-6,79 (m, 2H, Ar-H), 6,97 (t, J=7.5 Hz, 1H, Ar-H), 7,18 (d, J=7.7 Hz, 1H, Ar-H), 7,53-to 7.59 (m, 3H, Ar-H), 7,66 (t, J=8.0 Hz, 1H, Ar-H), 7,70-7,74 (m, 2H, Ar-H), 7,92 (d, J=2.0 Hz, 1H, Ar-H), to 7.99 (d, J=7.9 Hz, 2H, Ar-H), of 8.06 (d, J=8,2 Hz, 1H, Ar-H), 8,13 (s, 1H, Ar-H), 8,39-8,42 (m, 2H, Ar-H), is 8.75 (d, J=5,1 Hz, 1H, Ar-H), which 9.22 (t, J=5,6 Hz, 1H, -ONH), 9,62 (s, 1H, benzene-NH). LC-MS (m/z 573 (M+1).

Example 44

Obtaining N-(4-(((2-AMINOPHENYL)carbarnoyl)benzyl)-6-(8-trifloromethyl-4-yloxy)-1-naphthalide

Specified in the header of the connection (of 47.3 mg, yield 78%) was obtained in the form of a solid brown color of 6-(8-trifloromethyl-4-yloxy)-1-Naftowy acid (to 38.3 mg, 0.1 mmol) and 6-(aminomethyl)-N-(2-AMINOPHENYL)nicotinamide (29.0 mg, 0.12 mmol) by a procedure similar to that described in example 16.1H-NMR (DMSO-d6) δ with 4.64 (d, J=5.6 Hz, 2H, -CH2), to 4.87 (s, 2H, benzene-NH2), 6,60 (t, J=7.2 Hz, 1H, Ar-H), 6,78 (d, J=7.8 Hz, 1H, Ar-H), 6.89 in (d, J=5,1 Hz, 1H, Ar-H), 6,97 (t, J=7.2 Hz, 1H, Ar-H), 7,18 (d, J=7.9 Hz, 1H, Ar-H), 7,53-7,66 (m, 4H, Ar-H), 7,74 (d, J=6,9 Hz, 1H, Ar-H), 7,83 (t, J=7.9 Hz, 1H, Ar-H), 7.95 is-8,08 (m, 4H, Ar-H), 8,29 (d, J=7,0 Hz, 1H, Ar-H), 8,42 (d, J=9.1 Hz, 1H, Ar-H), 8,69 (d, J=8,3 Hz, 1H, Ar-H), 8,86 (d, J=5.0 Hz, 1H, Ar-H), which 9.22 (t, J=5.5 Hz, 1H, -CONH), being 9.61 (s, 1H, benzene-NH). LC-MS (m/z 607 (M+1).

Example 45

Getting pills

Composition (1000 tablets):

/tr>
The connection 315 g
Microcrystalline cellulose90 g
Carboximetilkrahmal sodium5 g
4% solution of polyvidone (K30) in absolute ethanol50 g
The talcum powder0.5 g

Compound 31 was sifted through a sieve of 100 mesh. Microcrystalline cellulose, carboximetilkrahmal sodium and talcum powder, respectively sieved through a sieve of 80 mesh. Microcrystalline cellulose and carboximetilkrahmal sodium was weighed in an include part number and uniformly mixed with the connection 31 by way of stepwise addition. To obtain wet granules were added an appropriate amount of 4% solution of polyvidone (K30) in absolute ethanol. The granules were dried and added talcum powder in which is included in the number. Then there was pressing to obtain tablets.

Example 46

Getting capsules

Composition (1000 capsules):

The connection 315 g
Microcrystalline cellulose55 g
Lactose35 g
Carboximetilkrahmal sodium5 g
Magnesium stearate0.5 g

Compound 31 was sifted through a sieve of 100 mesh. Microcrystalline cellulose, lactose, carboxymethylate is low sodium and magnesium stearate respectively sieved through a sieve of 80 mesh. Microcrystalline cellulose, lactose and carboximetilkrahmal sodium was weighed in an include part number and uniformly mixed with the connection 31 by way of stepwise addition. Then magnesium stearate was added in an include part number and uniformly mixed. Then there was the filling of capsules to obtain ready-to-use capsules.

Example 47

Obtaining injectable

Composition:

The connection 311.00 mg
DMSO0.10 ml
Ethanol1,00 ml

Compound 31 was dissolved in DMSO and then added ethanol to obtain injectable.

Example 48

Analiz-dependent ligands PDGF and VEGF cell proliferation under the action of the compounds of formula (I)

Measurement of inhibition ofin vivodependent receptor ligands of cell proliferation:

1. PDGF-dependent cell proliferation:

Methods engineering designed the cell line of mouse fibroblasts NIH-3T3 stable expression of human PDGFRβ and used for the evaluation of PDGF-dependent cell proliferation. Expressing human PDGFRβ cells NIH-3T3 you shall evali in 96-well plates in the amount of 5000 per well and incubated overnight in serum-free medium after 24 hours. Added to be checked connections and PDGF-BB (50 ng/ml) and cells were incubated for 72 hours in serum-free medium. Effects on proliferation was determined by way of MTS (Promega), in accordance with the instruction. Incubation was performed for 2 hours at 37°C in an incubator in an atmosphere of CO2and spectral absorption capacity at 490 nm was measured using a reader tablet ELISA (enzyme immunoassay).

2. VEGF-dependent cell proliferation:

The HUVEC cells were planted in 96-well plates in the amount of 6000 per well and after 24 hours were incubated in serum-free medium for 2 hours. Added to be checked connections and VEGF 165 (50 ng/ml) and incubated for 72 hours in serum-free medium. Effects on proliferation was determined by way of MTS (Promega), in accordance with the instruction. Incubation was performed for 2 hours at 37°C in an incubator in an atmosphere of CO2and spectral absorption capacity at 490 nm was measured using a reader tablet ELISA.

Experimental results are shown in table 2.

5
Table 2
Example (connection)GI50nm
(dependent on the ligand PDGF cell about iteracy)
GI50nm
(dependent on the ligand VEGF cell proliferation)
16483
17403
18157
191123
20236
21195
223723
2314818
256913
31465
32202
333008
3424890
351
3632
371594
387425
3932107
4010001000
41479105
42481000
431000288
4410001000

Example 49

Inhibition ofin vitrothe total enzymatic activity and HDAC inhibitionin vivothe enzymatic activity of HDAC subtype compounds of formula (I)

Analysis of the enzymatic activity of HDAC in vitro:

The total enzymatic activity of HDAC in vitrowas determined using kit fluorometric analysis of HDAC/detection of drugs (BIOMOL), in accordance with the manufacturer's instructions.

PR is the narc of the experiment is as follows: under the action of discontiuation (in the experiment was used nuclear extract of HeLa cells, which was rich in various HDAC subtypes), acetyl group is removed from a special substrateFluor de Lysthus, offer a free amino group. After adding the developer, the substrate produces fluorescence. For fluorescence wavelengths of excitation is 360 nm, and the wavelength of emission of 460 nm. The fuller the deacetylation of the substrate, the higher is called fluorescence. In the absence of inhibitors, the amount of fluorescence is taken as the control; when the inhibitor is excited, the magnitude of the induced fluorescence is reduced, whereas in the absence of excitation of the enzyme (corresponding to a complete inhibition of enzyme activity), the amount of fluorescence is not detected. In General, after the suppression, the magnitude of fluorescence will be from the control value to the absence of fluorescence. During the analysis of the substrate with the absence of fluorescence is used as 0, and the control is used as 1. A smaller value means a higher inhibitory activity.

1. Add analytical buffer, diluted trichostatin A and the test inhibitor into the appropriate wells tiralongo microplate. The following table presents the number used for each reagent of the different types of tests.

ReagentAnalytical bufferThe HeLa extract (breeding)The inhibitor (5×)SubstrateFluor de Lys™(2×)
Without fluorescence25 ál0025 ál
Control10 ál15 ál025 ál
Trichostatin A015 ál10 ál25 ál
The test sample015 ál10 ál25 ál

2. Add the diluted extract nucleoprotein HeLa to all wells, except those marked as "empty".

3. To enable substrateFluor de Lys™ and samples in titrations the microplate be balanced to 25°C.

4. To initiate the reaction HDAC addition of diluted substrate (25 μl) to each well and mix thoroughly.

5. Allow the reaction to proceed for 30 minutes and then remains is to package them by adding developer Fluor de Lys™(50 µl). Incubate the plate at room temperature (25°C) for 10-15 minutes

6. To read the value of the fluorescence of the samples on reading fluorimeter titration microplate at a wavelength of 369 nm excitation and wavelength of 451 nm emission.

Analysis of the selectivity of inhibitors against HDAC subtypes using gene-reporter:

Various HDAC subtypes can contact various transcription factors and participate in the regulation of expression of different genes. Appropriate regulatory elements for transcription factors selected for design genes reporters that can be used to assess selective inhibition of HDAC subtypes inhibitors. Briefly, HeLa cells were planted in 96-well tablets the day before transfection to ensure that the merger 50-80% during transfection. The cells were transferrable the plasmid containing the promoter sequence of the p21 or reactive element above in the course of transcription of the gene construct of luciferase using the transfection reagent FuGene6 according to the manufacturer's instructions (Roche). To normalize transfection efficiency, was cotranslationally expression plasmid GFP. After 24 hours was added compound or control vehicle (DMSO). After 24 hours, cells were collected and literally and the amount of luciferase was evaluated with use of the cation sets analysis of luciferase (Promega), in accordance with the manufacturer's instructions.

Experimental results are shown in table 3.

Table 3
Example (connection)% inhibition of total HDAC enzymatic activity at 30 μmHDAC class I
(analysis of the p21 reporter)
The multiplicity of induction at 10 µm
CS05550,433
168,61,3
1722,51,1
1817,11,1
19of 21.91,4
20of 21.91,5
2118,61,1
22171,1
2349,411,3
2512,1
31the 10.11,6
3221,71,8
3339,12,8
3438,85,0
3519,31,2
3614.4V1,2
3735,93,0
3839,33,1
3915,91,2
4022,21,3
4119,31,1
426,21,3
4338,76,1
4435,1 3,2
CS055: hydatid, the HDAC inhibitor, was developed by company Chipscreen Biosciences, has excellent antitumor activity and is currently in stage II clinical trials

Example 50

The inhibition of proliferation of tumor cells by compounds of the formula (I)

Tumor cells were trypsinization and were sown in 96-well plates (3,000 per well and incubated in complete medium with 10% FBS (fetal calf serum) for 24 hours. Added to be checked connections and media, and the final concentration of the compounds was in the range of 100 nmol/l to 100 μmol/l of Compound were incubated for 72 hours in complete medium. Added MTS reagent (Promega) in accordance with the instructions, incubated for 2 hours at C in the incubator in an atmosphere of CO2. Then the readings of absorbance at 490 nm was read using a reader tablet ELISA.

Experimental results are presented in table 4.

td align="center"> 17,7
Table 4
Example (connection)GI50,μm
in A-498
GI50,μm
in A549
GI50,μm
in Bel-7402
GI50,μm
in HCT-8
GI50,μm
in MCF-7
CS05512,08of 11.1518,937,7113,865
1630,030,030,012,330,0
1730,030,030,03,030,0
18the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
19the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
20the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
21 the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
22the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
2314,730,030,0the 5.74,3
2514,730,030,0a 4.96,1
319,5the 17.330,06,610,2
327,58,3the 17.36,615,9
331,92,12,81,52,0
347,911,25,55,2
359,17,719,58,913,3
364,27,412,14,18,9
3730,030,030,030,030,0
386,930,030,08,09,4
39the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
40the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
41the concentration isthe concentration isthe concentration isO the concentration is
42the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
43the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
44the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
the concentration is*: not defined
CS055: hydatid, the HDAC inhibitor, was developed by company Chipscreen Biosciences, has excellent antitumor activity and is currently in stage II clinical trials.

Example 51

Inhibition of the connection 31 of the cancer cells of the human lung A549, transplanted bare mice

Female mice nu/nu weighing approximately 14-16 g were fed a normal diet for 3 days. Then the cultured cells of the cancer of the human lung A549 implanted in the axilla 50 mice. When tumors reached a diameter of more than 6 mm, the mice were divided into 6 groups randomly. Each group consisted of 8 we is it. One group was treated by the media. One group was treated with sutent, a drug positive control. The other four groups were treated with compound 31 in doses of 5, 10, 20 and 40 mg/kg of body weight. Each group received input means orally once daily for 24 days. The volume of tumors along with the body weight was recorded twice a week. The next day after the introduction of 24 doses, mice were killed, and tumors were weighed. Inhibition of growth of tumors in each group was calculated using the following formula:

{[(average weight of tumors in the control group)-(average weight of tumors per group)]/(average weight of the tumors in the control group)}×100%.

Experimental results are presented in table 5 and figure 1.

td align="center"> 4,20 ±0,75
Table 5
GroupaDose (mg/kg)Body weight (g)The tumor weight (g)TGI (%)bP
startend
Media-20,3±0,925,4±2,3--
Sutent4020,3±1,424,4±2,3of 2.06 ±0,7150,9<0,001
The connection 314020,0±0,922,6±2,41,06 ±0,544,8<0,001
The connection 312020,6±1,124,2±0,71,50 ±0,414,3<0,001
The connection 311019,9±1,325,1±1,32,13 ±0,519,4<0,001
The connection 31521,1±0,624,6±1,32,20 ±0,577,6<0,001
an=8 animals per group.bInhibi the Finance tumor growth.

Example 52

Inhibition of compound 31 cell cancer of the colon human HCT-8, transplanted bare mice

Female mice nu/nu weighing approximately 18-20 g were fed a normal diet for 3 days. Then the cultured cells of cancer of the colon human HCT-8 implanted in the axilla 50 mice. When tumors reached a volume of not less than 100 mm3mice were divided into 6 groups randomly. Each group consisted of 8 mice. One group was treated by the media. One group was treated with sutent, a drug positive control. The other four groups were treated with compound 31 in doses of 2.5, 5, 10 and 20 mg/kg of body weight. Each group received input means orally once daily for 24 days. The volume of tumors along with the body weight was recorded twice a week. The next day after the introduction of 20 doses, mice were killed, and tumors were weighed. Inhibition of growth of tumors in each group was calculated using the following formula:

{[(average weight of tumors in the control group)-(average weight of tumors per group)]/(average weight of the tumors in the control group)}×100%.

Experimental results are presented in table 6 and figure 2.

Table 6
GroupaDose (mg/kg)Body weight (g)The tumor weight (g)TGI (%)bP
startend
Media-20,8±1,022,1±2,14,78 ±1,99--
Sutent4021,5±0,722,4±1,10,23 ±0,07for 95.3<0,001
The connection 312020,5±1,322,5±1,60,19 ±0,0696,1<0,001
The connection 311020,7±1,123,7±0,80,46 ±0,1590,3<0,001
Soy is inania 31 521,6±0,824,8±1,50,78 ±0,25is 83.8<0,001
The connection 312,520,3±0,824,5±1,12,18 ±1,2854,5<0,001
an=8 animals per group.bInhibition of tumor growth.

Example 53

Inhibition of compound 31 cell cancer of the colon of a person SSMC7721, transplanted bare mice

Female mice nu/nu weighing approximately 18-20 g were fed a normal diet for 3 days. Then the cultured cells of cancer of the colon of a person SSMC7721 implanted in the axilla 50 mice. When tumors reached a volume of not less than 100 mm3mice were divided into 6 groups randomly. Each group consisted of 8 mice. One group was treated by the media. One group was treated with sutent, a drug positive control. The other four groups were treated with compound 31 in doses of 2.5, 5, 10 and 20 mg/kg of body weight. Each group received input means orally once daily for 24 days. Installed RAM is Halsey along with the body weight was recorded twice a week. The next day after the introduction of 24 doses, mice were killed, and tumors were weighed. Inhibition of growth of tumors in each group was calculated using the following formula:

{[(average weight of tumors in the control group)-(average weight of tumors per group)]/(average weight of the tumors in the control group)} ×100%.

Experimental results are presented in table 7 and figure 3.

Table 7
GroupaDose (mg/kg)Body weight (g)The tumor weight (g)TGI (%)bP
startend
Media-20,8±0,825,1±1,54,78 ±1,99--
Sutent4021,0±0,824,8±1,21,00 ±0,6870,3<0,001
The connection 312020,2±1,721,0±2,20,53 ±0,2884,4<0,001
The connection 311020,4±1,623,6±1,50,70 ±0,4579,2<0,001
The connection 31520,8±1,224,8±1,51,16 ±0,5565,4<0,001
The connection 312,520,1±0,923,2±2,11,63 ±0,7051,7<0,001
an=8 animals per group.bInhibition of tumor growth.

Example 54

Inhibition of compound 33 and compound 34 cell cancer of the colon human HCT-8, transplanted bare mice

Female mice nu/nu weighing approximately 18-20 g were fed a normal diet for 3 days. Then the cultured cells cancer is howling tumors of the colon human HCT-8 implanted in the axilla 50 mice. When tumors reached a volume of not less than 100 mm3mice were divided into 6 groups randomly. Each group consisted of 8 mice. One group was treated by the media. One group was treated with sutent, a drug positive control. Two groups were treated with compound 33 in various concentrations. Two other groups were treated with compound 34 in various concentrations. Each group received input means orally once a day for 20 days. The volume of tumors along with the body weight was recorded twice a week. The next day after the introduction of 20 doses, mice were killed, and tumors were weighed. Inhibition of growth of tumors in each group was calculated using the following formula:

{[(average weight of tumors in the control group)-(average weight of tumors per group)]/(average weight of the tumors in the control group)}×100%.

Experimental results are presented in table 8 and figure 4.

Table 8
GroupaDose (mg/kg)Body weight (g)The tumor weight (g)TGI (%)bP
startend
Media-19,4±1,621,2±2,44,08 ±0,95--
Sutent4020,6±1,222,1±1,50,44 ±0,1570,3<0,001
The connection 336019,4±0,821,4±1,51,98 ±0,6151,5<0,001
The connection 333019,0±1,321,1±2,22,31 ±0,4343,3<0,001
The connection 346019,6±1,121,6±2,32,74 ±0,7732,7<0,001
The connection 343019,7±1,23,95 ±0,73of 3.07<0,05
an=8 animals per group.bInhibition of tumor growth.

Example 55

Inhibition of compound 33 and compound 37 cell cancer of the colon human HCT-8, transplanted bare mice

Female mice nu/nu weighing approximately 18-20 g were fed a normal diet for 3 days. Then the cultured cells of cancer of the colon human HCT-8 implanted in the axilla 50 mice. When tumors reached a volume of not less than 100 mm3mice were divided into 6 groups randomly. Each group consisted of 8 mice. One group was treated by the media. One group was treated with sutent, a drug positive control. Two groups were treated with compound 33 in various concentrations. Two other groups were treated with compound 37 in various concentrations. Compound 33 was administered twice a day with an interval of 6 hours. For other groups the administration was performed once a day. Each group received input means orally once a day for 20 days. The volume of tumors along with the body weight was recorded twice a week. The next day after the introduction of 20 doses, mice were killed, and tumors were weighed. Engibarov is the growth of tumors in each group was calculated, using the following formula:

{[(average weight of tumors in the control group)-(average weight of tumors per group)]/(average weight of the tumors in the control group)}×100%.

Experimental results are presented in table 9 and figure 5.

Table 9
GroupaDose (mg/kg)Body weight (g)The tumor weight (g)TGI (%)bP
startend
Media-21,1±0,723,4±1,56,13 ±0,28--
Sutent4021,3±0,623,7±0,80,29 ±0,08for 95.3<0,001
The connection 3360×220,1±0,919,0±1,8 0,45 ±0,0592,6<0,001
The connection 3330×221,1±1,222,6±1,60,73 ±0,36at 88.1<0,001
The connection 376020,8±0,824,1±2,13,36 ±0,8045,1<0,001
The connection 373020,6±0,823,6±2,23,89 ±1,1936,5<0,001
an=8 animals per group.bInhibition of tumor growth.

Example 56

Inhibition of compound 33 and compound 37 cancer cells human liver SSMC7721, transplanted bare mice

Female mice nu/nu weighing approximately 18-20 g were fed a normal diet for 3 days. Then the cultured cells of the cancer human liver SSMC7721 implanted in the axilla 50 mice. When tumors reached a volume of not less than 100 mm3the mouse is divided into 6 groups randomly. Each group consisted of 8 mice. One group was treated by the media. One group was treated with sutent, a drug positive control. Two groups were treated with compound 33 in various concentrations. Two other groups were treated with compound 37 in various concentrations. Each group received input means orally once a day for 30 days. The volume of tumors along with the body weight was recorded twice a week. The next day after the introduction of 30 doses, the mice were killed, and tumors were weighed. Inhibition of growth of tumors in each group was calculated using the following formula:

{[(average weight of tumors in the control group)-(average weight of tumors per group)]/(average weight of the tumors in the control group)}×100%.

Experimental results are presented in table 10 and figure 6.

Table 10
GroupaDose (mg/kg)Body weight (g)The tumor weight (g)TGI (%)bP
startend
Media -21,1±0,424,5±1,62,25 ±0,85--
Sutent4021,2±1,124,0±0,60,88 ±0,3961,1<0,001
The connection 336021,4±1,325,4±2,81,48 ±0,8934,4>0,05
The connection 333020,8±0,524,0±1,71,63 ±0,4727,8>0,05
The connection 376021,4±0,624,3±1,11,28 ±0,5143,3<0,05
The connection 373020,7±1,225,3±0,91,45 ±0,5835,6&t; 0,05
an=8 animals per group.bInhibition of tumor growth.

1. The compound of the formula I

where
Z represents CH or N;
each of the groups R1, R2and R3represents hydrogen, halogen, alkyl, alkoxy or trifluoromethyl;
R4is

X represents a benzene ring or a pyridine ring;
R5represents one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and trifloromethyl.

2. The compound according to claim 1, where
Z represents CH;
each of the groups R1, R2and R3represents hydrogen, halogen, alkyl, alkoxy or trifluoromethyl;
R4is

X represents a benzene ring or a pyridine ring;
R5represents one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and trifloromethyl.

3. The compound according to claim 1, where
Z represents CH;
each of the groups R1, R2and R3represents hydrogen or alkoxy;
R4is

X represents a benzene ring or a pyridine ring;
R5represents one or more substituents selected isgroup, consisting of hydrogen, halogen, alkyl, alkoxy and trifloromethyl.

4. The compound according to claim 1, where
Z represents CH;
each of the groups R1and R2represents hydrogen or methoxy;
R3represents H;
R4is

X represents a benzene ring or a pyridine ring;
R5represents one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and trifloromethyl.

5. The compound according to claim 1, where
Z represents CH;
each of the groups R1and R2represents hydrogen or methoxy;
R3represents H;
R4is

X represents a benzene ring or a pyridine ring;
R5represents H or F.

6. The method of obtaining the compounds of formula I

where
Z represents CH or N;
each of the groups R1, R2and R3represents hydrogen, halogen, alkyl, alkoxy or trifluoromethyl;
R4is

X represents a benzene ring or a pyridine ring;
R5represents one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and trifloromethyl;
including interaction
the compounds of formula (II)

with the compound of the formula (III)

in the presence of an organic solvent and peptide condensing agent, for the formation of compounds of formula (I).

7. The method according to claim 6, where the specified peptide condensing agent selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide (DCC) and N,N'-carbonyldiimidazole (CDI).

8. The method according to claim 6, where the specified organic solvent selected from the group consisting of benzene, toluene, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform and N,N-dimethylformamide.

9. Pharmaceutical preparation for the treatment of diseases associated with abnormal protein kinase activity or abnormal activity discontiuation that includes a suitable amount of the compounds of formula (I) according to claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.

10. The pharmaceutical preparation according to claim 9 in the form of tablets, capsules, powder, syrup, solution, suspension, injection or ointment.

11. The use of compounds according to claim 1 when getting medicines for the treatment of inflammatory diseases, autoimmune diseases, cancer, diseases of the nervous system and neurodegenerative diseases, allergies, asthma, cardiovascular disease and metabolic disease or sableman the th, associated with hormonal disorders.

12. The use of a pharmaceutical preparation according to claim 9 when getting medicines for the treatment of inflammatory diseases, autoimmune diseases, cancer, diseases of the nervous system and neurodegenerative diseases, allergies, asthma, cardiovascular diseases, and metabolic diseases, or diseases associated with hormonal disorders.

13. The pharmaceutical preparation according to claim 9, containing specified compound of formula (I) in an amount in the range from 0.001 to 200 mg



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a piperazine compound presented by formula , wherein R1 represents C1-6 alkyl; R2 represents hydroxy, C1-6 alkyl which can contain a substitute specified in saturated or unsaturated 5-6 member heterocycle with 1-3 heteroatoms specified in oxygen and nitrogen, -(C=O)-N(R3)(R4) or -(C=O)-OR5; R3 and R4 may be identical or different, and each represents hydrogen or C1-6 alkyl which can contain a substitute specified in saturated or unsaturated 5-6 member heterocycle with 1-3 heteroatoms specified in oxygen and nitrogen, or R3 and R4 bound through a nitrogen atom whereto R3 and R4 are attached, can form a saturated heterocyclic group specified in 5-6 member heterocycle with 1-3 heteroatoms specified in oxygen and nitrogen; R5 represents hydrogen or C1-6 alkyl; and n represents 1 or 2; or a salt thereof. Also, the invention refers to a pharmaceutical compositions and an agent exhibiting prostaglandin-D-synthase activity and based on the compound of formula I, as well as to a method of preventing and treating a disease wherein prostaglandin D2 is involved.

EFFECT: there are prepared and described new compounds which may be effective in treating the diseases wherein prostaglandin D2 is involved.

11 cl, 19 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzodiazepine compounds of general formula , wherein each R1, R2, R3 and R4 independently represent hydrogen or alkyl, or R2 and R3 together represent lower alkylene; A1 is lower alkylene optionally substituted by hydroxy; and R5 is a fragment of formula , wherein each R6 and R7 independently represents hydrogen, lower alkyl, cycloalkyl, phenyl, furyl, thienyl, pyrazolyl, etc.; each XA and XB independently represents a bond, lower alkylene, -CO-, -SO2- etc., a pharmaceutical composition containing them, and using the above compound as the pharmaceutical composition or for preparing the same.

EFFECT: new compounds may be used for preventing and treating cardiac arrhythmia.

8 cl, 1047 ex, 78 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new uracil derivatives possessing human dUTPase inhibitory activity. In formula (I) n is equal to an integer 1 to 3; X member a bond, an oxygen atom, a sulphur atom, an alkenyl group containing 2 to 6 carbon atoms, a bivalent aromatic hydrocarbon group containing 6 to 14 carbon atoms, or a bivalent 5-7-merous saturated or unsaturated heterocyclic group containing 1 nitrogen or sulphur atom; Y means a bond or a linear or branched alkylene group containing 1 to 8 carbon atoms optionally having a cycloalkylydene structure containing 3 to 6 carbon atoms on one carbon atom; and Z means -SO2NR1R2 or -NR3SO2-R4, wherein R4 means an aromatic hydrocarbon group containing 6 to 14 carbon atoms which is optionally substituted by 1-2 substitutes, or an unsaturated 5-7-member heterocyclic group containing 1 nitrogen or sulphur atom which is optionally substituted by 1-2 halogen atoms; the radical values R1, R2 and the substitutes of the group R4 are presented in the patent claim.

EFFECT: invention relates to a pharmaceutical compositions comprising said compounds, to a human dUTPase inhibitor and a method of treating a human dUTPase-associated disease.

10 cl, 85 tbl, 179 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel carboxyl- or hydroxyl-substituted benzimidazole derivatives of formula (I), or pharmaceutically acceptable salts thereof, where R1 is selected from and , R2 is hydrogen; R3 is cyclohexyl or bicyclo[2.2.1]heptyl; R4 is phenyl, which is substituted in the 4th position with a halogen or a lower fluoroalkyl, or a pyridyl, which is substituted with 1 or 2 substitutes independently selected from halogen and a lower alkoxy group; R5 and R6 independently denote hydrogen or fluorine; R7 and R9 are independently selected from a group consisting of hydrogen, lower alkyl, halogen, lower alkoxy group, lower fluoroalkyl, lower fluoroalkoxy group and cyano group; R8 is -(CR12R13)n-COOH, where n equals 0, 1 or 2, and R12 and R13 are independently hydrogen or lower alkyl, or -O-(CR14R15)p-COOH, where p equals 1 or 2, and R14 and R15 are independently hydrogen or lower alkyl, or R14 and R15 together with the carbon atom with which they are bonded form a cycloalkyl ring, or R8 is tetrazole; R10 is a hydroxy group or -(CH2)p-COOH, where p equals 0 or 1; m equals 0 or 1; R11 is -COOH. The invention also relates to specific carboxyl- or hydroxyl-substituted benzimidazole derivatives and a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel carboxyl- or hydroxyl-substituted benzimidazole derivatives, having selective activity with respect to farnesoid X receptor, are obtained.

26 cl, 126 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel of 2,4-pyrimidine diamine compounds of formula I, which inhibit degranulation of immune cells and can be used in treating cell reactions mediated by FcεRI or FcγRl receptors. In formula (I) each R2 and R4 is independently phenyl substituted with one or more R8 groups or a heteroaryl selected from a group consisting of , where the heteroaryl is optionally substituted with one or more R8 groups and at least one of R2 and R4 is a heteroaryl; R5 is selected from a group consisting of (C1-C6)alkyl, optionally substituted with one or more identical or different R8 groups, -ORd, -SRd, fluorine, (C1-C3)halogenalkyloxy, (C1-C3)perhalogenalkyloxy, -NRcRc, (C1-C3)halogenalkyl, -CN, -NO2, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, -C(NH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcRc; -OC(NH)NRcRc, - [NHC(O)]nORd, R35 is hydrogen or R8; each Y is independently selected from a group consisting of O, S and NH; each Y1 is independently selected from a group consisting of O, S and NH; each Y2 is independently selected from a group consisting of CH, CH2, S, N, NH and NR37. Other values of radicals are given in the claim.

EFFECT: improved efficiency.

19 cl, 6 tbl.

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds, which represent (4,5-dihydrooxazol-2-yl)-(5,6,7,8-tetrahydroquinoxylan-5-yl)-amino and (4,5-dihydrooxazol-2-yl(-(5,6,7,8-tetrahydroquinolin-5-yl)-amino or their pharmaceutically acceptable salt. Said compounds are applied in methods of intraocular pressure reduction and treatment of pain in mammals who require it.

EFFECT: obtaining compounds, which are alpha-adrenergic agonists.

3 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method of treating cancer in a patient, wherein the method involves administering a cancer-inhibiting amount of a compound of formula I into a patient's body. The method of treating cancer in the patient, including a human, wherein the method involves administering the cancer-inhibiting amount of a first compound of formula I or a physiologically acceptable salt thereof into the patient's body, wherein X represents CH or N, each R1 independently represents hydrogen or -CH2COR5; R5 represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamino; each R2 independently represents the group ZYR6; Z represents a bond or the C1-3 alkylene or oxoalkylene group optionally substituted by the group R7; Y represents a bond, an oxygen atom or the group NR6; R6 is a hydrogen atom, the group COOR8, the alkyl, alkenyl, cycloalkyl, aryl or aralalkyl group optionally substituted by one or more groups COOR8, CONR82, NR82, OR8, =NR8, =O, OP(O)(OR8)R7 and OSO3M; R7 is hydroxy, the optionally alkoxylated or aminoalkyl group; R8 is a hydrogen atom or the optionally hydroxylated, optionally alkoxylated alkyl group; M is a hydrogen atom or one equivalent of a physiologically acceptable cation; R3 represents the C1-8 alkylene group, 1,2-cycloalkylene group or 1,2-arylene group, optionally substituted by R7; and each R4 independently represents hydrogen or C1-3 alkyl.

EFFECT: invention refers to a pharmaceutical composition for treating cancer in the patient, containing the compound of formula I, as well as to a kit for treating cancer.

23 cl, 3 ex, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula (1a) possessing the properties of Syk-kinase inhibitors, pharmaceutically acceptable salts thereof, as well as to a based pharmaceutical composition. In general formula (1a), R4 represents or , R2 is specified in a group consisting of phenyl which can be substituted by one or more identical or different groups R8, (C1-C6) alkyl, and pyridyl can be substituted by one or more identical or different groups R8. R5 represents fluorine; each R6 represents hydrogen. The other radical values are specified in the patent claim.

EFFECT: compounds may be used for treating or preventing the autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematous, as well as multiple sclerosis.

12 cl, 11 ex, 16 dwg, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to applying a quinazolinone compound of formula: wherein R3 has the values presented in the description and the patent claim, in the free form or in the form of salt. Also, the invention refers to a pharmaceutical composition exhibiting vanilloid receptor antagonist activity on the basis of said compounds.

EFFECT: there are produced new compounds and pharmaceutical composition on their basis which can find application in medicine for treating and preventing pain, gastrointestinal disorder.

12 cl, 30 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I), where R1 - C1-C6alkyl, (C1-C6alkyl)C1-C6alkyl, di(C1-C6)C1-C6alkyl or C3-C6dicloalkyl; each R2 independently represents halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl or cyano; R3 - hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkinyl, hydroxyl, hydroxy-substituted C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, cyano, C(=O)H, phenyl, (C3-C6cycloalkyl)C1-C6alkoxy, (C1-C6alkoxycarbonylamino)C1-C6alkoxy or (C1-C6alkylcarbonylamino)C1-C6alkoxy; R4 represents hydroxyl, C1-C6alkoxy, the group -NH(C=O)R4a, where R4a is halogen-substituted C1-C6alkyl, or the group -NH(CH2)2OR4b, where R4b is benzyl or phenyl ethyl; and m = 1 or 2 in a free form or in the form of pharmaceutically acceptable salt. Besides the invention refers to a pharmaceutical composition of the compounds applied for treatment or prevention of a disease or condition wherein vaniloid receptor activation acts the part or participates.

EFFECT: invention refers to application of the named compounds for preparing a drug to be applied for treatment or prevention of pain or gastrointestinal disturbance.

20 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula IId and their pharmacologically acceptable salts. In formula IId M represents -CH- or -N-; R2c bonded with carbon atom of 5-member ring and is selected from hydrogen and methyl; R2d is bonded with carbon atom from 6-member ring and selected from hydrogen and fluorine; one of R2a and R2b represents methoxy, and other is Q1X1, where X1 represents -O-, and values of other radicals are given in formula IId, to pharmaceutical composition, inhibiting antiogenesis and/or reducing vessel permeability, which contains as active component compound of formula IId, to application of invention compounds for preparation of medication and to compounds of 7-benzyloxy-4(4-fluorine-2-methylindol-5-iloxy)-6-methoxyquinazoline and 4-(4-fluorine-2- methylindol -5-yloxy)-7-hydroxy-6-methoxyquinazo-line.

EFFECT: development of effective method of obtaining quinazoline compounds.

12 cl, 54 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

The invention relates to the derivatives of hintline formula I in which Z denotes-O-, -NH - or-S-; m = 1-5, integer, provided that when Z represents-NH-, m = 3 - 5; R1is hydrogen, C1-3alkoxy; R2is hydrogen; R3hydroxy, halogen, C1-3alkyl, C1-3-alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; X1denotes-O-, -NR7, -NR8CO-, where R7and R8each is hydrogen, C1-3alkyl; R4choose one of the listed in paragraph 1 of the claims of the seven groups, except 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin, or their salts

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new quinolone derivatives of general formula (1) or a pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group, cyclo C3-8 alkyl, a lower alkyl group or a lower alkoxy, a lower alkyl group; R2 represents a hydrogen, a lower alkyl group or a halogen-substituted lower alkyl group; R3 represents a phenyl group, a difurylglyoxal group, a thienyl group or pyridyl group with each group of the above is optionally substituted by one or two groups specified in a group consisting of the following (1) to (16) in an aromatic or heterocyclic ring, presented by the above R3: (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups; (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted by one or two lower alkyl groups, (12) carbamoyl groups optionally substituted by one or two lower alkyl groups, (13) cyclo C3-8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15) morpholinyl carbonyl groups and (16) a carboxyl group; R1 represents a halogen atom; R5 represents a hydrogen atom or a halogen atom; R6 represents a hydrogen atom; and R7 represents any of the above groups (1) to (15): (1) a hydroxyl group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted by one or two members specified in a group consisting of lower alkyl groups, lower alkoxy lower alkyl groups and cyclo C3-8 alkyl groups, (8) an amino lower alkoxy group optionally substituted in an amino group by one or two members specified in a group consisting of lower alkyl groups, lower alkanoyl group, lower alkyl sulphonyl groups and carbamoyl groups optionally substituted by one or two lower alkyl groups, (9) a cyclo C3-8 alkoxy group, (10) a cyclo C3-8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group specified in a group consisting of morpholinyl groups, pyrrolidinyl groups, difurylglyoxal groups, thienyl groups and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group and (15) a pyrrolidinyl carbonyl group. Also, the invention refers to a pharmaceutical composition, and a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method of treating or preventing the above diseases, to a method of preparing the compound of formula (1).

EFFECT: there are prepared new quinolone derivatives effective for treating and/or preventing the neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.

11 cl, 1 tbl, 104 ex

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