Novel azaindole thiazolinones as anti-cancer agents

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have CDK1 and/or CDK2 kinase inhibiting activity. In formula R1 is selected from hydrogen, hydroxy-lower alkyl, C3-C6 cycloalkyl and R2-(X)n; X is selected from lower alkylene, hydroxy-lower alkylene, lower cycloalkylene or lower alkanoyloxy-lower alkylene; R2 is and is selected from phenyl and a 5- or 6-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of sulphur and nitrogen; R5 and R6 are independently selected from a group consisting of hydrogen, lower alkyl, halogen and lower alkoxy; and n equals 0 or 1.

EFFECT: design of a pharmaceutical composition for treating and preventing diseases whose condition can be improved by inhibiting CDK1 and/or CDK2 kinase, containing an effective amount of formula I compounds.

47 cl, 19 ex

 

The scope of the present invention relates to a derivative of azaindolizines that demonstrate CDK1 and CDK2 antiproliferative activity and are useful as anticancer agents.

Cyclin-dependent kinase (CDK) are sprintringtonesyoaj, which play a critical role in regulating the transition to different phases of the cell cycle, such as the progression from stationary phase G1(the gap between mitosis and the beginning of DNA replication for a new round of cell division) to S (the period of active DNA synthesis), or the progression from the G2to M phase, which is active mitosis and cell division. (See, for example, articles, Science, 1996, 274, s-1677 and Ann. Rev. Cell Dev. Biol., 1997, 13, SS-291). CDK complexes are formed in the process of Association of the regulatory subunit cyclina (for example, cyclin A, B1In2D1D2D3and (E) and the catalytic subunit of the kinase (e.g., CDK1, CDK2, CDK4, CDK5and CDK6). As the name implies, CDK show absolute dependence on subunit cyclina to fosforilirovanii their target substrates, and different pairs kinase/cyclin function to regulate progression during specific phases of the cell cycle.

Based on the foregoing it is seen that these protein kinases are a class of proteins (enzymes)that Regulus who have different cellular functions. This is accompanied by the phosphorylation of specific amino acids in protein substrates, which leads to a conformational change of the protein substrate. The conformational change modulates the activity of the substrate or its ability to interact with other binding partners. The enzymatic activity of the protein kinase is associated with the speed with which the kinase adds a phosphate group to the substrate. It can be measured, for example, determining the amount of substrate, which turned into a product, as a function of time. Phosphorylation of the substrate occurs at the active site of the protein kinase.

Due to the above properties of these kinases play an important role in the development of signal conversion growth factor, which leads to cell proliferation, differentiation and migration. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) have been described as important mediators of angiogenesis induced by tumor. VEGF activates endothelial cells by transmitting a signal between the two receptors with high affinity, one of which is the receptor containing embedded in the kinase domain (KDR). (See article Hennequin L.F., etc., J. Med. Chem., 2002, 45(6), SS. FGF activates endothelial cells by transmitting a signal between FGF receptors (FGFR). Solid tumors are dependent on the ability of the growth of new cravens what's vessels (angiogenesis). Accordingly, inhibitors of receptor FGFR and KDR, which affect the growth signal transduction and thereby slow down or prevent angiogenesis, are useful agents for the prevention and treatment of solid tumors. (See article Klohs W.E., etc.. Current Opinion m Biotechnology, 1999, 10, s).

Because CDK, such as CDK1, act as a General activator of cell division, CDK1 inhibitors can be used as antiproliferative agents. These inhibitors can be used to develop therapeutic interventions to inhibit progression unregulated cell cycle.

In accordance with the present invention it was found that the compound of the formula I:

where R1selected from hydrogen, lower alkyl, hydroxynitrile of alkyl, cycloalkyl, lower alkoxylates of alkyl and R2- (X)n;

X is selected from lower alkylene, hydroxynitrile of alkylene, cycloalkyl, lower alkoxylates of alkylene and lower alkanolamines of alkylene;

R2represents a

; and

selected from the

aryl ring;

4-6-membered geteroseksualbnogo ring containing 3-5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; and

5 - or 6-member of the frame heteroaromatic ring, containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;

R5and R6independently selected from the group consisting of hydroxy, hydroxynitrile of alkyl, hydrogen, lower alkyl, halogen, perforning of alkyl and lower alkoxy; and

n is 0 or 1; or

N-oxides of compounds, where R2contains a nitrogen atom in the heteroaromatic ring, sulfones, where R2contains a sulfur atom heterocyclicamines ring or heteroaromatic ring; or

its pharmaceutically acceptable salts, inhibit the activity of cdks, particularly CDK1 and CDK2.

These agents according to the invention and pharmaceutical compositions containing such agents are useful for the treatment of various diseases or medical conditions associated with uncontrolled or unwanted cell proliferation, such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative disorders and cardiovascular diseases.

Inhibition and/or modulation of CDK activity, in particular CDK1 and CDK2, makes these compounds formulas and compositions containing these compounds, are useful for treating diseases caused by the activity of kinases, particularly as anticancer agents for the treatment of cancer, specifically breast cancer, prostate cancer, cancer of the Tolstoy colon and lung cancer.

As noted above, the compounds of formula I are potent antiproliferative agents and are useful for melirovanie and/or inhibition of CDK activity, in particular CDK1thereby providing antitumor agents for the treatment of cancer or other diseases related to uncontrolled or abnormal cell proliferation.

Among the preferred compounds of formula I are described compounds of the formula:

where R1' represents hydrogen, lower alkyl, hidrogenesse alkyl, lower alkoxylate alkyl or cycloalkyl; or

their pharmaceutically acceptable salts, and the compounds of formula:

where

R1" is an R2-(X)nand R2, X and n are as defined above; or

N-oxides of the compounds, when R2contains a nitrogen atom in the heteroaromatic ring, sulfones, when R2contains a sulfur atom heterocyclicamines ring or heteroaromatic ring; or

their pharmaceutically acceptable salts.

In compounds I and I-B, where R2and X are substituents, aryl group, preferred aryl group is a phenyl.

In a preferred embodiment, the present invention describes compounds form the s I-A, where

R1' represents hydrogen, hydroxy-(C1-C6)alkyl or cyclopropyl.

In another preferred embodiment, the present invention describes compounds of formula I-B where n is 1, X is a (C1-C6)alkylene, hydroxy-(C1-C6)alkylene, (C1-C6)alkanoyloxy-(C1-C6)alkylen or cyclopropyl;

R2is thiophenyl, pyrazinyl or phenyl; and

R5and R6independently selected from hydrogen, halogen and (C1-C6)alkyl.

As used here, the halogen includes all four Halogens, such as chlorine, fluorine, bromine and iodine. Fluorine and chlorine are particularly preferred.

As used in the description, the term "lower alkyl", alone or in combination, denotes a monovalent linear or branched saturated hydrocarbon alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like.

The term "cycloalkyl" means cyclonite alkyl substituent, which represents a monovalent unsubstituted 3-6 membered saturated carbocyclic hydrocarbon ring. Preferred cycloalkyl substituents are cyclopropyl, cyclobutyl, the cycle is hexyl, etc., where cyclopropyl is especially preferred.

The term "lower alkoxy" denotes a linear or branched alkoxygroup formed lower alkyl containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.

The term "aryl" denotes monovalent mono - or bicyclic unsubstituted aromatic hydrocarbon ring, such as phenyl or naphthyl, where phenyl is preferred.

The term "heteroseksualci" refers to a 4-6-membered monocyclic saturated ring containing from 3 to 5 carbon atoms and one or two heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur. Preferred heterocyclic alkyl groups include morpholinyl, tiopronin or tetrahydropyranyl.

The term "heteroaromatic ring" refers to monovalent 5 - or 6-membered monocyclic heteroaromatic ring containing 4 or 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur. Preferred heteroaromatic groups include thiophenyl, thiazolyl, pyridinyl, furanyl etc.

The term "lower alkylene" means divalently saturated linear or branched hydrocarbon Deputy containing from one to six atoms of carbon is A.

The term "lower alkanoyloxy" means the monovalent residue of a saturated aliphatic carboxylic acids containing 2-6 carbon atoms, where the hydrogen atom in carboxylate (-COOH) is removed. Preferred lower alkanoyloxy include the atomic charges, propenyloxy, butyryloxy.

The term "cycloalkyl" means divalently cyclonite alkylen, which is divalent unsubstituted 3-6 membered saturated carbocyclic hydrocarbon ring. Preferred cycloalkanones substituents are divalently cyclopropyl and divalently cyclobutyl.

The term "lower alkanoyloxy lower alkylene" indicates the lowest alkalinity Deputy, substituted, preferably monosubstituted, lower alkanoyloxy, where lower alkanoyloxy is the same as defined above.

The term "lower alkoxymethyl alkylen" indicates the lowest alkalinity Deputy, as defined above, substituted, preferably monosubstituted, lower alkoxygroup, where the lower alkoxy is as defined above.

The term "hidrogenesse alkylen" indicates the lowest alkalinity Deputy, substituted, preferably monosubstituted, hydroxy-group.

The term "aryloxy" means aryloxyalkyl, where aryl is as described above. Preferred is Riley group is phenyl, and the preferred arroceros is phenoxy.

The term "performansi alkyl" refers to any group of lower alkyl, where all the hydrogen atoms of the group lower alkyl substituted by fluorine. Preferred groups perforning of alkyl include trifluoromethyl, pentafluoroethyl, heptafluoropropyl etc. where trifluoromethyl is particularly preferred.

The term "pharmaceutically acceptable salt" refers to conventional acid additive salts or basic additive salts which retain the biological effectiveness and properties of the compounds of formulas I, I-A and I-B, and are formed from suitable non-toxic organic or inorganic acids, or organic or inorganic bases. Examples of the acid additive salts include salts formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and salts formed with organic acids such as p-toluensulfonate acid, salicylic acid, methanesulfonate acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid and the like. Examples of the basic additive salts include salts formed with hydroxy what AMI ammonium, potassium, sodium and Quaternary ammonium bases, such as, for example, a hydroxide of Tetramethylammonium. Chemical modification of pharmaceutical compounds (i.e. medicines) in salt method is well known to chemists pharmacists to provide increased physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, for example, the book N. Ansel and other Pharmaceutical Dosage Forms and Drug Delivery Systems (6th edition, 1995) s and s-1457.

In accordance with the present invention the compounds of formula I can be obtained from compounds of formula II:

.

The compound of formula II into a compound of formula I with the following reaction scheme 1, where R1is the same as defined above.

In accordance with this invention the compound of formula II is subjected to reaction with a compound of formula III-A [rodanim (2-thio-4-thiazolin-4-one)] using reaction knoevenagel with obtaining the compounds of formula IV. Any of the conditions suitable for the reaction of knoevenagel can be used for this condensation. Typically this reaction is carried out at the boiling temperature of the solvent in the presence of alkali metal acetate and acetic acid. In the next stage of the synthesis of substituted received iatridis formula IV is treated meteorous agent for methylation of tigraphy in the compound of formula IV to obtain the compounds of formula V. Preferred meteorous agent is methyliodide. This reaction is carried out in the presence of a base organic amine, such as diisopropylethylamine (DIEA). When carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. In fact, when carrying out this reaction can be used any conditions conventional for methylation of tigraphy.

In the next stage of the synthesis of the compound of formula V is subjected to reaction with a compound of formula VI to obtain the compounds of formula I. the Compound of formula VI is an amine and when carrying out this reaction can be any of the methods normally used in the substitution of the amine metalcorp. In accordance with one embodiment this substitution is carried out with the reaction of compounds of formula VI with the compound of the formula V in the presence of a conventional solvent, such as acetonitrile. Typically this reaction is carried out in the presence of an amine base, such as diisopropylethylamine.

On the other hand, the compound of the formula I can be obtained by reaction of the compound of formula II with the compound of the formula:

where R1is the same as defined above.

The reaction of the compound of formula VII with the compound formula with obtaining the compounds of formula I is carried out in high-boiling organic solvent, such as benzene or toluene, at a high temperature from 50°C to 200°C in a closed system. In this way the reaction is carried out at high temperatures and pressure. In addition, this reaction is ideal for obtaining the compounds of formula I, where R1represents hydrogen. Compound of formula VII can be directly obtained by direct substitution reaction of the compound of the formula:

where R1is the same as defined above,

with the compound of the formula III-A. substitution Reaction is usually carried out in the presence of an activator for the thienyl group in connection teenie formula IX in the presence of an amine base. The preferred activator is a dichloride of mercury. This reaction is carried out in an inert organic solvent. Can be used any conventional inert organic solvent, such as acetonitrile, methylene chloride, etc. When carrying out this reaction using an amine base, such as diisopropylethylamine. When carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. When carrying out this reaction may be used any conventional method of substitution thienyl group with the amine.

In the compound of formula VI, g is e R 1represents X, n represents 1 and X represents hydroxylase alkylen, these compounds can be obtained from the corresponding amino acids or esters of amino acids recovering the alkali metal borohydride. On the other hand, these hydroxynitrile alkylene compounds can be obtained from the corresponding esters cyanocobalamin acids restoring lydialydia. The reaction leads to the restoration of ceanography in the amino and ester groups in the hydroxy-group. This restoration must occur before the reaction of the compound of formula VI with the compound of the formula V.

When the ringrepresents the N-oxide nitrogen atom in the nitrogen-containing ring, which forms a ringthese N-oxides can be obtained from the tertiary nitrogen atom of ring oxidation reaction. Can be used any conventional method of oxidizing tertiary nitrogen atom in the N-oxide. The preferred oxidizing agent is metallocarborane acid (MSRA).

The compound of formula I-A include compounds where R1' represents hydrogen. Another class of compounds among the compounds of formula I-A is a compound where R1' is cyclonite alkyl, preferably cyclopropyl. Another class of compounds among the and compounds of formula 1A is a connection, where R1' is hydroxylase alkyl or lower alkoxy lower alkyl, where hydroxylase alkyl is particularly preferred.

In the compounds of formula I-B, where R1" is an R2(X)n, n may denote 0 or 1. When n represents 0, a preferred class of compounds is a compound whererepresents phenyl. A preferred class of compounds where n is 0 and R2represents phenyl, represents compounds, where R5and R6either both represent hydrogen or one of R5and R6represents hydrogen and the other represents a lower alkoxy or lower alkyl.

On the other hand, another preferred class of compounds of formula I-b is a compound where R1" is an R2-(X)nand n denotes 1. This class includes compounds in which X represents cyclonite alkylen, preferably cyclopropyl. In this class of compounds where n is 1 and X is cyclonite alkylen included connectionsrepresents phenyl and R5and R6both represent hydrogen or one of R5and R6represents hydrogen and the other represents the bottom of the second alkyl. Another class of compounds of formula I-b, where R2represents phenyl, represents a compound in which R5and R6represent hydrogen or halogen, where at least one of R5and R6represents a halogen. Another class of compounds of formula I-B, where n denotes 1, is a compound in which X represents a lower alkanoyloxy lower alkylene. In this class of compounds, where R1" is an R2-(X)nand n represents 1 and X represents a lower alkanoyloxy lower alkylen included compounds in which R2representsandrepresents phenyl, the compounds in which both R5and R6represent hydrogen or one of R5and R6represents hydrogen and the other represents a lower alkenyl or halogen. In accordance with another embodiment of the invention preferred are the compounds of formula I-B, where n represents 1 and X represents a lower alkenyl. Preferred variants of the implementation in this class of compounds are compounds in which R2representsandrepresents phenyl. In this embodiment of the invention predpochtite is determined as being the embodiment are compounds in which R5and R6both represent hydrogen, or R5and R6represent hydrogen or lower alkyl or halogen, where at least one of R5and R6is other than hydrogen. Another class of compounds of formula I-B, where n represents 1 and X represents a lower alkylene includes compounds in whichrepresents a heteroaromatic ring containing 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The preferred compounds of this class of compounds, in whichrepresents a heteroaromatic ring, are compounds with heteroaromatic rings, containing 1 heteroatom, preferably a sulfur atom. In this case, R5and R6can both represent hydrogen or one of R5and R6can be a hydrogen and the other represents a halogen or lower alkyl.

Another class of compounds of formula I-B, where n denotes 1, are compounds in which X represents hydroxylase alkylen. In this class of compounds, where X is hydroxylase alkylen described connectionsrepresents a phenyl ring. In this preferred class of compounds included with the unity, in which R5and R6both represent hydrogen, and compounds in which R5and R6represent hydrogen, lower alkyl, lower alkoxy or halogen, where at least one of R5and R6is other than hydrogen.

Pharmaceutical compositions in accordance with the present invention may, alternatively or together with the compound of the Formula I, contain as the active ingredient, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds and metabolites. Such compounds, prodrugs, multimer, salts and metabolites together here sometimes designated as "active agents" or "agents".

In the case of agents that are solid, skilled in the art it is clear that the compounds and salts according to the invention may exist in different crystal or polymorphic forms, each of which is included in the scope of the present invention and presents formulas.

Therapeutically effective amounts of active agents according to the invention can be used for the treatment of diseases mediated by modulation or regulation of protein kinases CDK1. "Effective amount" means that amount of an agent that significantly inhibits proliferation and/or prevents on the differentiation of eukaryotic cells, for example, mammalian cells, insect, plant, or fungus, and is effective for the manifestation of applicability, for example, specific treatment.

The amount of this agent, which corresponds to this number depends on factors such as the particular compound, disease state and its severity, the feature (e.g., weight) of the patient or organism in need of treatment, but may, nevertheless, is usually determined by the method known to the person skilled in the art in accordance with the specific circumstances of the case, including, for example, a particular input agent, route of administration, treatable treatable condition and the patient or the body. "Treatment" refers to at least the relief of painful conditions of the subject such as a mammal (e.g. human), which is exposed at least partially the activity of CDK1protein kinases, and includes: preventing the disease condition, occurring in a mammal, particularly in a mammal, which is predisposed to a painful condition, but does not yet have this diagnosis; modulating and/or inhibiting the disease condition; and/or alleviating the disease condition.

The present invention also relates to methods of modulating or inhibiting the activity of protein kinase CK 1for example, in a tissue of a mammal, the introduction of the agent according to the invention. Active agents as antiproliferative easily measured by known methods, for example, using whole cell cultures in the MTT assay. The active agents according to the invention as modulators of the activity of protein kinase CDK1can be measured by any method available to the specialist in the art, including the assays in vivo and/or in vitro. Examples of suitable assays for measuring the activity include assays described in WO 99/21845; article Parast, etc. Biochemistry, 1998, 37, SS-16801; Connell-Crowley and Harpes, Cell Cycle: Materials and Methods (Ed. by Michele Pagano, Springer, Berlin, Germany) (1995); WO 97/34876 and WO 96/14843. These properties can be estimated, for example, using one or more sets of biological procedures for testing the examples below.

The active agents according to the invention can be introduced into pharmaceutical compositions, as described below. The pharmaceutical compositions of the present invention include an effective modulating, regulating, or inhibiting amount of the compounds of formula I and an inert, pharmaceutically acceptable carrier or diluent. In one embodiment, the pharmaceutical compositions effective levels of the agents according to the invention are supported in such a way as to provide therapeutic benefits,including antiproliferative activity. Under the "effective level" means the level at which inhibited or controlled proliferation. These compositions are in the form of dosage units suitable for the particular route of administration, such as parenteral or oral administration.

The agent according to the invention can be administered in conventional dosage form obtained by combining a therapeutically effective amount of an agent (for example, the compounds of formula (I) as the active ingredient with suitable pharmaceutical carriers or diluents according to conventional techniques. These techniques may include mixing, granulating and compressing or dissolving the ingredients to obtain the desired composition.

Applied pharmaceutical carrier can be either solid or liquid. Examples of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include inhibiting material or releasing in time material known from the prior art, such as glycerylmonostearate or glycerylmonostearate separately or together with wax, ethylcellulose, hydroxypropylmethyl what Ulusoy, the methyl methacrylate and the like.

Can be used in various pharmaceutical forms. Thus, if you are using a solid carrier, the composition can be tableted, placed in a hard gelatin capsule in powder form or granules or in the form of lozenges or candy. The amount of solid carrier may vary. If you use a carrier liquid, the composition may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in the vial or vessel or nonaqueous liquid suspension.

To obtain a stable water-soluble dose form pharmaceutically acceptable salt of the agent according to the invention can be dissolved in an aqueous solution of an organic or inorganic acid. If the formation of soluble salts is not possible, the agent can be dissolved in a suitable co-solvent, or a combination of co-solvents.

It is clear that the true doses of agents used in the compositions of the present invention, modified in accordance with the specific complex, specific, compiled by the composition, method of administration and the particular site, the organism and the disease to be treated. Optimal dosages for a given set of conditions can be determined by a person skilled in the art using conventional testicle determine dosage, based on the experimental data of the agent.

The composition of the invention may be obtained by methods generally known to obtain pharmaceutical compositions, for example, using conventional techniques such as mixing, dissolving, granulating, production drops, grinding into powder, emulsifying, encapsulating, inclusion in capsule or lyophilization. The pharmaceutical compositions can be obtained in the usual way, using one or more physiologically acceptable carriers that can be selected from excipients and additives that facilitate the introduction of active compounds in the compositions, which can be used pharmaceutically.

For oral administration the compounds can be easily prepared by combining the compounds with pharmaceutically acceptable carriers known in the prior art. Such carriers enable you to prioritize compounds according to the invention into tablets, pills, coated tablets, capsules, liquids, gels, syrups, suspensions, suspensions and the like, for oral use by the patient to be treated. Pharmaceutical compositions for oral administration can be obtained by using solid excipient in a mixture with the active ingredient (agent), optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable for the included additives, if necessary, to obtain tablets or dragee cores.

The present invention is further illustrated by the following examples which are not intended to limit the scope of the invention. Unless specifically stated otherwise, temperatures are in degrees Celsius (°C).

Examples

Example 1

5-[1-(1H-Pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]-2-[(thiophene-2-ylmethyl)amino]thiazol-4-one

a) Obtaining 3-bromo-1H-pyrrolo[2,3-b]pyridine

To a solution of 7-azaindole (5 g, to 42.2 mmole) in THF (400 ml) was added first solid N-bromosuccinimide (8 g, 45.0 mmol), followed by 20 drops of conc. sulfuric acid at room temperature. Under stirring for 2 days was formed suspension. The mixture was diluted with a saturated solution of ammonium chloride and two layers were separated. The aqueous layer was extracted with ethyl acetate (4×150 ml). The combined organic extracts were washed with a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent in vacuo resulted in the receipt of crude yellow solid. This solid was dissolved in ethyl acetate (~100 ml) by heating and then kept in the refrigerator over night. The solid is collected by filtration and washed with ethyl acetate. After drying on vostokovedenie 6.2 g (75% yield) of 3-bromo-1H-pyrrolo[2,3-b]pyridine as a yellow solid: EI-HRMS m/e expect. for C7H5BrN2(M+) 195, 9636, detection. 195, 9636.

b) Obtaining 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

To a suspension of 3-bromo-1H-pyrrolo[2,3-b]pyridine (9,85 g, 50.0 mmol) in THF (300 ml) was added dropwise 2.5m solution of n-utility in hexane (42 ml, 105.0 mmol, 2.1 equiv.) at -70°C. the Temperature of the reaction mixture was raised to -60°C in the process of adding and received a clear solution. Received a brick-red solution was slowly warmed to -10°C for 1 h and then was stirred for 4 h at the same temperature. The mixture was again cooled to -70°C. and was added dropwise a solution of dimethylformamide (8.5 ml, 110.0 mmol) in THF (30 ml). After the addition the mixture was heated to room temperature and was stirred for 15 hours Then the mixture was diluted with a saturated solution of ammonium chloride and two layers were separated. The aqueous layer was extracted with ethyl acetate (2×150 ml). The combined organic extracts were washed with a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent in vacuo resulted in the receipt of crude brown solid, which was dissolved in ethyl acetate (~70 ml) under heating and then kept in the refrigerator over night. The solid is collected by filtration and washed with ethyl acetate. After dry the project on the air was allocated 6,05 g (83% yield) 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a yellow solid: EI-HRMS m/e expect. for C8H6N2O (M+) 146,0480, detection. 146,0478.

C) One-step receiving 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

To a suspension of 1H-pyrrolo[2,3-b]pyridine (11,80 g, 100 mmol) in water containing 33% acetic acid (200 ml)was added hexamethylenetetramine (16,8 g, 120 mmol) at room temperature. This solution was heated to 110-120°C (oil bath temperature) and stirred for 15 hours Then the reaction mixture was cooled to room temperature and during that time formed a solid substance. This suspension was poured into the chemical Cup (2 l)containing ice, and the flask was rinsed with water (50 ml). The mixture was then slowly neutralized with a saturated solution of sodium bicarbonate. After neutralization, the solid was collected by filtration and washed with water. After drying in air was allocated 9.5 g (65% yield) 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a white solid: EI-HRMS m/e expect. for C8H6N2O (M+) 146,0480, detection. 146,0478.

g) Obtaining 2-[(thiophene-2-ylmethyl)amino]thiazole-4-it

To a suspension thiophene-2-ylmethylamino (22,63 g, 200 mmol) and rhodanine (13,32 g, 100 mmol) in acetonitrile (200 ml) was added diisopropylethylamine (DIPEA) (34.8 ml, 45.0 mmol) at room temperature. Then for 2 min transparently dissolve this solution was cooled to 0°C. To the solution was added mercury chloride (27,15 g, 100 mmol) in three portions over 15 minutes After the addition, the suspension was heated to room temperature and was stirred for 2 days. The obtained solid substance was filtered through a layer of celite and washed with dichloromethane (500 ml) and methanol (1.0 l). The combined solvents were removed in vacuo and the crude residue was diluted with water (250 ml) and ethyl acetate (250 ml). Two layers were separated and the aqueous layer was extracted with dichloromethane (2×250 ml). Two organic extract was washed separately with a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent in vacuo resulted in the receipt of crude solid. This solid was dissolved in acetonitrile (~100 ml) by heating and then kept in the refrigerator over night. The solid is collected by filtration and washed with cold acetonitrile. After drying in air was allocated 12,32 g (58% yield) 2-[(thiophene-2-ylmethyl)amino]thiazole-4-it is in the form of a white amorphous solid: EI-HRMS m/e expect. for C8H8N2OS2(M+) 212,0078, detection. 212,0083.

d) 5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]-2-[(thiophene-2-ylmethyl)amino]thiazole-4-it

To a suspension of 2-[(thiophene-2-ylmethyl)amino]thiazole-4-it (225 mg,of 1.06 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (193,6 mg, of 1.35 mmole) in toluene (2 ml) in vitro for microwave ovens were added benzoic acid (13 mg, of 0.11 mmole) and piperidine (11 μl, of 0.11 mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 1 h Then the mixture was cooled to room temperature and was diluted with toluene. The solid is collected by filtration and washed with toluene. After drying in air was allocated 330 mg (from 91.5% yield) of 5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]-2-[(thiophene-2-ylmethyl)amino]thiazole-4-it is in the form of a whitish solid: tPL243-246°C; HRES(+) m/e expect. for C16H12N4OS2(M+H)+341,0526, detection. 341,0528.

Example 2

5-[1-(1H-Pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]-2-[(thiophene-2-ylmethyl)amino]thiazol-4-one, cleaners containing hydrochloride salt

To a suspension of 5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]-2-[(thiophene-2-ylmethyl)amino]thiazole-4-it (50 mg, 0.15 mmole) in methanol (2 ml) was added dropwise to trimethylchlorosilane (19 μl, 0.15 mmole) at room temperature. The mixture became a clear solution after 1 h and was stirred for 2 hours Then the mixture was diluted with tert-butylmethylamine ether (10 ml). The obtained solid substance was collected by filtration and washed with tert-butylmethylamine ether. After drying in air was allocated 40 mg (73% yield) 5-1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]-2-[(thiophene-2-ylmethyl)amino]thiazole-4-it is in the form of cleaners containing hydrochloride salt as an amorphous solid: HRES(+) m/e expect. for C16H12N4OS2(M+N)+341,0526, detection. 341,0528.

Example 3

2-(2-Hydroxy-1-(R)-phenylethylamine)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one

a) Obtaining 2-(2-(R)hydroxy-1-phenylethylamine)thiazole-4-it

To a suspension of (R)-(-)-2-phenylglycinol (15,34 g, 111,82 mmole) and rhodanine (14,65 g, 110 mmol) in acetonitrile (200 ml) was added DIPEA (20,03 ml, 115 mmol) at room temperature. Then received a clear solution for 2 min and the solution was cooled to 0°C. thereto was added mercury chloride (31,22 g, 115 mmol) in three portions over 15 minutes After the addition, the suspension was heated to room temperature and was stirred for 2 days. The obtained black solid was filtered through a layer of celite and washed with dichloromethane (500 ml) and methanol (1.0 l). The combined solvents were removed in vacuo and the crude residue was diluted with water (250 ml) and ethyl acetate (250 ml). Two layers were separated and the aqueous layer was extracted with dichloromethane (2×250 ml). Two organic extract was washed separately with a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent in vacuo resulted in the receipt of crude yellow solid. This solid was dissolved in Aceto is nitrile (~100 ml) by heating and then kept in the refrigerator over night. The solid is collected by filtration and washed with cold acetonitrile (20 ml). After drying in air was allocated 12,99 g (50% yield) of 2-(2-(R)hydroxy-1-phenylethylamine)thiazole-4-it is in the form of a white amorphous solid: EI-HRMS m/e expect. for C11H12N2O2S (M-H2O) 218,0514, detection. 218,0511.

b) Obtaining 2-(2-hydroxy-1-(R)-phenylethylamine)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it

To a suspension of 2-(2-(R)hydroxy-1-phenylethylamine)thiazole-4-it (100 mg, 0.43 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (77,3 mg of 0.53 mmole) in toluene (2 ml) in vitro for microwave ovens were added benzoic acid (5.2 mg, 0,043 mmole) and piperidine (4,3 μl, 0,043 mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 1 h Then the mixture was cooled to room temperature and was diluted with toluene. The solid is collected by filtration and washed with toluene. After drying in air was allocated 135 mg (87,5% yield) of 2-(2-hydroxy-1-(R)-phenylethylamine)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it is in the form of a yellow solid: tPL317-319°C; HRES(+) m/e expect. for C16H12N4OS2(M+H)+365,1067, detection. 365,1070.

Example 4

2-(3-Chloro-4-forbindelsen)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)IU is-(Z)-ridin]thiazole-4-one

a) Obtaining 2-(3-chloro-4-forbindelsen)thiazole-4-it

To a suspension of 3-chloro-4-forbindelsen (2.5 g, 15,66 mmole) and rhodanine (2 g, 15 mmol) in acetonitrile (50 ml) was added DIPEA (5,57 ml, 32 mmole) at room temperature. Then the solution was cooled to 0°C was added mercury chloride (4,34 g, 16 mmol) in two portions over 10 minutes After the addition, the suspension was heated to room temperature and was stirred for 2 days. The obtained black solid was filtered through a layer of celite and washed with dichloromethane (200 ml) and methanol (500 ml). The combined solvents were removed in vacuo and the crude residue was diluted with water (150 ml) and ethyl acetate (150 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. Filtration of the drying agent and partial removal of the solvent in vacuo resulted in the receipt of solids. After cooling in the refrigerator, the solid was collected by filtration and washed with cold ethyl acetate. After drying in air was allocated 2.5 g (64% yield) of 2-(3-chloro-4-forbindelsen)thiazole-4-it is in the form of a white amorphous solid: EI-HRMS m/e expect. for C10H8ClFN 2OS (M+) 258,0030, detection. 258,0029.

b) Obtaining 2-(3-chloro-4-forbindelsen)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it

To a suspension of 2-(3-chloro-4-forbindelsen)thiazole-4-it (100 mg, of 0.39 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (71 mg, 0.48 mmole) in toluene (2 ml) in vitro for microwave ovens were added benzoic acid (4.8 mg, of 0.39 mmole) and piperidine (3,9 μl, 0,039 mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 1 h Then the mixture was cooled to room temperature and was diluted with toluene. The solids were collected by filtration and washed with toluene. After drying in air was allocated 145 mg (97% yield) of 2-(3-chloro-4-forbindelsen)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it is in the form of a yellow solid: tPL318-320°C; HRES(+) m/e expect. for C16H12N4OS2(M+H)+387,0477, detection. 387,0477.

Example 5

2-((1R,2S)-2-Vinylcyclopropyl)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one

a) Obtaining 2-((1R,2S)-2-phenylcyclopropane)thiazole-4-it

To a suspension of (1R,2S)-2-phenylcyclopropane hydrochloride (0.85 grams, 5 mmol) and rhodanine (0.68 g, 5 mmol) in acetonitrile (20 ml) was added DIPEA (2,61 ml, 5 mmol) at room temperature. Then the solution was cooled to 0°C was added mercury chloride (1.35 g, 5 mmole) in two portions over 10 minutes After the addition, the suspension was heated to room temperature and was stirred for 2 days. The obtained black solid was filtered through a layer of celite and washed with ethyl acetate (500 ml). The solvent was removed in vacuum and the crude residue was diluted with water (100 ml) and ethyl acetate (100 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent in vacuo resulted in obtaining a crude residue, which was purified using column chromatography on silica gel Biotage obtaining 0,474 g (42% yield) of 2-((1R,2S)-2-phenylcyclopropane)thiazole-4-it, which was isolated as a white amorphous solid: EI-HRMS m/e expect. for C12H12N2OS (M+) 232,0670, detection. 232,0665.

b) Obtaining 2-((1R,2S)-2-vinylcyclopropyl)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it

To a suspension of 2-((1R,2S)-2-phenylcyclopropane)thiazole-4-it (225 mg, of 1.06 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (193,6 mg of 1.35 mmole) in toluene (2 ml) in vitro for microwave ovens we use and benzoic acid (13 mg, of 0.11 mmole) and piperidine (11 μl, of 0.11 mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 1 h Then the mixture was cooled to room temperature and was diluted with toluene. The solids were collected by filtration and washed with toluene. After drying in air was allocated 330 mg (from 91.5% yield) of 2-((1R,2S)-2-vinylcyclopropyl)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it is in the form of a dark brown solid: tPL308-310°C; HRES(+) m/e expect. for C20H16N4OS (M+H)+361,1118, detection. 361,1122.

Example 6

2-(1-(R) - hydroxymethyl-2-methylpropylamine)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one

a) Obtaining 2-(1-(R) - hydroxymethyl-2-methylpropylamine)thiazole-4-it

To a suspension of (R)-valinol (1 g, RS 9.69 mmole) and rhodanine (1.3 g, RS 9.69 mmole) in acetonitrile (40 ml) was added DIPEA (of 5.06 ml, 29 mmol) at room temperature. Then the solution was cooled to 0°C was added mercury chloride (2,72 g, 10 mmol) in two portions over 10 minutes After the addition, the suspension was heated to room temperature and was stirred for 2 days. The obtained black solid was filtered through a layer of celite and washed with ethyl acetate (500 ml). The filtrate was removed in vacuo and what ever got the residue was diluted with water (100 ml) and ethyl acetate (100 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent in vacuo resulted in obtaining a crude residue, which was purified using column chromatography on silica gel Biotage with the receipt of 0.82 g (42% yield) of 2-(1-(R) - hydroxymethyl-2-methylpropylamine)thiazole-4-it, which was isolated as a white amorphous solid: EI-HRMS m/e expect. for C8H14N2O2S (M+) 202,0776, detection. 202,0778.

b) Obtaining 2-(1-(R) - hydroxymethyl-2-methylpropylamine)-5-[1-(1H-pyrrolo[2,3,b]pyridin-3-yl)meth-(Z)-ridin]thiazole-4-it

To a suspension of 2-(1-(R) - hydroxymethyl-2-methylpropylamine)thiazole-4-it (70 mg, 0.35 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (63 mg, 0.43 mmole) in toluene (700 ml) in vitro for microwave ovens were added benzoic acid (4.3 mg, 0.035 mmole) and piperidine (3,5 μl, 0.035 mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 1 h Then the mixture was cooled to room temperature and was diluted with toluene. The solid is collected by filtration and washed with toluene. The obtained solid was treated with di is loretana and methanol to remove color and other impurities. Filtration of the solids and drying in air resulted in the receipt of 14 mg (36,7% yield) of 2-(1-(R) - hydroxymethyl-2-methylpropylamine)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it is in the form of a yellow solid: tPL269-271°C; HRES(+) m/e expect. for C16H18N4O2S (M+) 331,1223, detection. 331,1226.

Example 7

2-[4-Oxo-5-(1H-pyrrolo[2,3,b]pyridine-3-ylmethylene)-4,5-dihydrothieno-2-ylamino-2-(R)-phenethyl ester acetic acid

a) Obtaining 2-[4-oxo-4,5-dihydrothiazolo-2-ylamino]-2-(R)-phenethyl ester acetic acid

To a solution of 2-(2-(R)hydroxy-1-phenylethylamine)thiazole-4-it (6,37 g, 26.9 mmole) in dichloromethane (200 ml) was added triethylamine (7,52 ml, 54 mmole) and then acetylchloride (2.3 ml, 32,28 mmole) at 5°C. After the addition the solution was heated to room temperature and was stirred for 2 days. This solution was transferred into a separate funnel and washed with a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent in vacuo resulted in the receipt of a crude yellow oil, which was purified using column chromatography on silica gel Biotage (40 m) to obtain 4.6 g (61,5% yield) of the desired 2-[4-oxo-4,5-dihydrothiazolo-2-ylamino]-2-(R)-phenethyl ester UKS the red acid in the form of a white amorphous solid: ES-LRMS m/e expect. for C13H14N2O3S (M+) 279,33, detection. 279,1.

b) Obtain 2-[4-oxo-5-(1H-pyrrolo[2,3,b]pyridine-3-ylmethylene)-4,5-dihydrothieno-2-ylamino-2-(R)-phenethyl ester acetic acid

To a suspension of 2-[4-oxo-4,5-dihydrothiazolo-2-ylamino]-2-(R)-phenethyl ester acetic acid (400 mg, 1,43 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (77,3 mg of 0.53 mmole) in toluene (5 ml) in vitro for microwave ovens were added benzoic acid (17,64 mg, 0,144 mmole) and piperidine (14,5 μl, 0,144 mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 1 h Then the mixture was cooled to room temperature and was diluted with toluene. The solid is collected by filtration and washed with toluene and dichloromethane. After drying in air was allocated 313 mg (53,6% yield) 2-[4-oxo-5-(1H-pyrrolo[2,3,b]pyridine-3-ylmethylene)-4,5-dihydrothieno-2-ylamino]-2-(R)-phenethyl ester acetic acid as a white solid: PL 243,7-246,8°C; HRES(+) m/e expect. for C21H18N4O3S (M+H)+407,1173, detection. 407,1172.

Example 8

2-(2-Chlorobenzylamino)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one

a) Obtaining 2-(2-chlorobenzylamino)thiazole-4-it

To suspe the Ziya 2-chlorobenzylamino (7,88 g, 55 mmol) and rhodanine (6,65 g, 50 mmol) in acetonitrile (150 ml) was added DIPEA (19,15 ml, 110 mmol) at room temperature. Then the solution was cooled to 0°C was added mercury chloride (13.5 g, 50 mmol) in three portions over 15 minutes After the addition, the suspension was heated to room temperature and was stirred for 3 days. The obtained black solid was filtered through a layer of celite and washed with dichloromethane (1 l) and methanol (500 ml). The combined solvents were removed in vacuo and the crude residue was diluted with water (150 ml) and ethyl acetate (150 ml). After shaking formed solid substance was collected by filtration to obtain 1.25 g of the final product. Then the two layers were separated and an ethyl acetate layer was washed with a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. After filtering, an ethyl acetate solution was partially removed and then kept in the refrigerator. The obtained solid substance was collected by filtration to obtain 2.67 g of the final product. Then the aqueous layer was extracted with dichloromethane (2×150 ml). Dichloromethane extracts were washed with a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent in vacuo resulted in obtaining a crude residue, which was purified using column is cromatografia on silica gel Biotage (40 m) with the receipt of 4.2 g (product of 8.12 g, 67,5% yield) of 2-(2-chlorobenzylamino)thiazole-4-it is in the form of a white amorphous solid: EI-HRMS m/e expect. for C10H9ClN2OS (M+) 240,0124, detection. 240,0122.

b) Obtaining 2-(2-chlorobenzylamino)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it

To a suspension of 2-(2-chlorobenzylamino)thiazole-4-it (120 mg, 0.5 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (88 mg, 0.6 mmole) in toluene (3 ml) in vitro for microwave ovens were added benzoic acid (7.5 mg, 0.06 to mmole) and piperidine (5,9 μl, of 0.06 mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 30 minutes Then the mixture was cooled to room temperature and was diluted with toluene. The solid is collected by filtration and washed with toluene. His suspended in methanol (15 ml) and heated air dryer. It did not dissolve completely, however, it was cooled to room temperature and the solid was collected by filtration and washed with methanol. After drying in air was allocated 175 mg (95% yield) of 2-(2-chlorobenzylamino)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it is in the form of a yellow solid. HRES(+) m/e expect. for C18H13ClN4OS (M+H)+369,0572, detection. 369,0574.

Example 9

2-(2-Chloro-6-methylbenzylamino)-5-[1-(1H-pyrrolo[2,3-b]pyridin-yl)meth-(Z)-ridin]thiazole-4-one

a) Obtaining 2-(2-chloro-6-methylbenzylamino)thiazole-4-it

To a solution of 2-chloro-6-methylbenzylamine (650 mg, 4.2 mmole) and rhodanine (559 mg, 4.2 mmole) in acetonitrile (25 ml) was added DIPEA (of 1.74 ml, 10 mmol) at room temperature. Then the solution was cooled to 0°C was added mercury chloride (1.22 g, 4.5 mmole) in one portion. After the addition, the suspension was heated to room temperature and was stirred for 3 days. The obtained black solid was filtered through a layer of celite and washed with dichloromethane (500 ml) and methanol (250 ml). The combined solvents were removed in vacuo and the crude residue was dissolved in ethyl acetate (25 ml) by heating and kept in the refrigerator over night. Then the solid was collected by filtration and washed with ethyl acetate. After drying in air was allocated 305 mg (28,5% yield) of 2-(2-chloro-6-methylbenzylamino)thiazole-4-it is in the form of a white amorphous solid: EI-HRMS m/e expect. for C11H11ClN2OS (M+) 254,0281, detection. 254,0282.

b) Obtaining 2-(2-chloro-6-methylbenzylamino)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it

To a suspension of 2-(2-chloro-6-methylbenzylamino)thiazole-4-it (63 mg, 0.25 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (44 mg, 0.3 mmole) in toluene (2 ml) Probert is for microwave ovens were added benzoic acid (3.8 mg, 0.03 mmole) and piperidine (3 μl, 0.03 mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 30 minutes Then the mixture was cooled to room temperature and was diluted with toluene. The solid is collected by filtration and washed with toluene. This solid is suspended in methanol (10 ml) and heated air dryer. Although it did not dissolve completely, however, it was cooled to room temperature and the solid was collected by filtration and washed with methanol. After drying in air was provided 58 mg (61% yield) of 2-(2-chloro-6-methylbenzylamino)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it is in the form of a light green solid. HRES(+) m/e expect. for C19H15ClN4OS (M+H)+383,0730, detection. 383,0728.

Example 10

2-[(3-Methylthiophene-2-ylmethyl)amino)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one

a) Obtaining 2-[(3-methylthiophene-2-ylmethyl)amino]thiazole-4-it

To a solution of 3-methylthiophene-2-ylmethylamino (700 mg, 5.5 mmole) and rhodanine (732 mg, 5.5 mmole) in acetonitrile (30 ml) was added DIPEA (1,91 ml, 11 mmol) at room temperature. Then the solution was cooled to 0°C was added mercury chloride (1.52 g, 5.6 mmole) in one portion. After adding a suspension of n is gravely to room temperature and was stirred for 3 days. The obtained black solid was filtered through a layer of celite and washed with acetonitrile (200 ml) and ethyl acetate (250 ml). The combined solvents were removed in vacuo and the crude residue was dissolved in dichloromethane (150 ml) and washed with water (100 ml) and a saturated solution of sodium chloride. After drying with anhydrous magnesium sulfate, the filtrate was removed in vacuo and the residue was dissolved in dichloromethane (10 ml) and was diluted with hexane (10 ml). After cooling in the refrigerator overnight, the solid was collected by filtration and washed with dichloromethane. After drying in air was allocated 390 mg (31,5% yield) 2-[(3-methylthiophene-2-ylmethyl)amino]thiazole-4-it is in the form of a light yellow amorphous solid: EI-HRMS m/e expect. for C9H10N2OS2(M+) 226,0235, detection. 226,0232.

b) Obtain 2-[(3-methylthiophene-2-ylmethyl)amino)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it

To a suspension of 2-[(3-methylthiophene-2-ylmethyl)amino]thiazole-4-it (57 mg, 0.25 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (44 mg, 0.3 mmole) in toluene (2 ml) in vitro for microwave ovens were added benzoic acid (3.8 mg, 0.03 mmole) and piperidine (3 μl, 0.03 mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 30 minutes Then the mixture ohla is given to room temperature and was diluted with toluene (2 ml) and acetonitrile (2 ml) and the mixture was heated air dryer. After cooling to room temperature, the solid was collected by filtration and washed with toluene. This solid is suspended in methanol (10 ml) and heated air dryer. After cooling to room temperature, the solid was collected by filtration and washed with methanol. After drying in air was allocated 35 mg (39,5% yield) 2-[(3-methylthiophene-2-ylmethyl)amino)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it is in the form of an amorphous yellow solid. HRES(+) m/e expect. for C17H14N4OS (M+N)+355,0682, detection. 355,0686.

Example 11

2-(2-Chloro-4-forbindelsen)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one

a) Obtaining 2-(2-chloro-4-forbindelsen)thiazole-4-it

To a solution of 2-chloro-4-forbindelsen (4.5 g, 28,19 mmole) and rhodanine (3.75 g, 28.2 mmole) in acetonitrile (170 ml) was added DIPEA (9,82 ml of 56.4 mmole) at room temperature. Then the solution was cooled to 0°C was added mercury chloride (8,42 g, 31,02 mmole) in two portions over 10 minutes After the addition, the suspension was heated to room temperature and was stirred for 3 days. The obtained black solid was filtered through a layer of celite and washed with acetonitrile (1,0 L) and ethyl acetate (500 ml). The combined solvents were removed in vacuo the e and the crude residue was dissolved in ethyl acetate (150 ml) and washed with water (100 ml) and a saturated solution of sodium chloride (100 ml). After drying with magnesium sulfate, the filtrate was removed in vacuo and the residue was dissolved in ethyl acetate (50 ml). After cooling in the refrigerator overnight, the solids were collected by filtration and washed with hexane. After drying in air was provided 1.2 g (16,5% yield) of 2-(2-chloro-4-forbindelsen)thiazole-4-it is in the form of a white amorphous solid: EI-HRMS m/e expect. for C10H8FN2OS2(M+) 258,0030, detection. 258,0027.

b) Obtaining 2-(2-chloro-4-forbindelsen)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it

To a suspension of 2-(2-chloro-4-forbindelsen)thiazole-4-it (130 mg, 0.5 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (88 mg, 0.6 mmole) in toluene (4 ml) in vitro for microwave ovens were added benzoic acid (7.5 mg, 0.06 to mmole) and piperidine (6 μl, 0.06 to mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 30 minutes Then the mixture was cooled to room temperature and was diluted with toluene (2 ml) and acetonitrile (2 ml) and the mixture was heated air dryer. After cooling to room temperature, the solid was collected by filtration and washed with toluene. This solid substance was dissolved in DMSO (5 ml) by heating and was diluted with acetonitrile (25 ml). After cooling in the refrigerator in tip is the night solids were collected by filtration and washed with acetonitrile. After drying in air was allocated 69 mg (36% yield) of 2-(2-chloro-4-forbindelsen)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it is in the form of amorphous green solid. HRES(+) m/e expect. for C18H12ClFN4OS (M+H)+387,0477, detection. 387,0476.

Example 12

2-[(5-Methylpyrazine-2-ylmethyl)amino]-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one

a) Obtaining 2-[(5-methylpyrazine-2-ylmethyl)amino)thiazole-4-it

To a solution of 2-(aminomethyl)-5-methylpyrazine (3,69 g, 30 mmol) and rhodanine (3,59 g, 27 mmol) in acetonitrile (100 ml) was added DIPEA (10,45 ml, 60 mmol) at room temperature. Then the solution was cooled to 0°C was added mercury chloride (8,15 g, 30 mmol) in two portions over 10 minutes After the addition, the suspension was heated to room temperature and was stirred for 3 days. The obtained black solid was filtered through a layer of celite and washed with acetonitrile (1.0 l) and ethyl acetate (500 ml). The combined solvents were removed in vacuo and the crude residue was dissolved in acetonitrile (25 ml) under heating. After cooling in the refrigerator overnight, the solid was collected by filtration and washed with acetonitrile. After drying in air was allocated 1.5 g (25% yield) 2-[(5-methylpyrazine-2-ylmethyl)amino)thiazole-4-it is in view of the white solid: HRES(+) m/e expect. for C9H10N4OS (M+H)+223,0648, detection. 223,0648.

b) Obtain 2-[(5-methylpyrazine-2-ylmethyl)amino]-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it

To a suspension of 2-[(5-methylpyrazine-2-ylmethyl)amino)thiazole-4-it (112 mg, 0.5 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (88 mg, 0.6 mmole) in toluene (4 ml) in vitro for microwave ovens were added benzoic acid (7.5 mg, 0.06 to mmole) and piperidine (6 μl, 0.06 to mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 30 minutes Then the mixture was cooled to room temperature and was diluted with toluene (2 ml) and acetonitrile (2 ml) and the mixture was heated air dryer. After cooling to room temperature, the solid was collected by filtration and washed with toluene. After drying in air was allocated 80 mg (45,7% yield) 2-[(5-methylpyrazine-2-ylmethyl)amino]-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it is in the form of amorphous green solid. HRES(+) m/e expect. for C17H14N6OS (M+N)+351,1023, detection. 351,1021.

Example 13

2-[2-(3-Forfinal)ethylamino]-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one

a) Obtaining 2-[2-(3-forfinal)ethylamino]thiazole-4-it

RA is Toro 3-fortunetelling (a 3.06 g, 22 mmole) and rhodanine (2.66 g, 20 mmol) in acetonitrile (70 ml) was added DIPEA (7,66 ml, 44 mmole) at room temperature. Then the solution was cooled to 0°C was added mercury chloride (5,97 g, 22 mmole) in two portions over 10 minutes After the addition, the suspension was heated to room temperature and was stirred for 2 days. The obtained black solid was filtered through a layer of celite and washed with acetonitrile (1.0 l) and ethyl acetate (500 ml). The combined solvents were removed in vacuo and the crude residue was dissolved in ethyl acetate (100 ml) and water (100 ml). Two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined extracts were washed with a saturated solution of sodium chloride and dried with anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was removed in vacuo and the crude residue was dissolved in acetonitrile (25 ml) under heating. After cooling in the refrigerator overnight, the solids were collected by filtration and washed with acetonitrile. After drying in air was allocated 3,65 g (76,6% yield) 2-[2-(3-forfinal)ethylamino]thiazole-4-it is in the form of a white solid: HRES(+) m/e expect. for C11H11FN2OS (M+H)+239,0649, detection. 239,0647.

b) Obtain 2-[2-(3-forfinal)ethylamino]-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it

To a suspension of 2-[2-(3-forfinal)ethylamino]thiazole-4-it (120 mg, 0.5 mmole) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (88 mg, 0.6 mmole) in toluene (4 ml) in vitro for microwave ovens were added benzoic acid (7.5 mg, 0.06 to mmole) and piperidine (6 μl, 0.06 to mmole) at room temperature. Tube for microwave oven was closed and heated at 150°C. in a sealed microwave oven for 30 minutes Then the mixture was cooled to room temperature and was diluted with toluene (2 ml) and acetonitrile (2 ml) and the mixture was heated air dryer. After cooling to room temperature, the solid was collected by filtration and washed with acetonitrile. After drying in air was allocated 170 mg (93% yield) 2-[2-(3-forfinal)ethylamino]-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-it is in the form of a yellow solid. HRES(+) m/e expect. for C19H15FN4OS (M+H)+367,1024, detection. 367,1021.

Example 14

2 Cyclopropylamino-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-one

a) obtaining a 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)thiazole-4-it

A suspension of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (example 16, 1.2 g, by 8.22 mmole), rhodanine (1,09 g, by 8.22 mmole) and sodium acetate (2,69 g, 32,8 mmole) in acetic acid (12 ml) was stirred at boiling under reflux in t is the increase in the 12 o'clock After cooling to room temperature was added water (150 ml). The solid is collected by filtration, washed with water and dried to obtain 5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)-2-thioxothiazolidin-4-it (2.2 g, 100%) as a brown solid. LC-MS m/e 262 (MN+).

A suspension of 5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)-2-thioxothiazolidin-4-it (2.2 g, by 8.22 mmole), iodomethane (1,05 ml of 16.8 mmole) and DIEA (3.0 ml, is 16.8 mmole) in anhydrous ethanol (110 ml) was stirred at 100°C for 2 hours After adding water (200 ml), the solid was collected by filtration, washed with water and dried to obtain 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)thiazole-4-it (1.48 g, 60.8 per cent) as a gray solid. LC-MS m/e 276 (MN).

b) Obtaining 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)thiazole-4-it

A suspension of 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)thiazole-4-it (55 mg, 02 mmole, example 14a), cyclopropylamine (23 mg, 0.4 mmole) and diisopropylethylamine (DIEA) (70 μl, 0.4 mmole) in acetonitrile (1.0 ml) was stirred at 80°C for 12 hours After cooling to room temperature, the solid was collected by filtration, washed with a small amount of acetonitrile and dried. Express chromatography (silica gel Merck 60, 230-400 mesh mesh, 0%-10% methanol in methylene chloride for 30 min) resulted in obtaining 2-cyclopropylamino-5-[1-(1H-pyrrol the[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-it (40 mg, 71%) as a pale yellow solid. LC-MS m/e 285 (MN+).

Example 15

2-Amino-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-one

A suspension of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (example 16, 200 mg, 1.4 mmole), pseudothiohydantoin (159 mg, 1.4 mmole) and sodium acetate (459 mg, 5.6 mmole) in acetic acid (2 ml) was stirred at the boil under reflux for 12 hours After cooling to room temperature, added water. The solid is collected by filtration, washed with water and dried to obtain 2-amino-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-it (280 mg, 82%) as a pale yellow solid. LC-MS m/e 245 (MN+).

Example 16

2-((R)-1-Hydroxymethyl-3-methylbutylamine)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-one

Used a similar technique as described in example 146, based on 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)thiazole-4-it (example), 2-((R)-1-hydroxymethyl-3-methylbutylamine and DIEA obtaining 2-((R)-1-hydroxymethyl-3-methylbutylamine)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-it. LC-MS m/e 345 (MN+).

Example 17

2-[(R)-1-(4-Forfinal)-2-hydroxyethylamino-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-one

a) Obtaining (R)-2-(4-forfinal)1-hydroxymethylbilane

To a solution of sodium borohydride (0.54 g, 14.2 mmole) in THF (10 ml) was added D-4-florfenicol (1.0 g, 5.9 mmole). After cooling to 0°C was added dropwise a solution of iodine (1.5 g, 5.9 mmole) in THF (10 ml). The resulting mixture was stirred at the boil under reflux for 18 hours After cooling to room temperature, was added methanol (7 ml) to stop the reaction. After removal of solvent was added 20% potassium hydroxide (50 ml). The mixture was stirred for 4 h and was extracted with methylene chloride (3×50 ml). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuum. Express chromatography (Merck silica gel 60, 70-230 mesh, 0%-10% methanol in 0%-5% methanol in methylene chloride for 30 min) resulted in obtaining (R)-2-(4-forfinal)-1-hydroxymethylbilane (0,63 g, 69%).

b) Obtain 2-[(R)-1-(4-forfinal)-2-hydroxyethylamino]-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-it

Used a similar technique as described in example 14b, based on 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)thiazole-4-it (example 14a), 2-[(R)-1-(4-forfinal)-2-hydroxyethylamine and DIEA to obtain 2-[(R)-1-(4-forfinal)-2-hydroxyethylamino]-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-it. LC-MS m/e 383 (MN+).

Example 18

2-(2-Methoxyphenylazo)-5-[1-IT-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-one

Used a similar technique as described in example 14b, based on 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)thiazole-4-it (example 14a), 2-(2-methoxybenzylamine and DIEA obtaining 2-(2-methoxyphenylazo)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-it. LC-MS m/e 351 (MN+).

Example 19

Pharmacological tests

Pharmacological properties of the compounds of the present invention can be confirmed by a number of pharmacological assays. The following presents examples of pharmacological tests carried out with the compounds in accordance with the present invention and their salts. Compounds according to the invention show activity against CDK1/cyclin b and SOC/CYCLIN E with Ki values less than 5.0 μm. This shows that all these compounds are active in the inhibition of CDKl/cyclin b and SVK/cyclin E.

To determine the inhibitory activity against CDK1 carried out or FlashPlate™ (NEN™Life Science Products) analysis, or HTRF assay. Both types of analyses kinase was performed using recombinant complex CDK1/cyclin In person. GST-cyclin B (GST-cycB) and cDNA CDK1 clones in baculovirus vectors received from Dr. W. Harper at Baylor College of Medicine, Houston, TX. Proteins were coexpression in High Five™ cells and the complex was purified on glutathione Sepharose resin (Pharmacia, Piscataway, NJ)as described previously (article Harper, J.W. and other Cell 1993, 75, SC-816). 6x-histidine-tagged truncated form of the protein retinoblastoma (Rb) (amino acids 386-928) was used as substrate for the assay with CDK1/cyclin B (expressed plasmid was obtained from Dr. Veronica Sullivan, Department of Molecular Virology, Roche Research Centre, Welwyn Garden City, United Kingdom). Protein Rb is a natural substrate for CDK1 phosphorylation (see Herwig and Strauss, Eur. J. Biochem., 1997, T. 246, cs-601 and links provided here). The expression of protein 62Kd conducted under the control of the IPTG inducible promoter in strain 5 Ml E. coli. The cells were liofilizovane sonification and purification was performed when linking lysates from pH 8.0 to a column of Ni-chelated agarose, pre-treated with a 1 mm imidazole. The resin was then washed several times with buffers of increasing pH up to pH 6.0, and was suirable 500 mm imidazole. Suirvey protein dialyzed 20 mm HEPES with pH 7.5, 30% glycerol, 200 mm NaCl and 1 mm DTT. In purified fused protein Rb quantify the protein concentration, divided into aliquots and stored at -70°C.

For analysis of kinase FlashPlate 96-well tablets FlashPlates were covered by the Rb protein at a concentration of 10 μg/ml using 100 µl per well. The plates were incubated at 4°C overnight or at room temperature for 3 hours on a shaker. To control for nonspecific phosphorylation of a single row of holes were covered with 100 μl/well buffer coating (20 mm HEPES, 0 M NaCl). The tablets were then washed twice with washing buffer (0.01% of Tween 20 in phosphate buffered salt solution). Test compounds ("test compounds") were added to the wells with finite 5x concentration. The reaction was initiated by the immediate addition of 40 μl of reaction mixture (25 mm HEPES, 20 mm MgCl2, 0,002% Tween 20, 2 mm DTT, 1 μm ATP, 4 nm SSR-ATP) and a sufficient amount of enzyme to obtain the final values that are at least 10 times above the baseline level. The plates were incubated at room temperature on a shaker for 30 minutes. The tablets were washed four times with wash buffer, closed and quantitatively determined on a TopCount scintillation counter (Packard Instrument Co., Downers Grove, IL]. The percentage inhibition of Rb phosphorylation, which was measured by the inhibition of CDK activity, was determined in accordance with the following formula:

where "test connection" denotes the average value per minute of the test duplicates, "non-specific" refers to average values per minute without adding complex CDK1/cyclin B, and so on, and "total" denotes the average value per minute with no added compound. The value of the IC50represents the concentration of test compound which reduces by 50% the introduction of a radioactive label, is caused by the protein kinase, described the conditions of the esta. The value of the inhibition constants Ki were calculated as follows: Ki=IC50/(l+[S]/Km), where [S] is the concentration of ATP and Km is the Michaelis constant.

Analysis of kinase homogeneous fluorescence with a time resolution (HTRF) was carried out in 96-well polypropylene plates (BD Biosciences, Bedford, MA). The test compounds were first dissolved in DMSO and then diluted with buffer to analyze kinase 1 (25 mm HEPES, rn,0, 8 mm MgCl21.5 mm DTT and 162 μm ATP) concentration of DMSO 15%. The enzyme CDK1/cyclin b was diluted with buffer for analysis of kinase 2 (25 mm HEPES, pH 7.0, 8 mm MgCl2, 0,003% Tween 20, 0,045% BSA, 1.5 mm DTT and 0,675 μm protein Rb). To initiate the kinase reaction, 20 μl of a solution of the compound was mixed with 40 μl of a solution of CDK1/cyclin In in tablets for analysis with the final concentration of CDK1/cyclin b and Rb 0.1 ág/ml and 0,225 μm, respectively, and incubated at 37°C for 30 min 15 ál of antiphospho-Rb (Ser 780) antibodies (Cell Signaling Technology, Beverly, MA) with antibody dilution 1:7692. Incubation continued at 37°C for 25 min, after which the wells were added LANCE Eu-W1024 labeled anti-rabbit IgG (1 nm, PerkinElmer, Wellesley, MA) and anti-His antibody conjugated to SureLight-allophycocyanin (20 nm, PerkinElmer, Wellesley, MA). Incubation continued at 37°C for 40 minutes After the end of the incubation 35 μl of reaction mixture was transferred into a clean 384-well black tablet isolateral (Corning Incorporated, Corning, NY) and counted on the counter fluorescence with a wavelength of excitation of 340 nm and an absorption wavelength 665/615 nm.

To determine the inhibition of CDK2 activity used a similar methodology as described above for the analysis of CDK-1/cyclin b for activity SOC/cyclin E, except that the analysis used the complex SOC/cyclin E.

The values of Ki, showing activity against Cdk1/cyclina In, for compounds of the present invention comprise from about 0,001 microns to about 5,000 microns. Specific data for some of the examples are as follows:

ExampleCDK1, Ki (μm)CDK2, Ki (μm)
50,0100,017
100,0480,018
150,830,252
181,150,187

1. The compound of the formula:

where R1selected from hydrogen, hydroxy-lower alkyl, C3-C6cycloalkyl and R2(X)n;
X is selected from lower alkylene, hydroxy-Nisse is about alkylene, satelitarna lower alkylene and lower alkanoyloxy-lower alkylene;
R2represents a
;
andselected from phenyl and 5 - or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from the group consisting of sulfur and nitrogen;
R5and R6independently selected from the group consisting of hydrogen, lower alkyl, halogen and lower alkoxy; and
n is 0 or 1;
their pharmaceutically acceptable salts.

2. The compound according to claim 1, where the specified compound has the formula I-A:

where R1' is selected from hydrogen, hydroxy-lower alkyl and C3-C6cycloalkyl;
or its pharmaceutically acceptable salt.

3. The compound according to claim 2, where the specified connection is a 2-amino-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-one.

4. The compound according to claim 2, where R1' represents a C3-C6cycloalkyl.

5. The compound according to claim 4, where the specified connection is a 2-cyclopropylamino-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-one.

6. The compound according to claim 2, where R1' represents a hydroxy-lower alkyl.

7. The connection according to claim 6, where the specified connection is a 2-((R)-1-hydroxymethyl-3-methylbutylamine)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)ilidene]thiazole-4-one.

8. The connection according to claim 6, where the specified connection is a 2-(1-(R) - hydroxymethyl-2-methylpropylamine)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one.

9. The compound according to claim 1, where the specified compound has the formula I-B:

where R1" is an R2(X)n-;
and R2, n and X are such as defined in claim 1;
or its pharmaceutically acceptable salt.

10. The connection according to claim 9, where n denotes 1.

11. The connection of claim 10, where X represents sallisbury lower alkylene.

12. Connection claim 11, where the specified sallisbury lower alkylen is cyclopropyl.

13. The connection indicated in paragraph 12
where R2represents;
represents phenyl;
and R5and R6have the meanings given in claim 1.

14. The connection indicated in paragraph 13, where the specified connection is a 2-((1R,2S)-2-vinylcyclopropyl)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one.

15. The connection of claim 10, where X represents a lower alkanoyloxy lowest alkylen.

16. The connection indicated in paragraph 15
where R2represents;
represents phenyl;
and R5and R6have the meanings given in claim 1.

17. Connection P16, DG is the specified connection is a 2-[4-oxo-5-(1H-pyrrolo[2,3,b]pyridine-3-ylmethylene)-4,5-dihydrothieno-2-ylamino]-2-(R)-phenethyl ester acetic acid.

18. The connection of claim 10, where X represents the lowest alkylen.

19. Connection p,
where R2represents;
represents phenyl;
and R5and R6have the meanings given in claim 1.

20. The connection according to claim 19, where R5and R6represent hydrogen.

21. The connection according to claim 19, where R5independently represents halogen or lower alkyl; R6represents hydrogen, halogen or lower alkyl.

22. Connection item 21, where the specified connection is a 2-(2-chlorobenzylamino)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one.

23. Connection item 21, where the specified connection is a 2-(2-chloro-6-methylbenzylamino)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one.

24. Connection item 21, where the specified connection is a 2-(3-chloro-4-forbindelsen)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one.

25. Connection item 21, where the specified connection is a 2-(2-chloro-4-forbindelsen)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one.

26. Connection item 21, where the specified connection is a 2-[2-(3-forfinal)ethylamino]-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one.

27. Connection p,
where R2represents ;
andrepresents a heteroaromatic ring containing 1 or 2 heteroatoms selected from the group consisting of nitrogen and sulfur;
and R5and R6have the meanings given in claim 1.

28. Connection item 27, where the aforementioned heteroaromatic ring contains 1 heteroatom.

29. Connection p, where the heteroatom is an atom of sulfur.

30. Connection p, where R5and R6represent hydrogen or lower alkyl.

31. Connection item 30, where the specified connection is a 5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]-2-[(thiophene-2-ylmethyl)amino]thiazol-4-one.

32. Connection item 30, where the specified connection is a 2-[(3-methylthiophene-2-ylmethyl)amino)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one.

33. Connection item 27, where the aforementioned heteroaromatic ring containing two heteroatoms.

34. Connection p, where two heteroatoms are nitrogen atom.

35. The connection 34, where R5and R6independently selected from the group consisting of hydrogen and lower alkyl.

36. Connection p, where the specified connection is a 2-[(5-methylpyrazine-2-ylmethyl)amino]-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one.

37. The connection of claim 10, where X represents a hydroxy-lower alkylene.

38. The connection clause 37,
where R2represents;
represents phenyl;
and R5and R6have the meanings given in claim 1.

39. Connection § 38, where R5and R6independently selected from halogen, hydrogen and lower alkyl.

40. Connection § 39, where the specified connection is a 2-(2-hydroxy-1-(R)-phenylethylamine)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ridin]thiazole-4-one.

41. Connection § 39, where the specified connection is a 2-[(R)-1-(4-fluoro-phenyl)-2-hydroxyethylamino]-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-one.

42. The connection according to claim 9, where n denotes 0;
and R2represents;
represents phenyl;
and R5and R6have the meanings given in claim 1.

43. Connection § 42, where R5and R6independently selected from hydrogen, lower alkyl and lower alkoxy.

44. Connection p.43, where the specified connection is a 2-(2-methoxyphenylazo)-5-[1-(1H-pyrrolo[2,3-b]pyridine-3-yl)meth-(Z)-ilidene]thiazole-4-one.

45. The compound of formula I according to claim 1, having inhibitory activity against CDK1 and/or CDK2 kinases.

46. The pharmaceutical composition intended for the treatment or control of disease, a condition in which the s can be improved by inhibiting CDK1 and/or CDK2 kinase, containing an effective amount of a compound of formula I according to claim 1 as an active ingredient, together with pharmaceutically acceptable excipients.

47. The pharmaceutical composition according to item 46, intended for the preparation of drugs for the treatment of cancer, particularly breast cancer, prostate cancer, colon cancer and lung cancer.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula where L1 and L2 independently denote a bond, -S-, -NH- or unsubstituted C1-C5alkylene; A1 denotes a 6-member substituted aryl or unsubstituted heteroaryl; A2 denotes aryl or heteroaryl; R1 denotes halogen, -OR5, -NR6R7, -C(Z)R8, -S(O)wR9, -CN, -NO2, -S(O)2NH2, alkyl, aryl or heteroaryl; X1 denotes -C(R2)=, -C(R2)(R3)-, -N(R4)- or -O-; R2 and R3 independently denote hydrogen, -OR5 or alkyl; R4 denotes hydrogen or alkyl; Z denotes O or NH; w is integer from 0 to 2; R5 independently denotes hydrogen or alkyl; R6 and R7 independently denote hydrogen, -S(O)2R11 alkyl or heteroalkyl; R11 denotes hydrogen or alkyl; R8 independently denotes hydrogen, -NR14R15, -OR16, heteroalkyl or cycloalkyl; R14, R15 and R16 independently denote hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl; R9 independently denotes hydrogen or alkyl; and where R6 and R7, R14 and R15 independently and optionally together with the nitrogen atom to which they are bonded form a substituted or unsubstituted heterocycloalkyl. The invention also relates to a method of modulating protein kinase activity, as well as to use of compounds in paragraph 1 and a pharmaceutical composition based on the said compounds.

EFFECT: new compounds which can be useful in treating diseases mediated by kinase activity are obtained and described.

47 cl, 2 ex, 40 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel condensed heterocylic protein kinase modulators of formula I where L1 and L2 independently denote a bond, and R1 and R2 denote a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl, as well as to pharmaceutical compositions containing such compounds, and methods of using the compounds to prepare medicine for diseases mediated by protein kinase activity.

EFFECT: increased effectiveness of using the compounds.

24 cl, 20 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from compounds of formulae Ia, lb and Ic, which have protein kinase activity on kinase selected from CDKs, Aurora, Jak2. Rock, CAMKI, FLT3, Tie2, TrkB, FGFR3 and KDR, abnormal activity of which is observed in pathological conditions such as nonmalignant and malignant proliferative diseases. In compounds of formulae , and : n equals 0 or 1, R1 is selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted CpC6alkyl and halogen-substituted C1-C6alkoxy, R2 is selected from a group comprising phenyl, 6-member heteroaryl containing 1-2 nitrogen atoms in the heteroaryl ring as heteroatoms, and phenyl(C0-C4)alkyl, where the said phenyl and heteroaryl in R2 are optionally substituted with 1-3 radicals independently selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy, -S(O)0-2R5, -COOR5 and -NR5C(O)R6, where R5 is selected from C1-C6alkyl, and R6 is selected from phenyl, where the said phenyl in R6 is optionally substituted with 1-3 radicals independently selected from a group comprising C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy, X is selected from CR7 and N, where R7 is selected from hydrogen or C1-C6alkyl.

EFFECT: increased effectiveness of using the compounds.

7 cl, 3 dwg, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydropyridoindole derivatives of general formula , where R1, R2, R3 and R4 independently represent hydrogen; C1-C5alkyl, which can be optionally substituted and represents trifluoromethyl if C1-C5alkyl is substituted; C1-C3alkoxy or halogen, and R5 is C1-C6alkylcarbonyl, C1-C5alkylcarbamoyl, C1-C5alkoxycarbonyl, C2-C5alkenylcarbonyl, C3-C6cycloalkylcarbonyl, C3-C6cycloalkyl(C1-C3)alkylcarbonyl, C3-C6cycloalkylcarbamoyl, C3-C6cycloalkylthiocarbamoyl, phenylcarbonyl or phenyl(C1-C3)alkylcarbonyl, where the phenyl residue in these two groups contains one, two, three or four substitutes, independently selected from a group comprising C1-C4alkyl, C1-C3alkoxy, halogen, trifluoromethyl and trifluoromethoxy, monosubstituted with a C3-C6cycloalkyl group, or monosubstituted with a phenyl group which in turn is substituted with a C1-C3alkyl group; phenyl(C1-C3)alkoxycarbonyl, phenylcarbamoyl or phenylthiocarbamoyl (where these two groups are optionally independently monosubstituted with a C1-C5alkyl group or halogen atoms); phenyl(C1-C3)alkylcarbamoyl, phenyl(C1-C3)alkylthiocarbamoyl, biphenylcarbamoyl, naphthylcarbonyl, naphthyl(C1-C3)alkylcarbonyl or naphthylcarbamoyl (where the naphthyl residues in these three groups are optionally monosubstituted with substitutes independently selected from a group comprising C1-C3alkyl, C1-C3alkoxy and halogen); fluorenylcarbonyl, optionally substituted with an oxo group, fluorenyl(C1-C3)alkoxycarbonyl; or 5-9-member heteroarylcarbonyl groups containing one or two heteroatoms, independently selected from a group comprising oxygen, nitrogen and sulphur, where the said groups can be substituted with one or two groups independently selected from C1-C3alkyl and halogen, provided that if R1, R2, R3, R4 are hydrogen, R5 is not ethoxycarbonyl or tert-butoxycarbonyl, or salt thereof. The invention also relates to a pharmaceutical composition based on the compound of formula I and to use of the compound in preparing a medicinal agent.

EFFECT: obtaining novel tetrahydropyridoindole derivatives which have CRTH2 receptor antagonistic activity.

14 cl, 14 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel therapeutically suitable derivatives of pyridazin-3(2H)-one of formula and pharmaceutical compositions containing the said derivatives. These compounds are used for treating, preventing or inhibiting corresponding pathological conditions, diseases or disorders, mainly asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable colon syndrome.

EFFECT: obtaining compounds which are active and selective phosphodiesterase 4 (PDE4) inhibitors.

11 cl, 1 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), their N-oxide forms, pharmaceutically acceptable additive salts and stereochemically isomeric forms as 11-HSD1 inhibitors, to their use, a pharmaceutical composition based on the said compounds and method of obtaining the said compounds. In general formula (I) , X is C or N; Y is C or N; L is methyl or a single bond; Z1 is a single bond, C1-2alkyl or a radical of formula -CH=; Z2 is a single bond, C1-2alkyl; R1 is hydrogen, halogen, hydroxy; R2 is hydrogen, halogen or C1-4alkyloxy; A is phenyl or a monocyclic heterocycle selected from a group consisting of thiophenyl or pyrridinyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by 11-HSD1.

9 cl, 7 dwg, 2 tbl, 34 ex

FIELD: medicine.

SUBSTANCE: invention relates to method of treating human patient with cancer by means of combined therapy with application of ET-743 in doses smaller than 1200 mcg/ m2 per day and platinum anti-tumour agent - carboplatin in doses from 200 to 400 mcg/ m2 per day. Application of ET-743 in combination with carboplatin in the same range of dosage as it is used in case of individual carboplatin introduction results in overcoming of resistance to platinum anti-tumour compound without increase of toxicity of each medication.

EFFECT: invention also relates to medical set which includes combination of ET-743 and carboplatin in said dosages, pharmaceutically acceptable carrier and treatment scheme instruction.

29 cl, 10 tbl, 5 ex

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to biotechnology, specifically obtaining hemopoietic cells from blood, and may be used in medicine. The homopoietic cell CD34+ is extracted from peripheral blood of cancer patients undergone a growth factor treatment course. The obtained cell is transduced by a ligand which induces apoptosis with participation of the tumour necrosis factor, and is used to treat tumours.

EFFECT: invention enables to obtain a hemopoietic cell CD34+ which has anti-tumuor activity.

6 cl, 3 dwg, 8 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to ophthalmology and concerns treating conjunctiva nevus. That is ensured by administration of tabletted or capsulated chitosan in a dose 125-300 mg 2-3 times a day within a month.

EFFECT: method provides effective treatment of the disease without surgical intervention.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new condensed compounds (versions) or their pharmaceutically acceptable salts having inhibitory effect on HER2 and/or EGFR kinase, having the following formula, for example: or , where R1a is a hydrogen atom; R2a is a C1-8alkyl group, C2-8alkenyl group or C2-8alkynyl group, each of which is substituted with substitute(s), R3a is a hydrogen atom or C1-6alkyl group; or R1a and R2a are optionally bonded with formation or R2a and R3a are optionally bonded with formation of C2-4alkylene; Ba is a benzene ring optionally substituted with 1-4 substitutes selected from halogen and optionally halogenated C1-4alkyl; Ca is a phenyl group substituted with 1-5 substitutes selected from (i) halogen, (ii) optionally halogenated C1-4alkyl, (iii) hydroxy- C1-4alkyl, (iv) a 5-8-member heterocycle- C1-4alkyl, where the said 5-8-member heterocycle contains 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and optionally oxidised sulphur atom, (v) optionally halogenated C1-4alkyloxy, (vi) cyano and (vii) carbamoyl, optionally substituted with C1-8alkyl, and, respectively, R2e is a C1-4alkyl group optionally substituted with -O-(CH2)n-OH, where n is an integer from 1 to 4; R3e is a hydrogen atom; Be is a benzene ring optionally substituted with a halogen; and Ce is a phenyl group optionally substituted with halogenated C1-4alkyl.

EFFECT: obtained new compounds can be used for treating cancer.

22 cl, 2 tbl, 280 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula where L1 and L2 independently denote a bond, -S-, -NH- or unsubstituted C1-C5alkylene; A1 denotes a 6-member substituted aryl or unsubstituted heteroaryl; A2 denotes aryl or heteroaryl; R1 denotes halogen, -OR5, -NR6R7, -C(Z)R8, -S(O)wR9, -CN, -NO2, -S(O)2NH2, alkyl, aryl or heteroaryl; X1 denotes -C(R2)=, -C(R2)(R3)-, -N(R4)- or -O-; R2 and R3 independently denote hydrogen, -OR5 or alkyl; R4 denotes hydrogen or alkyl; Z denotes O or NH; w is integer from 0 to 2; R5 independently denotes hydrogen or alkyl; R6 and R7 independently denote hydrogen, -S(O)2R11 alkyl or heteroalkyl; R11 denotes hydrogen or alkyl; R8 independently denotes hydrogen, -NR14R15, -OR16, heteroalkyl or cycloalkyl; R14, R15 and R16 independently denote hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl; R9 independently denotes hydrogen or alkyl; and where R6 and R7, R14 and R15 independently and optionally together with the nitrogen atom to which they are bonded form a substituted or unsubstituted heterocycloalkyl. The invention also relates to a method of modulating protein kinase activity, as well as to use of compounds in paragraph 1 and a pharmaceutical composition based on the said compounds.

EFFECT: new compounds which can be useful in treating diseases mediated by kinase activity are obtained and described.

47 cl, 2 ex, 40 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and can be used in treating the patients with Non Hodgkin Lymphoma. That is ensured by administration of a combination containing an effective amount of CCI-779 and rituximab in the form of a dosage form with one or more neutral components added. The combination is introduced simultaneously, separately or consistently with the other agents.

EFFECT: method allows improving clinical effectiveness for the given pathology, including in the patients resistant to rituximab due to synergetic interactions of these preparations.

5 cl

Cancer treatment // 2389507

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to new drugs and preparations containing effective anticancer agent with anti-Hsp90 antibody.

EFFECT: invention improves clinical effectiveness in treating cancer and leukemia.

48 cl, 25 tbl

Cancer treatment // 2389507

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to new drugs and preparations containing effective anticancer agent with anti-Hsp90 antibody.

EFFECT: invention improves clinical effectiveness in treating cancer and leukemia.

48 cl, 25 tbl

FIELD: medicine.

SUBSTANCE: group of the inventions refers to medicine, namely to oncology and immunology and can be used for treating renal cell carcinoma or thymoma. The method is implemented as follows: Polypeptide containing amino acid precipitations 1-182 of a sequence SEQ ID NO:29 or precipitations 1-176 of a sequence SEQ ID NO: 159, is used for preparing a drug for treating renal cell carcinoma. Another aspect of the invention concerns application of polypeptide containing amino acid precipitations 1-176 of the sequence SEQ ID NO: 159 for preparing a drug for treating thymoma.

EFFECT: application of the inventions allows improving clinical effectiveness in said diseases due to tumour induction polypeptide reaction with reducing cytotoxic by-effects.

5 cl, 35 tbl, 6 dwg, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula where L1 and L2 independently denote a bond, -S-, -NH- or unsubstituted C1-C5alkylene; A1 denotes a 6-member substituted aryl or unsubstituted heteroaryl; A2 denotes aryl or heteroaryl; R1 denotes halogen, -OR5, -NR6R7, -C(Z)R8, -S(O)wR9, -CN, -NO2, -S(O)2NH2, alkyl, aryl or heteroaryl; X1 denotes -C(R2)=, -C(R2)(R3)-, -N(R4)- or -O-; R2 and R3 independently denote hydrogen, -OR5 or alkyl; R4 denotes hydrogen or alkyl; Z denotes O or NH; w is integer from 0 to 2; R5 independently denotes hydrogen or alkyl; R6 and R7 independently denote hydrogen, -S(O)2R11 alkyl or heteroalkyl; R11 denotes hydrogen or alkyl; R8 independently denotes hydrogen, -NR14R15, -OR16, heteroalkyl or cycloalkyl; R14, R15 and R16 independently denote hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl; R9 independently denotes hydrogen or alkyl; and where R6 and R7, R14 and R15 independently and optionally together with the nitrogen atom to which they are bonded form a substituted or unsubstituted heterocycloalkyl. The invention also relates to a method of modulating protein kinase activity, as well as to use of compounds in paragraph 1 and a pharmaceutical composition based on the said compounds.

EFFECT: new compounds which can be useful in treating diseases mediated by kinase activity are obtained and described.

47 cl, 2 ex, 40 tbl

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