Acyl thiourea derivative or salt thereof and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to novel acyl thiourea derivatives of formula or a pharmaceutically acceptable salt thereo, where R1 is a hydrogen atom or a C1-3 alkyl group; R2 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C6-14 aromatic hydrocarbon group or an optionally substituted saturated or unsaturated 5-7-member heterocyclic group containing 1 or 2 nitrogen or sulphur atoms, or R1 and R2, together with the nitrogen atom which they are bonded, can form an optionally substituted nitrogen-containing saturated heterocyclic group selected from a group comprising pyrrolinyl, piperidinyl, piperazinyl or morpholino group; where the substitute is selected from a group comprising a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-6 alkanoyl group, a C1-6 alkyl group, a C3-10 cycloalkyl group, a C2-6 alkenyl group, C1-6 alkoxy group, an amino group, a C1-6 alkylamino group, a C1-6 alkanoylamino group, a C1-6 alkylaminocarbonyl group, a C1-6 alkylsulphonyl group, a C6-14 aromatic group, a saturated or unsaturated 5-7-member heterocyclic group containing 1-4 nitrogen and/or oxygen atoms, a saturated or unsaturated 5-7-member heterocycyl-carbonyl group containing 1 or 2 nitrogen and/or oxygen atoms, and an oxo group; R3 is a C1-6 alkyl group; and R4 is a halogen atom; R5 and R6, which can be identical or different from each other, denote a hydrogen atom, a halogen atom, a C1-3 alkyl group which can be substituted with a halogen atom, or a C1-6 alkoxy group. The invention also relates to a pharmaceutical or anti-tumour agent based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel acetyl thiourea derivatives having c-Met inhibiting activity are obtained.

11 cl, 2 dwg, 4 tbl, 56 ex

 

The scope of the invention

The present invention relates to a new derivative ulltimately or its salts, and to its use.

Background of the invention

The enzyme c-Met is a receptor tyrosine kinase identified as a proto-oncogene and manifests its physiological function when attached to HGF serving as a ligand. In normal tissues c-Met plays a role in regeneration, the treatment of wounds and the formation of bodies. However, in many cancer cells (cancer cells, kidney, stomach cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, cancer of the liver cells, head and neck cancer, melanoma, and so on) promoterwise manifestation of overexpression, mutation or translocation of c-Met, which leads to excessively activated state (non-patent document 1). In such conditions, the c-Met plays a role in cell proliferation, infiltration/metastasis, tumorigenesis, the formation of new blood vessels and anti-apoptosis (see non-patent documents 2, 3 and 4). In addition, many studies have revealed that overexpression and increased levels of activated c-Met in cancer cells negatively correlated with prediction of the future course of the disease, and it is known that c-Met is a factor associated with adverse prognosis of the cancer (see non-patent documents 5 and 6).

Thus, if titsa drug, which specifically inhibits c-Met in cancer cells/tumor, in which c-Met is activated by overexpression, proliferation, infiltration and metastasis of cancer cells could be ingibirovany more specifically and intensively, and, thus, considered to be the drug will contribute to the treatment of cancer, prolonging the life of patients and improve QOL. Meanwhile, in modern therapy, because the expression level and activation of c-Met serve as indicators to stratify patients, patients could receive appropriate treatment, which is highly preferable from an ethical point of view.

To the present time has been widely studied application of derivatives ulltimately as pharmaceutical agents or other agents (see, for example, patent documents 1 to 7). However, never reported derivative ulltimately of the present invention, represented by formula (I)where the specified connection has aminocarbonyl group as a substituent in the 6-position of the quinoline ring and an alkoxy group as a substituent in the 7-position of the quinoline ring.

Documents related to the level of technology

Non-patent documents

Non-patent document 1: Cancer Letters 225, p. 1-26 (2005).

Non-patent document 2: J. Cell Biol. 111, p. 2097-2108 (1990).

Non-patent is a document 3: Semin Cancer Biol, 11, p. 153 to 165 (2001).

Non-patent document 4: Am. J. Pathol., 158, p. 1111-1120 (2001).

Non-patent document 5: Jpn. J. Cancer Res., 87, p. 1063-1069 (1996).

Non-patent document 6: Cancer, 85(9), p.1894-1902 (1999).

Patent documents

Patent document 1: WO 2001/047890.

Patent document 2: WO 2002/032872.

Patent document 3: WO 2003/000660.

Patent document 4: WO 2005/030140.

Patent document 5: WO 2005/121125.

Patent document 6: WO 2006/104161.

Patent document 7: WO 2006/108059.

The invention

Objectives of the invention

The object of the present invention is an antitumor agent, which shows excellent inhibition of c-Met activity and which reduces side effects by selective destruction of tumor cells, which is specifically expressed c-Met.

Means for solving the assigned tasks

The creators of the present invention conducted intensive studies to solve the above problems and found that, compared with the above-mentioned compounds that possess inhibiting c-Met activity, derived ulltimately of the present invention, represented by formula (I), a compound that aminocarbonyl group as a substituent in the 6-position of the quinoline ring and an alkoxy group as a substituent in the 7-position of the quinoline ring (1) has an inhibitory c-Met, equivalent to or higher than that possessed by the well-known compounds in in vitro studies, (2) shows a higher electoral striking action against tumor cells in which c-Met is over-expressed or highly activated, compared with tumor cells in which c-Met is expressed in a lower degree, and normal cells, and (3) reduces side effects and shows a strong regression of tumors in vivo studies that use xenotransplantation model. In other words, the creators of the present invention discovered that a derivative ulltimately represented by the formula (I), which selectively acts on tumor cells, which is specifically expressed c-Met, reduces side effects and can be used as an excellent anticancer agent. The present invention has been established on the basis of this discovery.

Accordingly, the present invention relates to a derivative ulltimately represented by the formula (I):

where each of R1and R2that may be the same or different, represents a hydrogen atom, optionally substituted C1-6alkyl group, optionally substituted C3-10cycloalkyl group, not necessarily alsenoy C 6-14aromatic hydrocarbon group or optionally substituted saturated or unsaturated heterocyclic group, or R1and R2may form, together with the nitrogen atom to which they are attached, optionally substituted nitrogen-containing heterocyclic ring;

R3represents a C1-6alkyl group; and

each of R4, R5and R6that may be the same or different from each other, represents a hydrogen atom, halogen atom, optionally substituted C1-6alkyl group, a C1-6alkoxy group, a C1-6alkylamino group, optionally substituted aromatic hydrocarbon group or optionally substituted saturated or unsaturated heterocyclic group, or R5and R6may form a ring together with the phenyl ring to which they are attached,

or its salt.

The present invention relates also to a pharmaceutical agent containing, as an active ingredient, a derivative ulltimately represented by the formula (I) or its salt.

The present invention relates also to pharmaceutical compositions containing the derivative ulltimately represented by the formula (I)or its salt, and a pharmaceutically acceptable carrier.

The present izobreteyonija also use derivative ulltimately, represented by formula (I), or salts thereof when receiving anticancer agent.

The present invention relates also to a method of cancer treatment, which consists in the introduction to the subject, when necessary, an effective amount of a derivative ulltimately represented by the formula (I)or its salt.

The implementation of the invention

In patent document 6 describes a connection similar to the connection of the present invention, where the aforementioned described compound is quinoline ring and the structure of ulltimately. However, in patent document 6 is not described in such connection, which has aminocarbonyl group as a substituent in the 6-position of the quinoline ring, and the Deputy is a characteristic sign of the present invention. As shown in the examples of the studies described here, the connection of the present invention, characterized in that it has aminocarbonyl group as a substituent in the 6-position of the quinoline ring, showing the in vitro inhibitory activity against the kinase c-Met is equivalent to or higher than the activity of such compounds are described in patent document 6 (comparative compound 1). However, quite unexpectedly, at the dose at which comparative compound 1 was least toxic, with the Association of the present invention does not show toxicity (i.e., loss of body weight). Thus, the dose of a compound could be increased, and in vivo studies on naked mice were observed for effective action to reduce tumor.

As indicated above, the compound (I) of the present invention or its salt has excellent inhibiting c-Met activity in in vitro studies indicated inhibition of c-Met activity has high selectivity towards tumor cells, which is specifically expressed c-Met, and shows a strong reducing tumor effect in vivo studies. Therefore, the connection according to the invention is useful antitumor agent that reduces side effects.

Diseases that can be treated by administration of medicinal products containing the compound of the present invention include, for example, malignant tumors such as head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder/bile duct cancer, bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, a sarcoma of bone and soft tissue, leukemia, malignant lymphoma, multiple myeloma, skin cancer, brain tumors, and mesothelioma. In addition, the connection according to the invention persons of the NGOs is effective in the treatment of proliferative diseases including the stimulation of differentiation and proliferation of cells (e.g., proliferative and immunological malignant diseases of the skin, including keratinization or inflammation, such as psoriasis); is useful as an immunosuppressant in the treatment of immunological diseases such as rheumatoid arthritis; and for the transplantation of organs.

Brief description of drawings

Fig. 1 is a graph showing the effect on body weight of mice of compounds of the present invention and comparative compounds.

Fig. 2 is a graph showing the antitumor effects in vivo studies of compounds of the present invention and comparative compounds.

Detailed description of the invention

In the description of the present invention, when the expression "optionally substituted" add to the description of structures, it refers to the fact that the relevant structure can have one or more substituents in position(s)that(s) may be chemically substituted.

Type, number and position of the substituent(s)represented by(s) in the structure is not specifically limited. When there are two or more substituents, they may be identical or different from one another. Examples of the "substituent" include halogen atom, hydroxyl group, cyano group, nitro group, C1-6alkanoyloxy group, Csub> 1-6alkyl group, a C3-10cycloalkyl group, C2-6alkenylphenol group, C1-6alkoxy group, amino group, C1-6alkylamino group, C1-6alkanolamine group, C1-6alkylaminocarbonyl group, C1-6alkylsulfonyl group, C6-14aromatic hydrocarbon group, saturated or unsaturated heterocyclic group, saturated or unsaturated heterocyclyl-carbonyl group and oxo group. When you have or have substituent(s), their number is usually from 1 to 3.

In the formula (I), "C1-6alkyl group" in the definition of "optionally substituted C1-6alkyl group"defined as R1or R2represents a C1-C6 linear or branched alkyl group. Examples of alkyl groups include methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, second-boutelou, tert-boutelou, n-pentelow, isopentanol, n-hexoloy and isohexyl group.

In the formula (I), "C3-10cycloalkyl group" in the definition of "optionally substituted C3-10cycloalkyl group, designated as R1or R2represents a C3-C10 cycloalkyl group. Examples include cyclopropyl, cyclobutyl, cyclopentyl and tsiklogeksilnogo group.

In the formula (I), "C6-14aromatic hydrocarbon g is the SCP" in the definition of "optionally substituted C 6-14aromatic hydrocarbon group"defined as R1or R2represents a C6-C14 aromatic hydrocarbon group. Examples include phenyl and naftalina group.

In the formula (I) saturated or unsaturated heterocyclic group" in the definition of "optionally substituted saturated or unsaturated heterocyclic group"defined as R1or R2represents a monocyclic or bicyclic saturated or unsaturated heterocyclic group containing one or two atoms selected from oxygen atom, nitrogen atom and sulfur atom. Examples include pyrrolidinyl, piperidinyl, piperazinilnom, morpholino, thiomorpholine, homopiperazine, tetrahydrocannibinol, imidazolidinyl, thienyl, follow, pyrrolidino, oxazolidinyl, isoxazolyl, thiazolidine, isothiazolinone, pyrazolidine, triazolyl, tetrazolyl, pyridyloxy, perilou, pyrimidinyl, pyridazinyl, indolenine, isoindolyl, indazolinone, methylenedioxyaniline, ethylenedioxythiophene, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, parinello, pinolillo, izohinolinove, chinazolinei and khinoksalinona group. Of these, preferred are a 5-7-membered saturated GE is eroticly, where everyone has one or two nitrogen atom; for example, pyrrolidinyl, piperidinyl, piperazinilnom, homopiperazine and tetrahydroquinoline group.

In the formula (I), examples of the "nitrogen-containing heterocyclic ring" in the definition of "optionally substituted nitrogen-containing heterocyclic ring formed by R1and R2together with the nitrogen atom to which they are attached, include a nitrogen-containing saturated heterocyclic groups such as pyrrolidinyl, piperidinyl, piperazinilnom, morpholino group. Of these, pyrrolidinyl and piperidinyl group are preferred.

In the formula (I) examples of C1-6alkyl group"defined as R3include the above alkyl groups. Of these, C1-3alkyl groups are preferred, with a methyl group is more preferred.

In the formula (I), examples of the halogen atom denoted as R4, R5or R6include a fluorine atom, a bromine atom, a chlorine atom and iodine atom. Of these, a fluorine atom and a chlorine atom are preferred.

In the formula (I), "C1-6alkyl group" in the definition of "optionally substituted C1-6alkyl group"defined as R4, R5or R6includes the above alkyl groups. Of these, Milna group is preferred.

In the formula (I), "C1-6alkoxy group" in the definition of "optionally substituted C1-6alkoxy group"defined as R4, R5or R6represents a C1-C6 linear or branched alkoxy group. Examples include methoxy, ethoxy, n-propyloxy, isopropoxy, n-Butylochka, sec-Butylochka, tert-Butylochka, n-pentyloxy and n-hexyloxy group. Of these, C1-3alkoxy groups are preferred, with methoxy group is more preferred.

In the formula (I), "C1-6alkylamino group" in the definition of "optionally substituted C1-6alkylamino group, designated as R4, R5or R6represents an amino group, mono - or di-substituted by the above C1-6alkyl groups. Examples include methylamino, ethylamino, dimethylamino, methylethylamine, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, n-pentylamine and n-hexylamino group.

In the formula (I) "aromatic hydrocarbon group" in the definition of "optionally substituted aromatic hydrocarbon group"defined as R4, R5or R6represents the above-mentioned C6-C14 aromatic hydrocarbon group. Examples of preferred members include phenyl and naftalina group.

In the formula (I) saturated and the unsaturated a heterocycle" in the definition of "optionally substituted saturated or unsaturated heterocycle", designated as R4, R5or R6includes the above-mentioned saturated or unsaturated heterocyclic group. Examples of preferred members include 5-7-membered saturated heterocycles, each of which has one or two nitrogen atom, such as pyrrolidinyl, piperidinyl and piperazinilnom group.

Examples of the ring formed together with the phenyl ring to which is attached R5and R6include naphthalene ring, quinoline ring, hintline ring, indole ring, a benzimidazole ring, methylenedioxyaniline ring and ethylenedioxythiophene ring.

In more detail, the above substituents described below. Examples of the halogen atom include the aforementioned halogen atoms. Examples of C1-6alkanoyloxy groups include formyl, acetyl, propionyl and Butylimino group. Examples of C1-6the alkyl group include the above C1-6alkyl groups. Examples of C3-10cycloalkyl groups include the above C3-10cycloalkyl group. Examples of C2-6alkenylphenol groups include vinyl and 2-propenyloxy group. Examples of C1-6alkoxy groups include the above C1-6alkoxy group. Examples of C1-6alkylamino groups include the above C1-6alkylamino group. Examples of C1-6Alka is olamine groups include amino groups, each of which is substituted by the above C1-6alkanolamine groups. Examples of C1-6alkylaminocarbonyl groups include aminocarbonyl groups, each of which is mono - or di-substituted by the above C1-6alkyl groups. Examples of C1-6alkylsulfonyl groups include sulfonylurea groups, each of which is substituted by the above C1-6alkyl groups. Examples of C6-14the aromatic hydrocarbon groups include the above C6-14aromatic hydrocarbon group. Examples of saturated or unsaturated heterocyclic group include the above-mentioned saturated or unsaturated heterocyclic group.

R1preferably represents a hydrogen atom or a C1-3alkyl group, with a hydrogen atom and methyl are preferred. Of these, a hydrogen atom is particularly preferred.

R2preferably represents optionally substituted C1-6alkyl group, optionally substituted C6-14aromatic hydrocarbon group or optionally substituted saturated or unsaturated heterocyclic group.

C1-6an alkyl group denoted as R2that is, more preferably, C1-4alkyl group, with methyl, Atila is, n-sawn, ISO-propyl, n-bucilina and second-bucilina group are particularly preferred. Then the Deputy, "C1-6alkyl group"defined as R2will be described in detail. Deputy preferably selected from a hydroxyl group, a C3-10cycloalkyl group, C1-6alkoxy group, a C1-6alkylamino group, C1-6alkanolamine group, C1-6alkylsulfonyl group, aromatic hydrocarbon group, saturated or unsaturated heterocyclic group, a C1-6alkylaminocarbonyl group and a saturated or unsaturated heterocyclyl-carbonyl group. C3-10cycloalkyl group, more preferably is tsiklogeksilnogo group. C1-6alkoxy group, more preferably is C1-3alkoxy group, with methoxy, ethoxy, isopropoxy group are particularly preferred. C1-6alkoxy group may optionally have a substituent. This Deputy is preferably a hydroxyl group. C1-6alkylamino group, more preferably, is diethylamino group. C1-6alkanolamine group, more preferably is an acetylamino group. C1-6alkylsulfonyl group, more preferably, is methylsulfonyl group. Aromatic Ugledar the ne group, more preferable is a phenyl group. Saturated or unsaturated heterocyclic group, more preferably, a is a 5-7-membered heterocyclic group containing 1-4 nitrogen atom and/or oxygen atom, with pyrrolidinyl, morpholino, DIOXOLANYL, tetrahydropyranyl, Peregrina and tetrataenia group are particularly preferred. Saturated or unsaturated heterocyclic group may optionally have a substituent. This Deputy, preferably, is C1-6alkyl group (particularly methyl group) or an oxo group. C1-6alkylaminocarbonyl group, more preferably, is ethylaminomethyl, dimethylamino or methylbutylamine group. C1-6alkylaminocarbonyl group may optionally have a substituent. This Deputy, preferably, is a hydroxyl group or a C1-6alkoxy group (particularly methoxy group). Saturated or unsaturated heterocyclyl-carbonyl group, particularly preferably is a 5-7-membered saturated heterocyclyl-carbonyl group containing 1 or 2 nitrogen atom and/or oxygen atom, with pyrrolidinylcarbonyl and morpholinosydnonimine group are particularly preferred. Saturated or unsaturated heterocyclyl-carbonyl which group may optionally have a substituent. This Deputy preferably is a halogen atom (particularly fluorine atom), or C1-6alkyl group (particularly methyl group), which may have a hydroxyl group.

C6-14aromatic hydrocarbon group, designated as R2preferable is a phenyl group. A specific example of the substituent C6-14aromatic hydrocarbon groups designated as R2preferably is C1-6alkyl group, with methyl group is more preferred.

Saturated or unsaturated heterocyclic group, designated as R2is a 5-7-membered saturated, a heterocycle containing 1 or 2 nitrogen atom or sulfur atom, with piperidinyl, homopiperazine and tetrahydroquinoline group are more preferred. A specific example of the substituent a saturated or unsaturated heterocyclic group, designated as R2preferably, a is a hydroxyl group, a C1-6alcoolica group, C1-6alkoxycarbonyl group, C1-6alkylaminocarbonyl group or oxo group, with a hydroxyl group, acetyl group, ethylaminomethyl group, tert-butyloxycarbonyl group and oxo group are more preferred.

R2represents the t a, particularly preferably, methyl, methoxyaniline, morpholinoethyl, morpholinosydnonimine, 2-hydroxy-n-boutelou, 2-hydroxy-2-methyl-n-sawn or 1-hydroxy-n-butane-2-ilen group. In the case of 1-hydroxy-n-butane-2-ilen group (S)-form is particularly preferred.

R4represents preferably a halogen atom, with a fluorine atom and a chlorine atom are particularly preferred. Position R4preferably the 2-position or 3-position, 2-position is particularly preferred.

Each of R5and R6represents preferably a hydrogen atom, halogen atom, optionally substituted C1-6alkyl group or a C1-3alkoxy group. Deputy C1-6alkyl group, defined as R5or R6preferably is a halogen atom, with a fluorine atom is more preferred.

In one preferred case, one of R5and R6represents a hydrogen atom and the other represents a hydrogen atom, halogen atom, triptorelin group or methoxy group. In one preferred implementation of one of R5and R6represents a hydrogen atom and the other represents a hydrogen atom or a halogen atom. When one of R5and R6 represents a hydrogen atom and the other represents a halogen atom, R6is preferably 2-position or 4-position.

The present invention particularly preferred are the following derivative ulltimately and their salts.

4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-methylinosine-6-carboxamide,

4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(methoxyethyl)quinoline-6-carboxamide,

4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(2-morpholinoethyl)quinoline-6-carboxamide,

4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(2-morpholino-2-oxoethyl)quinoline-6-carboxamide,

4-(2-fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-N-(2-hydroxybutyl)-7-methoxyquinoline-6-carboxamide,

4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(2-hydroxy-2-methylpropyl)-7-methoxyquinoline-6-carboxamide,

(S)-4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide,

4-(2-fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-7-methoxy-N-(2-morpholinoethyl)quinoline-6-carboxamide,

(S)-4-(2-fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide,

(S)-4-(2-fluoro-4-(3-(2-(2-forfinal)acetyl)touraid)phenoxy)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide,

(S)-4-(4-(3-(2-(4-chlorophenyl)as ITIL)touraid)-2-pertenece)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide.

Derived ulltimately of the present invention, presented in the form of formula (I), also covers its stereoisomer, optical isomer and its MES, such as a hydrate.

Derived ulltimately of the present invention, presented in the form of formula (I)may be in the form of a salt. Salt preferably is a pharmaceutically acceptable salt. Examples of salts include salts of inorganic bases, salts with organic base, salt with inorganic acid, salt with organic acid, salts with acidic amino acid, and salts with basic amino acid.

Specific examples of salts of inorganic bases include salts of an alkali metal (e.g. sodium or potassium) salt and alkaline earth metal (e.g. magnesium or calcium).

Examples of organic bases, forming salts include trimethylamine, triethylamine, pyridine, N-methylpyridine, N-organic, ethanolamine, diethanolamine, triethanolamine and dicyclohexylamine.

Examples of inorganic acids include hydrochloric acid, sulfuric acid, Hydrobromic acid, yodiewonderdog acid, nitric acid and phosphoric acid.

Examples of organic acids include formic acid, acetic acid, propionic acid, malonic acid, succinic acid, glutaric acid, fu the steam acid, maleic acid, lactic acid, malic acid, citric acid, grape acid, benzosulfimide acid, p-toluensulfonate acid and methansulfonate acid.

Examples of acidic amino acids include glutamic acid and aspartic acid, and examples of basic amino acids include lysine, aspartic acid and ornithine.

Derived ulltimately of the present invention, presented in the form of formula (I)may be a pharmaceutically acceptable prodrug. There are no specific limitations as to pharmaceutically acceptable prodrugs, and can be used any prodrug to the extent until the prodrug can be converted to a compound represented as formula (I), under physiological conditions in vivo (gastric acid or enzyme) via hydrolysis, oxidation or recovery. Examples of prodrugs include derivatives of esters, which modify carboxyl group, such as methyl ether, ethyl ether, propyl ether, phenyl ether, carboxycellulose ether and ethoxycarbonylethyl ether. The typical examples of prodrugs are compounds that, in physiological conditions, are converted into compounds (I)described in "Development of Drugs, vol. 7, p. 163-198)", published by Hirokawa Shoten (1990).

Derived ulltimately on n the present invention, presented in the form of formula (I)or its salt also covers its hydrate, its MES and its crystalline polymorph.

The compound of the present invention can be obtained in accordance with the following scheme. Source products required for the synthesis of compounds of the present invention may be commercial products or can be obtained by a method described in the literature. In the diagram, the substituents have the same meanings, which are defined for formula (I).

In the diagram L represents a removable group, P represents a lower alkyl group or benzyl group, with the Deputy, especially methyl, ethyl, methoxymethyl, tert-boutelou, benzyl, 4-nitrobenzyl, 4-methoxybenzyl group and so on. Other groups have the same values, which are defined for formula (I).

Stage 1

In stage 1, the compound (I-2) is produced from compound (I-1). In particular, compound (I-1), which can be obtained in accordance with the method described in document WO 2002-032872, is treated with thionyl chloride, phosphorus oxychloride, and so forth, serving as a solvent, introducing thus, the halogen in the form of a removable group L. the reaction Temperature is from 0°C to the boiling point, preferably from 80°C to the boiling point. The time re the work ranges from 0.1 to 100 hours, preferably from 1 to 24 hours. If required, can be added N,N-dimethylformamide, from 0.001 to 1 volume, preferably from 0.002 to 0.1, relative to the compound (I-1).

After completing the above reaction, in addition to the removal of group L, carboxyl group at the 6-position was also transformed in gelegenheid acid. Thus, halogenmethyl acid were subjected to interaction with alcohol P-OH, optionally, in the presence of a base, thus introducing the protective group P, as a result can be obtained compound (I-2). There are no specific limitations to the solvent, to the extent until the solvent is not reactive towards gelegenheid acid, and the solvent can be used as a basis. Examples of the alcohol P-OH include methanol, ethanol, tert-butanol, benzyl alcohol, 4-nitrobenzyloxy alcohol and 4-methoxybenzyloxy alcohol. Alcohol can be used in amounts of 1 equivalent relative to an equivalent amount of solvent, preferably 10 equivalents relative to an equivalent amount of solvent. Examples of the base include organic amines such as trimethylamine, triethylamine, Tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and kallidin; sodium bicarbonate, Carbo is at sodium, the sodium methoxide, potassium methoxide, ethoxide sodium, ethoxide and potassium tert-piperonyl potassium. The base can be used in a relative amount of from 1 to 200, preferably from 1.5 to 100, relative to the compound (I-1). The reaction temperature ranges from -30°C up to the boiling temperature, preferably from 0 to 50°C. the reaction Time is from 0.1 to 100 hours, preferably from 1 to 24 hours.

Stage 2

Stage 2 involves the reaction of condensation between the compound (I-2) and compound (I-3), giving thus the compound (I-4). The compound (I-3) can be used in relative amounts of 1 to 100 equivalents, preferably from 1.1 to 10 equivalents, relative to compound (I-2). The condensation reaction preferably is carried out in the presence of a base. Examples of the base include organic amines such as trimethylamine, triethylamine, Tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and kallidin; and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate. The base can be used in relative amounts of 1 to 100 equivalents, preferably from 2 to 10 equivalents. There are no specific limitations to the solvent used in the reaction, to the extent until the solvent is not stupe is easily react with the compounds (I-2), (I-3) and (I-4) and so on. Examples of the solvent include N,N-dimethylacetamide, diphenyl ether, chlorobenzene, 1,2-dichlorobenzene, N-methylpyrrolidine-2-he and dimethyl sulfoxide. These solvents may be used alone or in combination. The reaction temperature is from -30 to 300°C, preferably from 30 to 200°C. the reaction Time is from 0.1 to 100 hours, preferably from 0.5 to 24 hours.

Stage 3

In stage 3, the nitro group of compound (I-4) restore, thus obtaining the compound (I-5). The restoration of the nitro group can be carried out using a reducing agent such as iron-ammonium chloride or iron-acetic acid. If the compound (I-4) does not contain as a group P Cl, Br or I, or a functional group, such as benzyl, 4-nitrobenzyl or 4-methoxybenzyl can be selected catalytic reduction. When using iron-ammonium chloride, the solvent can be used water, methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, toluene, methylene chloride, chloroform, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine-2-it, dimethyl sulfoxide and so on. These solvents may be used alone or in combination. The reaction temperature is 0 to 200°C, preferably from 30 to 100°C. the reaction Time is about the 0.1 to 100 hours, preferably from 0.5 to 24 hours.

When using catalytic reduction, examples of the catalyst used in the reaction include 5-10% Pd-C and palladium hydroxide. The catalyst may be used in a relative amount of from 0.01 to 10, preferably from 0.02 to 5, relative to the compound (I-4). The source of hydrogen, for example, formic acid, ammonium formate, cyclohexene or dicyclohexano, can be used in an amount of from 1 to 200 equivalents, preferably from 1.1 to 100 equivalents. When using hydrogen, the hydrogen pressure may be from 0.01 to 3.0 MPa, and is preferably from 0.1 to 1.0 MPa. Examples of the solvent include methanol, ethanol, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, and dimethylformamide, and these solvents may be used alone or in combination.

Stage 4

In stage 4, the compound (I-7) is produced from compound (I-5) using thioisocyanate (I-6). Thioisocyanate (I-6) can be obtained separately by the method described in document WO 2005-082855, from gelegenheid acid or carboxylic acid. The compound (I-6) can be used in an amount of from 1 to 100 equivalents relative to the compound (I-5), preferably from 1.1 to 30 equivalents. There are no specific limitations to the solvent used in the reaction, and can be is used hexane, toluene, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidine-2-he, methanol, ethanol, isopropanol and so on. These solvents may be used alone or in combination. The reaction temperature is from -30 to 200°C, preferably from 0 to 100°C. the reaction Time is from 0.1 to 100 hours, preferably from 0.5 to 24 hours.

Stage 5

Stage 5 carboxylic acid (I-8) is obtained from the complex ester (I-7). The reaction can be carried out in basic or acidic conditions, or can be made catalytic reduction, so that the ester was converted to carboxylic acid.

When the group P represents methyl or ethyl, removing the protective groups, preferably, is carried out in basic conditions. Examples of bases include sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide. The base can be used in an amount of from 1 to 100 equivalents, preferably from 1.1 to 30 equivalents. Examples of the solvent include water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane and N,N-dimethylformamide. These solvents may be used alone or in combination.

When the P is, for example, tert-butyl, removing the protective groups, preferred is a recreational carried out in acidic conditions. Examples of acids include hydrochloric acid, acetic acid, triperoxonane acid, sulfuric acid and toluensulfonate acid. The acid may be used in concentrations of 1H with respect to the solvent-equivalent amount, preferably 2n relative to the solvent-equivalent amount. Examples of the solvent include water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, methylene chloride and chloroform. These solvents may be used alone or in combination.

When the P is, for example, benzyl, 4-nitrobenzyl or 4-methoxybenzyl, removing the protective groups, preferably carried out by catalytic reduction in the presence of a catalyst. Catalyst recovery can be 5-10% Pd-C or palladium hydroxide. The catalyst may be used in a relative amount of from 0.01 to 10 with respect to the compound (I-7), preferably from 0.02 to 5. The source of hydrogen, for example, hydrogen, formic acid, ammonium formate, cyclohexene or 1,4-DICYCLOHEXYL, can be used in an amount of from 1 to 200 equivalents, preferably from 1.1 to 100 equivalents. Examples of the solvent include methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate and N,N-dimethylformamide, and these solvents can b shall be used by themselves or in combination.

In any combination, the reaction temperature is from -30 to 200°C, preferably from 0 to 100°C, and the reaction time is from 0.1 to 100 hours, preferably from 0.5 to 24 hours.

Stage 6

Stage 6 involves the reaction of condensation between the carboxylic acid (I-8) and the amine (I-9). Step 6 to obtain compound (I) can be carried out with the participation of gelegenheid acid derived from carboxylic acid (I-8), or using commonly used condensing agent.

In the way involving gelegenheid acid, first carboxylic acid (I-8) is converted into its acid chloride using thionyl chloride, phosphorus oxychloride, and so forth, in the solvent-equivalent amount. The reaction temperature is from -30 to 200°C, preferably from 0 to 100°C. the reaction Time is from 0.1 to 100 hours, preferably from 1 to 24 hours.

Then, through the introduction of amine (I-9) thus obtained gelegenheid acid, can be obtained compound (I). If required, can be used as a basis. Examples of the base include organic amines such as trimethylamine, triethylamine, Tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine and kallidin; and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, CT is eat cesium, the sodium methoxide, potassium methoxide, ethoxide sodium, ethoxide and potassium tert-piperonyl potassium. Amin (I-9) can be used in an amount of from 1 to 100 equivalents, preferably from 1.1 to 50 equivalents. Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, toluene, methylene chloride, chloroform, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

Alternatively, upon receipt of the compound (I) can be used condensing agent. Examples of the condensing agent include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC), diphenylphosphoryl azide (DPPA), hexaflurophosphate benzotriazol-1-yl-oxides(dimethylamino)phosphonium (BOP), hexaflurophosphate benzotriazol-1-yl-exitapplication (PyBOP), phosphate 7-asobancaria-1-yl-oxides(pyrrolidino)phosphonium (PyAOP), hexaflurophosphate bromotris(pyrrolidino)phosphonium (BroP), hexaflurophosphate chlorotris(pyrrolidin-1-yl)phosphonium (PyCroP), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-he (DEPBT), hexaflurophosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (HATU) and the hydrochloride of 4-(5,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholin (DMTMM). In combination with the condensing agent can be used for additional compounds such as 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzo the triazole (HOAt) and N-hydroxysuccinimide (HOSu). These additional compounds may be used in quantities of from 0.1 to 100 equivalents, preferably from 1 to 10 equivalents. If required, can be used a base, such as trimethylamine, triethylamine, Tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, lutidine or kallidin in the amount of from 0.1 to 100 equivalents, preferably from 1 to 10 equivalents. Can be used amine (I-9) in the same amount as above. There are no specific limitations to the solvent, and can be used water, methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, toluene, methylene chloride, chloroform, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and so on. The reaction temperature is from -30 to 200°C, preferably from 0 to 100°C. the reaction Time is from 0.1 to 100 hours, preferably from 0.5 to 24 hours.

The compound (I-5) can be converted to its amide other than the above methods, in accordance with the stages 5 and 6, and then the compound (I) can be obtained in accordance with stage 4. When the group P is a methyl, the compound (I-5) can be converted to its amide well-known method, such as aminals, and then the compound (I) can be obtained in accordance with stage 4.

Received the th thus the connection of the present invention and its synthetic intermediate products can usually be isolated and purified by known means of selection/purification (for example, recrystallization, crystallization, distillation or column chromatography). Typically, the compound of the present invention and its intermediate products of the synthesis can be converted into their pharmaceutically acceptable salts are known technique, and the salt can be converted into the free form.

When the compound (I) of the present invention are used as medicines, it is mixed with additional pharmaceutical carrier, and the mixture can be formed into various dosage forms, in accordance with the preventive or therapeutic purposes. Can be used in any forms, and examples include oral contraceptives, liquids, injections, suppositories, ointments and poultices. Of these, preferably used oral contraceptives. These dosage forms can be obtained by methods commonly known and used in the field.

As pharmaceutical carriers can be used various organic and inorganic carriers, which are usually used for making drugs. Examples of media for solid drug include additional substance, a binder, baking powder, lubricating substance and the dye, and examples of the carrier for the liquid preparation include solvent, solubilizers agent, susp hiroumi agent, agent, giving toychest, buffer and soothing agent. If required, can also be used for additional connections to the drug, such as preservative, antioxidant, coloring agent, sweetener and stabilizer.

Oral solid form can be obtained by mixing the compounds of the present invention with an additional substance, and with optional additional substance, a binder, baking powder, lubricating agent, coloring agent, flavoring/deodorizing agent and so forth, and then forming the mixture into tablets, coated tablets, granules, powder, capsules and so forth method known in this field.

Examples of additional substances include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose and anhydrous silicic acid.

Examples of the coupling agent include water, ethanol, 1-propanol, 2-propanol, simple syrup, liquid glucose, liquid α-starch, liquid gelatin, D-mannitol, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, and polyvinylpyrrolidone.

Examples of the powder include dry starch, sodium alginate, powdered agar, sodium bicarbonate, calcium carbonate, laurissl is at sodium, monoglycerol stearate and lactose.

Examples of the lubricating agent include purified talc, stearate sodium (salt), magnesium stearate, borax and polyethylene glycol.

Examples of colorants include titanium oxide and iron oxide.

Examples of aromatic/deodorizing agent include sucrose, orange peel, citric acid and grape acid.

Liquid oral preparation may be obtained by mixing the compounds of the present invention with a flavouring agent, buffer, stabilizer, deodorant, and so forth, and then molding the mixture into a liquid agent for internal reception, syrup, elixir, and so forth method known in this field. Flavouring/deodorizing agent used in the preparation may be any of the above agents. Examples of the buffer include sodium citrate. Examples of the stabilizer include tragakant, gum Arabic and gelatin. If required, oral drug may be covered in a known manner by a material resistant to gastric juice, or the material for the coating to preserve its validity. Examples of such material to cover include hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethyleneglycol and tween 80 (registered trademark).

And yaktine solutions can be obtained by mixing the compounds of the present invention with additional compounds, such as the pH Adjuster, buffer, stabilizer agent, giving toychest, and local anesthetic agent, and then molding the mixture by a method known in this field, obtaining thus subcutaneous, intramuscular and intravenous injection of liquids. Examples of the pH regulator and buffer include sodium citrate, sodium acetate and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid and timelocal acid. Examples of local anesthetic agent include procaine hydrochloride and lidocaine hydrochloride. Examples of the agent, giving toychest include sodium chloride, glucose, D-mannitol, and glycerin.

Suppositories can be obtained by mixing the compounds of the present invention with a carrier for drugs known in this field, such as polyethylene glycol, lanolin, cocoa butter and triglyceride fatty acid, and optionally surface-active agent such as tween 80 (registered trademark), and then molding the mixture into suppositories by a method known in this field.

Ointments can be obtained by mixing the compounds of the present invention with an optional additional compound is usually used in this field, such as base, stabilizer, humectant and preservative, and then molding the mixture into a MAZ the way, known in this field. Examples of bases include liquid paraffin, white petrolatum, white wax, octyldodecanol alcohol and paraffin. Examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and propyl p-hydroxybenzoate.

Poultices can be obtained by applying the above ointments, creams, gel, paste and so on on a commonly used substrate in the usual way. Examples of suitable substrates include woven and non-woven factory cotton, staple fiber or chemical fiber and film and foam sheet made of safe vinyl chloride, polyethylene, polyurethane, and so forth.

The number of compounds according to the present invention, a part of any of the foregoing standard dosage forms, modified in accordance with the form of medicines and signs of illness from the patient who enter the specified connection. However, typically, in a standard dosage form, the amount is preferably from about 0.05 to 1,000 mg (oral agent), from about 0.01 to 500 mg (injection solution), or from about 1 to 1,000 mg (suppository).

Daily dose medicines, having any of the above dosage forms, modified in accordance with the symptom of the disease, body weight, age, gender and so on the patient, and cannot be uniquely defined, However, daily dose for an adult (body weight: 50 kg) is usually from about 0.05 to about 5,000 mg, preferably from 0.1 to 1,000 mg, Preferably, the drug is administered as a single daily dose, or it may be separated (for example, 2 or 3).

Examples

Detailed embodiments of the present invention is described by way of examples and pharmacological examples of studies that should not be considered as limiting thus the invention.

Example 1

tert-Butyl 4-chloro-7-methoxyquinoline-6-carboxylate (1a)

4-Hydroxy-7-methoxyquinoline-6-carboxylic acid (described in WO 2002/032872) (25 g) was dissolved in thionyl chloride (100 ml), and to the solution was added N,N-dimethylformamide (5 ml), followed by boiling under heating for 2 hours. The reaction mixture was concentrated under reduced pressure and subjected to azeotropic distillation with toluene. The product was added to a solution of tert-butoxylate (150 g, 6-fold amount) in tert-butanol (300 ml) in an ice bath, and then stirred for 17 hours. The reaction mixture was concentrated under reduced pressure, and added (300 ml) water in an ice bath, then was extracted with n-hexane (300 ml). The organic phase was washed with saturated saline (300 ml) and dried over sodium sulfate, then concentrated under reduced pressure, so clicks the zoom connection 1a (10.5 g, yield: 31%).

1H-NMR (CDCl3) δ: 8,73 (1H, d, J=4,2 Hz)and 8.50 (1H, s), 7,49 (1H, s), 7,38 (1H, d, J=4,8 Hz), a 4.03 (3H, s)of 1.64 (9H, s); ESI-MS m/z 294 (MN+).

tert-Butyl 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxylate (1b)

Compound 1a (of 3.60 g) was dissolved in N-methylpyrrolidine-2-Ohe (14 ml), and to the solution was added diisopropylethylamine (6,55 ml) and 2-fluoro-4-NITROPHENOL (2,89 g). The mixture was heated to a temperature of 140°C and was stirred for 4 hours. To the reaction mixture was added distilled water in an ice bath, and the precipitate was filtered, thus obtaining the compound 1b (4.71 g, yield: 93%).

1H-NMR (DMSO-d6) δ: rate of 8.75 (1H, d, J=4,8 Hz), of 8.47 (1H, DD, J=10.4 Hz, 2.8 Hz), scored 8.38 (1H, s)8,23 (1H, DDD, J=8,8 Hz, 1.2 Hz, 1.2 Hz), 7,74 (1H, t, J=8.0 Hz), 7,55 (1H, s), is 6.78 (1H, d, J=5,2 Hz)to 3.99 (3H, s), and 1.54 (9H, s); ESI-MS m/z 415 (MN+).

tert-Butyl 4-(4-amino-2-pertenece)-7-methoxyquinoline-6-carboxylate (1c)

Compound 1b (400 mg) was dissolved in water-ethanol mixture (1:1) (10 ml), was added iron powder (1.0 g) and ammonium chloride (1.0 g), then stirred at a temperature of 80°C for 2 hours. The reaction mixture was filtered through celite to remove so iron powder, and to the filtrate was added water (100 ml), then was extracted with ethyl acetate (50 ml). The organic phase was washed with saturated saline (100 ml) and dried over sodium sulfate, then concentrated under reduced pressure, obtaining the same the way the compound 1c (335 mg, yield: 93%).

1H-NMR (DMSO-d6) δ: 8,65 (1H, d, J=5,2 Hz), 8,40 (1H, s)of 7.48 (1H, s), 7,10 (1H, t, J=9,2 Hz), 6,55 (1H, DD, J=13,2 Hz and 2.8 Hz), 6.48 in-6,44 (2H, m), the 5.51 (2H, s), of 3.96 (3H, s)of 1.55 (9H, s); ESI-MS m/z 385 (MN+).

tert-Butyl 4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxylate (1d)

Phenylacetyl chloride (1,10 ml) and potassium thiocyanate (1,21 g) was dissolved in acetonitrile (15 ml), then stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Then the product was separated using aqueous saturated solution of sodium bicarbonate (100 ml) and ethyl acetate (50 ml). The organic layer was washed with saturated saline (100 ml) and dried over sodium sulfate, then concentrated under reduced pressure, thus obtaining phenylacetyl thioisocyanate. This product (phenylacetyl thioisocyanate) were not subjected to additional purification and dissolved in toluene (8 ml). Solution (12 ml) of compound 1c in a mixture of toluene-ethanol (5:1) was added to the toluene solution, and then stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (eluent: 100% ethyl acetate), thus obtaining the compound 1d (620 mg, yield: 53%).

1H-NMR (CDCl3) δ: br12.62 (1H, s), to 8.70 (1H, is), 8,58 (1H, s), of 8.09 (1H, DD, J=11.8 Hz, 2.0 Hz), 7,81 (1H, s), 7,51-7,30 (7H, m), of 6.71 (1H, s), 4,18 (3H, s), of 3.78 (2H, s)of 1.64 (6H, s); ESI-MS m/z 562 (MN+).

The hydrochloride of 4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxylic acid (1e)

Compound 1d (88,0 mg) was dissolved in a solution of 4n HCl-dioxane and then stirred at 70°C for 1 hour. Formed in the reaction mixture, the precipitate was filtered, thus obtaining a compound 1e (67,1 mg, yield: 79%).

1H-NMR (DMSO-d6) δ: 12,54 (1H, s), up 11,86 (1H, s), 8,98 (1H, d, J=6.4 Hz), to 8.70 (1H, s), 8,11 (1H, d, J=12,4 Hz), 7,74-7,73 (1H, m), 7,65-of 7.60 (2H, m), 7,37-to 7.32 (4H, m), 7,30-of 7.25 (1H, m)6,91 (1H, d, J=6.0 Hz), Android 4.04 (3H, C)a 3.83 (2H, s); ESI-MS m/z 506 (MN+).

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(3-isopropoxyphenyl)-7-methoxyquinoline-6-carboxamide (1)

Compound 1e (13.2 mg), 3-isopropoxypropylamine (9,11 μl), and N-hydrate of the hydrochloride of 4-(5,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (hereinafter indicated as DMTMM·N-hydrate) (8,67 mg) was dissolved in tetrahydrofuran (1 ml), then stirred at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure and to the residue was added water. The precipitate was filtered, thus obtaining specified in the header connection 1 (11.6 mg, yield: 79%).

1H-NMR (DMSO-d6) δ: 12,51 (1H, s), 11,83 (1H, s), 8,69 (1H, d, J=5.6 Hz), 8,54 (1H, s), 8,39 (1H, t, J=4,8 Hz), of 8.04 (1H, DD, J=12,4 Hz, J=2.0 Hz), 7,58-7,49 (3H, m), 7,9-7,34 (4H, m), 7,32-7,27 (1H, m), 6,53 (1H, d, J=5,2 Hz), was 4.02 (3H, s), a-3.84 (2H, s), to 3.58-3,50 (1H, m), of 3.45 (2H, t, J=6.0 Hz), 3,40-to 3.36 (2H, m), 1,79 by 1.68 (2H, m)of 1.09(6H, d, J=6.0 Hz); ESI-MS m/z 605 (MN+).

Example 2

N-((2,2-Dimethyl-1,3-dioxolane-4-yl)methyl)-4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamide (2)

A method similar to that described in example 1, from compound 1e (to 19.4 mg), (2,2-dimethyl-1,3-dioxolane-4-yl)methanamine (13,5 mm) and N-hydrate (DMTMM (to 11.9 mg) has been specified in the title compound 2 (9.3 mg, yield: 42%).

1H-NMR (CDCl3) δ: 12,50 (1H, s), 9,26 (1H, s), 8,66 (1H, DD, J=5.4 Hz, 0.8 Hz), charged 8.52 (1H, s)8,23 (1H, t, J=5.6 Hz), of 7.96 (1H, DD, J=11.2 Hz, J=2,8 Hz), 7,53 (1H, s), 7,46-7,37 (4H, m), 7,32-7,28 (3H, m), 6,44 (1H, DD, J=7,2 Hz), 4,43-to 4.38 (1H, m), 4,13-4.09 to (1H, m), of 4.12 (3H, s), 3,79-3,71 (3H, m), 2,42 (2H, t, J=8.0 Hz), 3,76 (2H, s), for 1.49 (3H, s), 1,43 (1H, s)of 1.39 (2H, s); ESI-MS m/z 619 (MN+).

Example 3

N-(2, 3-Dihydroxypropyl)-4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamide (3)

A method similar to that described in example 1, from compound 1e (20,1 mg), 3-amino-1,2-propane diol (8,45 mg) and N-hydrate (DMTMM (12.3 mg) has been specified in the title compound 3 (5.1 mg, yield: 24%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), 8,69 (1H, s), 8,69 (1H, d, J=5,2 Hz), 8,48 (1H, t, J=5.6 Hz), 8,39 (1H, t, J=4,8 Hz), of 8.04 (1H, DD, J=12.0 Hz, J=2.4 Hz), 7,58 is 7.50 (3H, m), 7,37-7,33 (4H, m), 7,31-7,26 (1H, m)of 6.52 (1H, d, J=5.4 Hz), to 4.92 (1H, usher.), the 4.65 (1H, usher.), a 4.03 (3H, s), 3,82 (2H, s), the 3.65 (1H, t, J=5.6 Hz), 3,52-of 3.46 (1H, m), 3,43-3,37 (3H, m, J=6.0 Hz); ESI-MS m/z 579 (MN+).

Example 4

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(pyridine-3-ylmethyl)quinoline-6-carboxamide (4)

A method similar to that described in example 1, from compound 1e (16,7 mg), 3-picolylamine (7,79 μl) and N-hydrate (DMTMM (10,2 mg) has been specified in the title compound 4 (8,1 mg, yield: 44%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), 11,81 (1H, s), 9,01 (1H, t, J=7,6 Hz), 8,69 (1H, d, J=5,2 Hz), 8,58 (1H, d, J=1.6 Hz), to 8.57 (1H, s), to 8.45 (1H, DD, J=4,8 Hz, 1.0 Hz), 8,02 (1H, DD, J=12,8 Hz to 1.6 Hz), to 7.77 (1H, d, J=8.0 Hz,), 7,56-of 7.48 (4H, m), 7,39-7,33 (6H, m), 7,31-7,26 (1H, m), of 6.52 (1H, d, J=5.6 Hz), 4,55 (2H, d, J=6.0 Hz), a 4.03 (3H, s), 3,82 (2H, s); ESI-MS m/z 596 (MN+).

Example 5

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(3-(2-oxopyrrolidin-1-yl)propyl)quinoline-6-carboxamide (5)

A method similar to that described in example 1, from compound 1e (18,8 mg), N-(3'-aminopropyl)-2-pyrrolidinone (12,2 μl) and N-hydrate (DMTMM (11,5 mg)were specified in the title compound 5 (5.5 mg, yield: 25%).

1H-NMR (CDCl3) δ: of 12.53 (1H, s), 9,24 (1H, s), 8,76 (1H, s), 8,65 (1H, d, J=5.6 Hz), 8,53 (1H, t, J=6.0 Hz), 7,95 (1H, DD, J=12.0 Hz, J=2.4 Hz), 7,52 (1H, s), 7,45-7,37 (4H, m), 7,32-7,30 (2H, m), 7.23 percent (1H, d, J=8,4 Hz), 6.42 per (1H, DD, J=5,2 Hz, 1.2 Hz), 4,17 (3H, s), 3,76 (2H, s), 3,52-of 3.42 (6H, m), 2,42 (2H, t, J=8.0 Hz), to 2.06 (2H, TT, J=7,6 Hz)to 1.86 (2H, TT, J=6.0 Hz); ESI-LRMS m/z 630 (MN+).

Example 6

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-methylinosine-6-carboxamide (6)

A method similar to that described in example 1, compound 1e (20 mg), 40% aqueous solution of methylamine (5 ml) and N-hydrate (DMTMM (22 mg) was dissolved in tetrahydrofuran (1 ml), then stirred at a temperature of 30°C is for 1 hour, getting so specified in the title compound 6 (of 18.4 mg, yield: 96%).

1H-NMR (DMSO-d6) δ: 12,51 (1H, s), 11,83 (1H, s), 8,69 (1H, d, J=4,8 Hz), at 8.60 (1H, s), scored 8.38 (1H, d, J=4,8 Hz), 8,03 (1H, DD, J=12,4 Hz, J=2.0 Hz), 7,58 is 7.50 (4H, m), 7,39-7,34 (4H, m), 6,53 (1H, d, J=5,2 Hz), a 4.03 (3H, ), a-3.84 (2H, s)2,84 (3H, d, J=4,8 Hz); ESI-MS m/z 518 (MN+).

Example 7

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(methoxyethyl)quinoline-6-carboxamide (7)

A method similar to that described in example 1, compound 1e (20 mg), 2-methoxyethylamine (6 mg), N-hydrate (DMTMM (22 mg) was dissolved in ethanol (1 ml), then stirred at 30°C for 1 hour, thus obtaining specified in the title compound 7 (17.3 mg, yield: 83%).

1H-NMR (DMSO-d6) δ: 12,51 (1H, s), 11,83 (1H, s), 8,71-8,69 (1H, m), to 8.62 (1H, s), 8,54-8,44 (1H, m), of 8.04 (1H, DD, J=12,4 Hz to 1.6 Hz), 7,58 is 7.50 (3H, m), of 7.36-7,34 (4H, m), 7,32-7,27 (1H, m), 6,53 (1H, d, J=4,8 Hz), Android 4.04 (3H, C)of 3.84 (2H, s), 3,50-of 3.48 (4H, m), 3,30 (3H, s); ESI-MS m/z 562 (MN+).

Example 8

N-(2-(Diethylamino)ethyl)-4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamide (8)

A method similar to that described in example 1, from compound 1e (to 22.6 mg), 2-(diethylamino)ethylamine (14,8 μl) and N-hydrate (DMTMM (13,8 mg) has been specified in the title compound 8 (12.3 mg, yield: 49%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), 11,83 (1H, s), 8,73-to 8.70 (1H, m), 8,72 (1H, s), 8,51 (1H, t, J=5,2 Hz), of 8.04 (1H, DD, J=12,8 Hz to 1.6 Hz), 7,58 is 7.50 (3H, m), 7,38-7,33 (4H, m), 7,31-7,27 (1H, m), 6,53 (1H, d, J=6.0 Hz), 4,05 (3H, what), of 3.84 (2H, s), 3,42-3,37 (2H, m), 2,67 of $ 2.53 (6H, m), a 1.01 (6H, t, J=7.2 Hz); ESI-MS m/z 604 (MN+).

Example 9

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(2-morpholinoethyl)quinoline-6-carboxamide (9)

A method similar to that described in example 1, from compound 1e (9.6 mg), 2-morpholinoethyl (5,77 μl) and N-hydrate (DMTMM (5,88 mg) has been specified in the title compound 9 (3,3 mg, yield: 30%).

1H-NMR (CDCl3) δ: of 12.53 (1H, s), 9,26 (1H, s), the remaining 9.08 (1H, t, J=3.6 Hz), 8,72 (1H, s), 8,66 (1H, d, J=5.0 Hz), 7,95 (1H, DD, J=11,6 Hz, 2.4 Hz), 7,55 (1H, s), 7,45 was 7.36 (4H, m), 7,32-7,24 (3H, m), 6,44 (1H, DD, J=5,2 Hz, 0.8 a Hz), 4,37 (2H, d, J=4.0 Hz), 4,18 (3H, s), 3,79-3,72 (7H, m), of 3.77 (2H, s), 3,52 (2H, t, J=4,8 Hz); ESI-MS m/z 618 (MN+).

Example 10

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(2-(2-hydroxyethoxy)ethyl)-7-methoxyquinoline-6-carboxamide (10)

A method similar to that described in example 1, from compound 1e (9.7 mg), 2-(2-aminoethoxy)ethanol (of 4.44 ml) and N-hydrate (DMTMM (5,94 mg) has been specified in the title compound 10 (3.0 mg, yield: 28%).

1H-NMR (DMSO-d6) δ: 12,51 (1H, s), 11,83 (1H, s), to 8.70 (1H, d, J=5,2 Hz)8,64 (1H, s), 8,49 (1H, t, J=5,2 Hz), of 8.04 (1H, d, J=and 12.2 Hz), 7,58 is 7.50 (3H, m), 7,38-7,34 (4H, m), 7,31-7,27 (1H, m), of 6.52 (1H, d, J=5,2 Hz), 4,62 (1H, t, J=5,2 Hz), Android 4.04 (3H, s), a-3.84 (2H, s)to 3.58 (2H, t, J=5.6 Hz), 3,54-3,47 (6H, m); ESI-MS m/z 592 (MN+).

Example 11

N-(2-Acetamidomethyl)-4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamide (11)

A method similar to that described in example 1, from compound 1e (20.7 mg), N-acetyl what etilendiamina (9.75 mg) and N-hydrate (DMTMM (12.7mm mg) has been specified in the title compound 11 (5.4 mg, yield: 20%).

1H-NMR (DMSO-d6) δ: 12,49 (1H, s), 11,82 (1H, s), 8,68 (1H, DD, J=5,2 Hz, 2.8 Hz), 8,63 (1H, d, J=2.4 Hz), 8,48 (1H, t, J=5.6 Hz), 8,02 (1H, d, J=12,4 Hz), 7,98 (1H, s), 7,56-7,49 (3H, m), of 7.36-to 7.32 (4H, m), 7,30-7,26 (1H, m,), 6,51 (1H, d, J=5,2 Hz), was 4.02 (3H, s), 3,82 (2H, s), 3,38-to 3.35 (2H, m), 3,28-up 3.22 (2H, s), equal to 1.82 (3H, s); ESI-MS m/z 590 (MN+).

Example 12

N-(1,3-Dihydroxypropyl-2-yl)-4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamide (12)

A method similar to that described in example 1, from compound 1e (37,1 mg), 2-amino-1,3-propane diol (15.6 mg) and N-hydrate (DMTMM (22.7 mg) has been specified in the title compound 12 (11.5 mg, yield: 29%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), a total of 8.74 (1H, s), 8,69 (1H, d, J=5,2 Hz), 8,29 (1H, d, J=8.0 Hz), 8,03 (1H, DD, J=12.0 Hz, 2.0 Hz), EUR 7.57-to 7.50 (3H, m), 7,35-7,33 (4H, m), 7,31-7,26 (1H, m), of 6.52 (1H, d, J=5,2 Hz), 4,80 (2H, t, J=5,2 Hz), Android 4.04 (3H, s), 3,99-of 3.94 (1H, m), 3,83 (2H, s), 3,61 of 3.56 (2H, m), 3,54-3,47 (2H, m); ESI-MS m/z 579 (MN+).

Example 13

tert-Butyl 4-(4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamido)-6-carboxamido)piperidine-1-carboxylate (13)

A method similar to that described in example 1, from compound 1e (750 mg), 4-amino-1-Boc-piperidine (332 mg), triethylamine (230 μl) and N-hydrate (DMTMM (459 mg) has been specified in the title compound 13 (446 mg, yield: 52%).

1H-NMR (CDCl3) δ: 12,50 (1H, s), 9,24 (1H, s), 8,66 (1H, d, J=5.4 Hz), 8,49 (1H, s), of 7.96 (1H, DD, J=11,6 Hz, 2.4 Hz), 7,83 (1H, d, J=7,6 Hz), 7,53 (1H, s), 7,47-7,37 (4H, m), 7,33-7,29 (3H, m), 6,44 (1H, d, J=5.0 Hz, 1,2 Hz), 4,23 (1H, usher.), 4,11 3H, C), a 4.03-4,01 (1H, m), 3,76 (2H, s), 3.04 from (3H, t, J=12.0 Hz), 2,92 (1H, t, J=10,8 Hz), 2,09-to 1.98 (3H, m)to 1.48 (9H, s); ESI-MS m/z 688 (MN+).

Example 14

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(piperidine-4-yl)quinoline-6-carboxamide the dihydrochloride (14)

Compound 13 (446 mg) was dissolved in 4n HCl solution of dioxane and then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene, thus obtaining specified in the title compound 14 (406 mg, yield: 95%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), 8,67 (1H, d, J=5,2 Hz), 8,44 (1H, s), 8,30 (1H, d, J=7,6 Hz), 8,02 (1H, DD, J=12,8 Hz to 1.6 Hz), EUR 7.57-7,44 (3H, m), 7,37-7,33 (4H, m), 7,31-7,26 (1H, m), 6,51 (1H, d, J=5,2 Hz), Android 4.04-of 3.96 (1H, usher.), to 3.99 (3H, s), 3,93 (2H, s), 3.96 points-with 3.79 (4H, m), 3,83 (2H, s), of 2.92 (2H, usher.), to 1.83 (1H, m); ESI-MS m/z 588 (MN+).

Example 15

N-(1-(Ethylcarbamate)piperidine-4-yl)-4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamide (15)

Compound 14 (335 mg) suspended in tetrahydrofuran (5 ml) and to the suspension was added triethylamine (212 μl) and ethyl isocyanate (71,2 ml), then stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the formed solid product was filtered, thus obtaining specified in the title compound 15 (271 mg, yield: 81%).

1H-NMR (DMSO-d6 ) δ: 12,50 (1H, s), 11,82 (1H, s), 8,67 (1H, d, J=5.6 Hz), 8,44 (1H, s), of 8.28 (1H, d, J=8.0 Hz), 8,02 (1H, d, J=12,8), 7,56-of 7.48 (3H, m), 7,35-7,28 (5H, m), 6,51 (1H, d, J=4,8 Hz), 6,45 (1H, t, J=4,8 Hz), to 3.99 (4H, s), 3,88 (2H, d, J=12,8 Hz), 3,82 (2H, s), 3,06-to 2.99 (2H, m), 2,82 (3H, t, J=12.0 Hz), 1,43 is 1.34 (3H, m), 0,99 (3H, t, J=7.2 Hz); ESI-MS m/z 659 (MN+).

Example 16

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(2-oxazepan-3-yl)quinoline-6-carboxamide (16)

A method similar to that described in example 1, from compound 1e (260 mg), DL-α-amino-ε-caprolactam (73,7 mg), triethylamine (134 μl) and N-hydrate (DMTMM (159 mg) has been specified in the title compound 16 (221 mg, yield: 75%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), 9,19 (1H, d, J=6.0 Hz), of 8.90 (1H, s)8,71 (1H, d, J=5,2 Hz), 8,05-of 7.96 (2H, m), 7,60-7,51 (3H, m), 7,37-7,33 (4H, m), 7,31-7,26 (1H, m), 6,53 (1H, d, J=4.4 Hz), 4,65-br4.61 (1H, m), 4,10 (3H, s), of 3.96 (2H, s), 3,83 (2H, s)2,07 (1H, d, J=12,8 Hz), 1,94-1,90 (1H, m), 1,79 was 1.69 (2H, m), 1,47-to 1.38 (1H, m), 1,29-1,20 (1H, m); ESI-MS m/z 616 (MN+).

Example 17

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)quinoline-6-carboxamide (17)

A method similar to that described in example 1, from compound 1e (304 mg), hydrochloride 2-amino-1-(pyrrolidin-1-yl)ethanone (120 mg), triethylamine (235 μl) and N-hydrate (DMTMM (186 mg) was obtained is listed in the title compound 17 (220 mg, yield: 64%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), 8,83 (2H, d, J=1.2 Hz), 8,71 (1H, DD, J=5,2 Hz, 1.6 Hz), 8,05-to 7.99 (1H, m), 7,60-7,53 (3H, m), 7,35-7,33 (4H, m), 7,30-7,28 (1H, m), 6,53 (1H, d, J=5,2 Hz), 4,14 (2H, d, J=4.0 Hz),4,08 (3H, d, J=1.2 Hz), 3,83 (2H, s), 3,48-3,44 (2H, m), 3,39-3,24 (2H, m), 1,94-of 1.88 (2H, m), 1,83 to 1.76 (2H, m); ESI-MS m/z 616 (MN+).

Example 18

N-(1-Acetylpiperidine-4-yl)-4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamide (18)

A method similar to that described in example 1, from compound 1e (14.3 mg), hydrochloride of 1-(4-aminopiperidin-1-yl)ethanone (5,66 mg), triethylamine (of 9.21 μl) and N-hydrate (DMTMM (8,76 mg) has been specified in the title compound 18 (6.0 mg, yield: 36%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), 8,67 (2H, d, J=5,2 Hz), to 8.45 (1H, s), 8,02 (1H, DD, J=12,4 Hz, 2.4 Hz), 7,56-7,49 (3H, m), 7,37-7,33 (4H, m), 7,31-7,26 (1H, m), of 6.52 (1H, d, J=5,2 Hz)to 4.23 (1H, d, J=13,2 Hz), 4,10-3,98 (1H, usher.), of 4.00 (3H, s), 3,83 (2H, s), of 3.78 (1H, d, J=14.4 Hz), 3,21 is 3.15 (2H, m), 2,78 (1H, t, J=10,8 Hz), 2,68-to 2.65 (1H, m), from 2.00 (3H, s), 1.93 and-a 1.88 (1H, m), 1,86-of 1.81 (1H, m); ESI-MS m/z 630 (MN+).

Example 19

tert-Butyl 4-(2-fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxylate (19a)

4-Florfenicol acid (900 mg) was dissolved in thionyl chloride (5 ml)and the solution boiled under heating for 2 hours. The reaction system was concentrated under reduced pressure and subjected to azeotropic distillation with toluene, thus obtaining 4-pertenecer chloride in the form of a crude product. This chloranilic acid was dissolved in acetonitrile (20 ml) and to the solution was added thioisocyanate potassium (851 mg), then stirred at 70°C for 5 hours. Reacciona the mixture was cooled to room temperature and concentrated under reduced pressure. Then the product was separated using a saturated aqueous solution of sodium bicarbonate (100 ml) and ethyl acetate (50 ml). The organic layer was washed with saturated saline (100 ml) and dried over sodium sulfate, then concentrated under reduced pressure, thus obtaining 4-pertenecer thioisocyanate. This thioisocyanate was not subjected to additional purification and dissolved in tetrahydrofuran (20 ml). Solution (20 ml) of compound 1c (374 mg) in tetrahydrofuran was added to thioisocyanate solution, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the formed solid product was filtered, thus obtaining a compound 19a (452 mg, yield: 79%).

1H-NMR (CDCl3) δ: 12,47 (1H, s), 11,82 (1H, s), 8,73 (1H, s), 8,65 (1H, d, J=4.4 Hz), 7,95 (1H, DD, J=11.2 Hz, 2.8 Hz), 7,49 (1H, s), 7,43-7,40 (1H, m), 7,31-of 7.25 (3H, m), to 7.15 (2H, m), 6.42 per (1H, DD, J=5,2 Hz, 1.2 Hz), 4,03 (3H, s), 3,74 (2H, s)of 1.64 (9H, s); ESI-MS m/z 580 (MN+).

The hydrochloride of 4-(2-Fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxylic acid (19b)

Compound 19a (385 mg) was dissolved in 4n solution of a mixture of HCl-dioxane (10 ml) and the solution was stirred at a temperature of 80°C for 4 hours. Formed in the reaction mixture, the precipitate was filtered, thus obtaining the compound 19b (245 mg, yield: 66%).

1H-NMR (DMSO-d6) δ: to 12.52 (1H, s), 11,85 (1H, s), to 8.94 (1H, d, J=6.0 Hz), 8,68 (1H, s), 8,11 (1H, d, J=12,4 Hz), 7,66 (1H, s), a 7.62 (1H, d, J=3,4 Hz), 7,39 (2H, DD, J=8,4 Hz, 5.6 Hz), 7,19 (2H, t, J=8,8 Hz), 6,85 (1H, d, J=6.0 Hz), Android 4.04 (3H, C)of 3.84 (2H, s); ESI-MS m/z 524 (MN+).

4-(2-Fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-7-methoxy-N-(2-oxazepan-3-yl)quinoline-6-carboxamide (19)

A method similar to that described in example 1, from compound 19b (53,0 mg), DL-α-amino-ε-caprolactam (14.3 mg), triethylamine (38,9 μl) and N-hydrate (DMTMM (30.9 mg) has been specified in the title compound 19 (16,9 mg, yield: 29%).

1H-NMR (DMSO-d6) δ: 12,47 (1H, s), 11,81 (1H, s), 9,20 (1H, d, J=5.6 Hz), of 8.90 (1H, s)8,71 (1H, d, J=5,2 Hz), 8,04-of 7.96 (2H, m), 7,60 (1H, s), EUR 7.57-7,51 (2H, m), 7,39 was 7.36 (2H, m), 7,20-to 7.15 (2H, m), 6,53 (1H, d, J=5,2 Hz), 4,65-br4.61 (1H, m), 4,10 (3H, s), 3,83 (2H, s), 3,48-3,44 (2H, m), 2,08-2,05 (1H, m), 1,94-1,90 (1H, m), 1,79-1,72 (2H, m), 1,44-of 1.40 (1H, m), 1,29-1,19 (1H, m).

Example 20

(S)-tert-Butyl 2-(3-ftorpirimidinu-1-yl)-2-oxoethylidene (20a)

(S)-3-Ftorpirimidinu hydrochloride (535 mg), N-Boc glycine (746 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1,41 g), 1-hydroxybenzotriazole (993 mg) and triethylamine (1,19 ml) was dissolved in tetrahydrofuran (5 ml)and the solution was stirred at 70°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and was added to the residue aqueous saturated sodium bicarbonate solution (20 ml), then was extracted with ethyl acetate(10 ml). The organic layer was washed sequentially with 0,1N HCl (10 ml) and saturated SOLEV the m solution (10 ml) and dried over sodium sulfate, then was concentrated under reduced pressure, thus obtaining a compound 20a (98,1 mg, yield: 9.3 per cent).

1H-NMR (CDCl3) δ: the 5.45 (1H, usher.), 5,40-5,19 (1H, m), 4,00-3,82 (3H, m), 3.72 points-to 3.49 (3H, m, 4,10 (3H, s), 3,83 (2H, s), 3,48-3,44 (2H, m), 2,41-of 2.24 (1H, m), 2,19 is 1.91 (1H, m); FAB-MS m/z 247 (MN+).

(S)-2-Amino-1-(3-ftorpirimidinu-1-yl)Etalon hydrochloride (20b)

Compound 20a (98,1 mg) was dissolved in 4n solution of a mixture of HCl-1,4-dioxane, and the solution was stirred at room temperature for 4 hours, thus obtaining a compound 20b (of 33.5 mg, yield: 46%).

1H-NMR (DMSO-d6) δ: 8,28 (3H, usher.), 5,48 with 5.22 (1H, m), 3,88-of 3.27 (6H, m), 2,29-1,89 (2H, m).

(S)-4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(2-(3-ftorpirimidinu-1-yl)-2-oxoethyl)-7-methoxyquinoline-6-carboxamide (20)

A method similar to that described in example 1, from compound 1e (35,3 mg), compound 20b (14.3 mg), triethylamine (22,7 μl) and N-hydrate (DMTMM (to 21.6 mg) has been specified in the title compound 20 (15.1 mg, yield: 37%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), 8,83 (1H, t, J=4.4 Hz), 8,81 (1H, s)8,71 (1H, d, J=5,2 Hz), to 7.59 (1H, s), EUR 7.57-7,51 (2H, m), 7,37-7,33 (5H, m), 7,31-of 7.25 (1H, m), 6,53 (1H, d, J=5.6 Hz), 5,49-27 (1H, m), 4,27-4,13 (2H, m), 4,08 (3H, s), 3,82 (2H, s), 3,86-3,63 (3H, m), 2,32-2,05 (3H, m); ESI-MS m/z 634 (MN+).

Example 21

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(2-morpholino-2-oxoethyl)quinoline-6-carboxamide (21)

A method similar to that described in example 1, from compound 1e (24,2 mg), hydrochloride 2-the Mino-1-morpholinoethoxy (synthesized as described in document J. Med. Chem., 1988, 31(11), 2145-2152) (9,67 mg), triethylamine (18,7 μl) and N-hydrate (DMTMM (14,8 mg) has been specified in the title compound 21 (18,4 mg, yield: 65%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), cent to 8.85-8,83 (1H, m), 8,82 (1H, s)8,71 (1H, DD, J=5,2 Hz), 8,03 (1H, d, J=12.0 Hz), 7,60 (1H, s), 7,55 (1H, s), 7,55 is 7.50 (1H, m), 7,35-7,28 (5H, m), of 6.52 (1H, d, J=5,2 Hz), 4,24 (2H, d, J=4,8 Hz), 4,08 (2H, s), of 3.96 (3H, s), 3,82 (2H, s)and 3.59 (2H, d, J=13,2 Hz), 3,53-of 3.48 (2H, m), 3,15-of 3.00 (2H, m); ESI-MS m/z 632 (MN+).

Example 22

N-(2-(Dimethylamino)-2-oxoethyl)-4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamide (22)

A method similar to that described in example 1, from compound 1e (37,0 mg), hydrochloride 2-amino-N,N-dimethylacetamide (11.4 mg), N-hydrate (DMTMM (22.7 mg) and triethylamine (23,8 µl) were specified in the title compound 22 (6.8 mg, yield: 17%).

1H-NMR (DMSO-d6) δ: 12,51 (1H, s), 11,82 (1H, s), 8,87-8,84 (2H, m), 8,72 (1H, DD, J=5.4 Hz, 0.6 Hz), 7,60-7,52 (3H, m), 7,38-7,33 (4H, m), 7,31-7,26 (1H, m), is 6.54 (1H, d, J=4,8 Hz), is 4.21 (2H, d, J=4,8 Hz), 4.09 to (3H, s), 3,83 (2H, s)of 3.00 (3H, s), 2,89 (3H, m); ESI-MS m/z 590 (MN+).

Example 23

4-(2-Fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-N-(2-hydroxybutyl)-7-methoxyquinoline-6-carboxamide (23)

A method similar to that described in example 1, from compound 19b (25.0 mg), 1-amino-2-butanol (10,6 μl) and N-hydrate (DMTMM (14,8 mg) has been specified in the title compound 23 (14,2 mg, yield: 53%).

1H-NMR (DMSO-d6) δ: 12,47 (1H, s), 11,81 (1H, s), 8,69 (1H, d, J=4.0 Hz), 8,65 (1H, s), 8,39 (1H, t, J=8,8 Hz), 8,02(1H, d, J=11.2 Hz), 7,55-7,49 (3H, m), 7,37 (2H, DD, J=7,0 Hz, 6.0 Hz), 7,17 (2H, t, J=8,8 Hz), of 6.52 (1H, d, J=5.4 Hz), 4,80 (1H, d, J=4,8 Hz), a 4.03 (3H, s), 3,86 (2H, s), 3,82 (2H, s)and 1.51-of 1.45 (2H, m), 1,39-of 1.31 (2H, m)of 0.90 (3H, t, J=7.2 Hz); ESI-MS m/z 595 (MN+).

Example 24

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(2-hydroxy-2-methylpropyl)-7-methoxyquinoline-6-carboxamide (24)

A method similar to that described in example 1, from compound 1e (49,1 mg), 1-amino-2-methylpropan-2-ol (synthesized as described in document Angew. Chem. Int. Ed., 2007, 46(25), 4751-4753) (20.2 mg) and N-hydrate (DMTMM (30.1 mg) has been specified in the title compound 24 (36,1 mg, yield: 69%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), RS 11.80 (1H, s), 8,69 (1H, d, J=5.6 Hz), 8,66 (1H, s), a 8.34 (1H, t, J=6.0 Hz), 8,02 (1H, d, J=11.2 Hz), EUR 7.57-7,52 (3H, m), 7,37-7,33 (4H, m), 7,30-7,27 (1H, m), of 6.52 (1H, d, J=5.6 Hz), 4,63 (1H, s), Android 4.04 (3H, s), 3,83 (2H, s), 3,81 (1H, d, J=2.4 Hz), 1.55V (1H, s)to 1.14 (6H, s); ESI-MS m/z 577 (MN+).

Example 25

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-((1-hydroxycyclohexyl)methyl)-7-methoxyquinoline-6-carboxamide (25)

A method similar to that described in example 1, from compound 1e (17.9 mg), hydrochloride of 1-(aminomethyl)cyclohexanol (synthesized as described in document J. Org. Chem., 1989. 54(24), 5651-5654) (6,57 mg) and N-hydrate (DMTMM (11.0 mg) has been specified in the title compound 25 (8.2 mg, yield: 40%).

1H-NMR (CDCl3) δ: 12,51 (1H, s), a 9.25 (1H, s), 8,66 (1H, d, J=5,2 Hz), 8,55 (1H, s)8,23 (1H, t, J=5.4 Hz), of 7.96 (1H, DD, J=11,6 Hz, 2.4 Hz), 7,53 (1H, s), 7,46-7,37 (4, m), 7,33-of 7.23 (3H, m), 6,44 (1H, DD, J=5,2 Hz, 0.8 Hz), 4,12 (3H, s), 3,76 (2H, s)to 3.58 (1H, d, J=5.8 Hz), 1,65-1,52 (10H, m)to 1.37 (1H, user.); ESI-MS m/z 617 (MN+).

Example 26

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-((4-hydroxycitrate-2H-Piran-4-yl)methyl)-7-methoxyquinoline-6-carboxamide (26)

A method similar to that described in example 1, from compound 1e (241 mg), hydrochloride 4-(aminoethyl)tetrahydro-2H-Piran-4-ol (synthesized as described in document US 2005/0696358 A1) (89,4 mg), triethylamine (155 μl) and N-hydrate (DMTMM (147 mg) was obtained is listed in the title compound 26 (236 mg, yield: 86%).

1H-NMR (CDCl3) δ: 12,51 (1H, s), 9,26 (1H, s), 8,67 (1H, d, J=5.4 Hz), to 8.45 (1H, s), compared to 8.26 (1H, t, J=6.0 Hz), of 7.96 (1H, d, J=11,6 Hz, 2.4 Hz), 7,55 (1H, s), 7,47-7,38 (4H, m), 7,33-7,24 (3H, m), of 6.52 (1H, DD, J=5,2 Hz, 0.8 a Hz), 4,13 (3H, s), 3,83-of 3.78 (4H, m), 3,76 (2H, s), 3,61 (2H, d, J=6.4 Hz), 3,30 (1H, usher.), of 1.78 (2H, m), 1,64 (2H, d, J=12,8 Hz); ESI-MS m/z 619 (MN+).

Example 27

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(2-(methylsulphonyl)ethyl)quinoline-6-carboxamide (27)

A method similar to that described in example 1, compound 1e (25 mg), 2-(methylsulphonyl)ethanamine (6 mg), triethylamine (19 μl) and N-hydrate (DMTMM (20 mg) was dissolved in ethanol (1 ml) and the solution was stirred at room temperature for 1 hour, thus obtaining specified in the title compound 27 (20.6 mg, yield: 73%).

1H-NMR (DMSO-d6) δ: 12,50 (1H, s), 11,83 (1H, s), 8,77 (1H, t, J=5.6 Hz), 8,70-8,69 (2H, m), 8,03 (1H, DD, J=12.2 G is, 1,8 Hz), EUR 7.57-to 7.50 (4H, m), 7,38-7,34 (4H, m), 7,31-7,26 (1H, m), 6,53 (1H, d, J=5.6 Hz), a 4.03 (3H, s), 3,83 (2H, s), 3,76 (2H, dt, J=6.2 Hz), 3,42 (2H, d, J=6.8 Hz), of 3.07 (3H, s); ESI-MS m/z 611 (MN+).

Example 28

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-o-trilinolein-6-carboxamide (28)

In a manner similar to that described for obtaining compound 1, from compound 1e (32 mg), o-toluidine (to 7.59 ml) and N-hydrate (DMTMM (19.6 mg) has been specified in the title compound 28 (19,8 mg, yield: 56%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,51 (1H, s), 11,82 (1H, s), 9,96 (1H, s), 8,76 (1H, s), 8,72 (2H, d, J=5,2 Hz), to 7.64 (1H, s), 7,81 (1H, d, J=7,2 Hz), 7,58-7,52 (2H, m), of 7.36-7,33 (4H, m), 7,30-7,21 (3H, m), 7,12 (1H, t, J=7,6 Hz), 6,55 (1H, d, J=5.6 Hz), 4,12 (3H, s), 3,83 (2H, s), of 2.34 (3H, s); ESI-MS m/z 595 (MN+).

Example 29

(S)-4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(2-hydroxy-1-phenylethyl)-7-methoxyquinoline-6-carboxamide (29)

In a manner similar to that described for obtaining compound 1, from compound 1e (44 mg), (S)-2-amino-2-phenylethanol (15,5 mg) and N-hydrate (DMTMM (19.1 mg) has been specified in the title compound 29 (47.0 mg, yield: 86%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), 8,83 (1H, d, J=8.0 Hz), 8,69 (1H, d, J=5,2 Hz), 8,58 (1H, s), 8,02 (1H, DD, J=11,6 Hz to 1.6 Hz), EUR 7.57 (1H, s), EUR 7.57-7,49 (2H, m), 7,41-7,31 (7H, m), 7,29-7,22 (3H, m), of 6.52 (1H, d, J=5,2 Hz), 5,09 (1H, q, J=7,6 Hz), 5,02 (1H, t, J=5.6 Hz), 4,06 (3H, s), 3,82 (2H, s), 3,70-to 3.67 (2H, m); ESI-MS m/z 625 (MN+).

Example 30

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(2-hydroxy-2-(2-methyl-2H-tetrazol-5-yl)ethyl)-7-methods is chinolin-6-carboxamide (30)

In a manner similar to that described for obtaining compound 1, from compound 1e (30.0 mg), 2-amino-1-(2-methyl-2H-tetrazol-5-yl)ethanol (12.7mm mg) and N-hydrate (DMTMM (19.7 mg) has been specified in the title compound 30 (31,2 mg, yield: 83%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), 8,68 (1H, d, J=5,2 Hz)8,64 (1H, s), 8,58 are 8.53 (1H, m), 8,03 (1H, d, J=11,6 Hz), EUR 7.57-7,52 (3H, m), of 7.36-7,33 (4H, m), 7,30-7,26 (1H, m), of 6.52 (1H, d, J=5.6 Hz), 6,07 (1H, d, J=6.4 Hz), 4,34 (3H, s), of 4.00 (3H, s), 3,83-3,82 (3H, m), 3,78-3,70 (2H, m); ESI-MS m/z 649 (MN+).

Example 31

(S)-4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide (31)

In a manner similar to that described for obtaining compound 1, from compound 1e (81,7 mg), (S)-2-aminobutane-1-ol (22,8 mm) and N-hydrate (DMTMM (of 53.7 mg) has been specified in the title compound 31 (89,6 mg, yield: 96%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), 8,68 (1H, d, J=5,1 Hz), 8,55 (1H, s)to 8.12 (1H, d, J=8.6 Hz), 8,02 (1H, DD, J=12.0 Hz, 1.4 Hz), 7,58-of 7.48 (3H, m), of 7.36-of 7.25 (4H, m), 7,31-of 7.25 (1H, m), 6,51 (1H, d, J=5.4 Hz), and 4.75 (1H, t, J=5.6 Hz), to 4.01 (3H, s), 3,92-of 3.85 (1H, m), 3,82 (2H, s), 3,52-3,47 (1H, m), 3.45 points-to 3.38 (1H, m), 1,78 is 1.70 (1H, m), 1,50-of 1.40 (1H, m)to 0.92 (3H, t, J=7,6 Hz); ESI-MS m/z 577 (MN+).

Example 32

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(1-hydroxyderivatives-3-yl)-7-methoxyquinoline-6-carboxamide (32)

In a manner similar to that described for obtaining compound 1, from compound 1e (of 25.7 mg), hydrochloride 4-aminotetrahydrofuran-3-ol (16,9 mg), N-hydrate DMTM (11,5 mg) and triethylamine (14,2 mm) has been specified in the title compound 32 (30,2 mg, yield: 93%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), 8,81 (1H, s)8,71 (1H, d, J=5,2 Hz), to 8.57 (1H, d, J=7,2 Hz), 8,03 (1H, DD, J=13,2 Hz, 2.4 Hz), 7,58 (1H, s), EUR 7.57-to 7.50 (2H, m), of 7.36-of 7.25 (5H, m), is 6.54 (1H, DD, J=5,2 Hz, 0.8 a Hz), 4,37 (2H, d, J=4,8 Hz)4,06 (3H, s), 3,83 (2H, s), 3,10 (1H, DD, J=12.0 Hz, 4.4 Hz), to 3.02 (1H, DD, J=9.6 Hz, 7.2 Hz), 2,80-2,62 (3H, m); ESI-MS m/z 625 (MN+).

Example 33

tert-Butyl 2-(4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamido)acetate (33a)

In a manner similar to that described for obtaining compound 1, from compound 1e (65,2 mg), hydrochloride tert-butyl ester of glycine (18,9 mg), N-hydrate (DMTMM (39.9 mg) and triethylamine (42,1 ml) was obtained the compound 33a (67.2 per mg, yield: 90%).

1H-NMR (400 Hz, CDCl3) δ: 12,51 (1H, s), 9.28 are (1H, d, J=4,8 Hz), 8,66 (1H, d, J=5.6 Hz), 8,59 (1H, usher.), 8,51 (1H, DD, J=4,8 Hz), 7,95 (1H, DD, J=12.0 Hz, 2.4 Hz), 7,46 and 7.36 (5H, m), 7,32-of 7.23 (3H, m), 6,44 (1H, d, J=4,8 Hz, 1.2 Hz), 4,24 (2H, d, J=4,8 Hz), 4,16 (3H, s), 3,76 (2H, s)of 1.53 (9H, s); ESI-MS m/z 619 (MN+).

Hydrochloride of 2-(4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamido)acetic acid (33b)

In a manner similar to that described for obtaining compounds 1e, from compound 33a (55.7 mg) was obtained compound 33b (37,2 mg, yield: 63%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,55 (1H, s), up 11,86 (1H, s), 8,98 (1H, d, J=6.0 Hz), 8,87 (1H, DD, J=5.6 Hz), 8,76 (1H, s)to 8.12 (1H, DD, J=12,4 Hz, 1.2 Hz), 7,74 (1H, s)of 7.64 to 7.62 (2H, m), of 7.36-7,34 (5H, m), 7,32-7,27 (1H, m)6,91 (1H, d, J=6.4 Hz), 4.09 to (3H, s)to 4.01 (2H, d, J=5.6 Hz), 3,83 (2H, s); ESI-MS m/z 563 (MN+).

In a manner similar to that described for obtaining compound 1, from compound 33b (50 mg), 2-methoxyethylamine (11 μl), N-hydrate (DMTMM (34,6 mg) and N-methylmorpholine (18,4 µl) were specified in the title compound 33 (12.0 mg, yield: 23%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,51 (1H, s), 11,83 (1H, s), 8,76 (1H, s), is 8.75 (1H, t, J=5.4 Hz), 8,71 (1H, d, J=5.4 Hz), 8,06-of 8.00 (2H, m), to 7.59 (1H, s), EUR 7.57-to 7.50 (2H, m), 7,38-7,26 (5H, m), 6,53 (1H, d, J=5.4 Hz), 4,07 (3H, s), of 3.97 (2H, d, J=5.4 Hz), a-3.84 (2H, s), 3,39-to 3.35 (2H, m), 3,30-of 3.27 (2H, m)of 3.25 (3H, s); ESI-MS m/z 620 (MN+).

Example 34

(S)-4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)-7-methoxyquinoline-6-carboxamide (34)

In a manner similar to that described for obtaining compound 1, from compound 33b (50 mg), (S)-pyrrolidin-2-ylmethanol (11 μl), N-hydrate (DMTMM (30 mg) and N-methylmorpholine (24 μl) were specified in the title compound 34 (32 mg, yield: 60%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,51 (1H, users), 11,83 (1H, users), 8,88-8,83 (2H, m), 8,72 (1H, d, J=5,1 Hz), of 8.04 (1H, d, J=and 12.2 Hz), 7,63-7,51 (3H, m), 7,39-7,26 (5H, m), is 6.54 (1H, d, J=5,1 Hz), 4,74 (1H, t, J=5.5 Hz), 4,39-4,22 (1H, m), 4,18 is 4.13 (1H, m), 4,10 (3H, s), 4,05-of 3.95 (1H, m), a-3.84 (2H, s), 3,56-to 3.41 (3H, m), 2,02 to 1.76 (5H, m); ESI-MS m/z 646 (MN+).

Example 35

N-(2-(Ethyl(2-hydroxy-2-methylpropyl)amino)-2-oxoethyl)-4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamide (35)

In a manner similar to that described for obtaining compound 1, from compound 33b (35,0 mg), 1-(ethylamino)-2-methyl shall ropan-2-ol (17,1 mg) and N-hydrate (DMTMM (to 19.4 mg) has been specified in the title compound 35 (12.3 mg, yield: 32%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,50 (1H, s), 11,82 (1H, s), 8,86 (1H, usher.), 8,84 (1H, d, J=2.7 Hz), 8,71 (1H, d, J=5.4 Hz), 8,03 (1H, DD, J=11.7 Hz, 2.0 Hz), to 7.59 (1H, s), EUR 7.57-7,52 (2H, m), 7,37-to 7.32 (4H, m), 7,21-of 7.25 (1H, m), 6,53 (1H, d, J=5.6 Hz), 4,32-4,27 (2H, m), 4.09 to, 4,07 (3H, C), 3,82 (2H, s), 3,50-3,20 (4H, m), 1,18-1,13 (5H, m), 1,09-1,01 (5H, m); ESI-MS m/z 662 (MN+).

Example 36

tert-Butyl 2-(4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamido)propanoate (36a)

In a manner similar to that described for obtaining compound 1, from compound 1e (100 mg), hydrochloride tert-butyl ester of alanine (47 mg) and N-hydrate (DMTMM (71 mg) was obtained compound 36a (109 mg, yield: 87%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,57 (1H, s)11,89 (1H, s), 8,76 (1H, d, J=5,2 Hz), 8,65 (1H, s), 8,61 (1H, t, J=5,2 Hz), 8,10 (1H, d, J=12,4 Hz), 7,60-7,30 (8H, m), 6,60 (1H, d, J=5,2 Hz), 4,08 (3H, s), 3,90 (2H, s), of 3.57 (2H, TD, J=6,5 Hz, J=6.5 Hz), to 2.57 (2H, t, J=6.5 Hz), of 1.47 (9H, s); ESI-MS m/z 633 (MN+).

Hydrochloride of 2-(4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxyquinoline-6-carboxamido)propanoic acid (36b)

In a manner similar to that described for obtaining compounds 1e, from compound 36a (95 mg) was obtained compound 36b (92 mg, yield: 100%).

1H-NMR (400 Hz, DMSO-d6) δ; 12,55 (1H, s), up 11,86 (1H, s), to 8.94 (1H, d, J=5,9 Hz), 8,68 (1H, s), 8,65 (1H, t, J=5,9 Hz), 8,11 (1H, d, J=12,4 Hz), 7,69-7,58 (3H, m), 7,38-of 7.25 (5H, m), 6.87 in (1H, d, J=5,9 Hz), of 4.05 (3H, s), a-3.84 (2H,, (C), of 3.54 (2H, TD, J=6,7 Hz, J=6,7 Hz)to 2.55 (2H, t, J=6,7 Hz); ESI-MS m/z 577 (MN+).

N-(3-(Dimethylamino)-3-oxopropyl)-4-(2-fluoro-4-(3-(2-Hairdryer shall lazeil)touraid)phenoxy)-7-methoxyquinoline-6-carboxamide (36)

A method similar to that described in example 1, from compound 36b (30 mg), dimethylamine hydrochloride (6.0 mg), N-hydrate (DMTMM (20 mg) and N-methylmorpholine (16 μl) were specified in the title compound 36 (21.2 mg, yield: 68%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,51 (1H, s), 11,83 (1H, s), 8,72 (1H, s) to 8.70 (1H, d, J=5,2 Hz), 8,66 (1H, t, J=5,9 Hz), of 8.04 (1H, d, J=and 12.2 Hz), 7,58-of 7.25 (8H, m), 6,53 (1H, d, J=5,2 Hz), Android 4.04 (3H, s), a-3.84 (2H, s), of 3.54 (2H, dt, J=6,4 Hz, J=6.4 Hz), of 2.97 (3H, s), 2,85 (3H, s), 2,61 (2H, t, J=6.4 Hz); ESI-MS m/z 604 (MN+).

Example 37

4-(2-Fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-7-methoxy-N-(2-morpholinoethyl)quinoline-6-carboxamide (37)

A method similar to that described in example 1, from compound 19b (523 mg), 2-morpholinoethyl (171 mg) and N-hydrate (DMTMM (360 mg) has been specified in the title compound 37 (462 mg, yield: 73%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,47 (1H, s), 11,82 (1H, s), to 8.70 (1H, d, J=5,2 Hz), to 8.70 (1H, s) 8,53-8,48 (1H, m), 8,02 (1H, d, J=13,0 Hz), to 7.59-of 7.48 (3H, m), 7,43-7,33 (2H, m), 7,24-7,13 (2H, m), 6,53 (1H, d, J=5,2 Hz), 4,07 (3H, ), a-3.84 (2H, s), 3,63-3,59 (4H, m), 3,49-of 3.32 (6H, m), 2,50-to 2.40 (2H, m); ESI-MS m/z 636 (MN+).

Example 38

(S)-4-(2-Fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide (38)

A method similar to that described in example 1, from compound 19b (50 mg), (S)-2-aminobutane-1-ol (12 ml) and N-hydrate (DMTMM (34 mg) was obtained is listed in the title compound 38 (25 mg, yield: 45%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,48 (1H, usher.), 11,82 (1H, with the Il.), 8,69 (1H, d, J=5,2 Hz), to 8.57 (1H, s), 8,13 (1H, d, J=8,3 Hz), 8,03 (1H, d, J=13,2 Hz), 7,58 is 7.50 (3H, m), 7,39 (2H, DD, J=8.5 Hz, J=5.6 Hz), 7,22-to 7.15 (2H, m), of 6.52 (1H, d, J=5,2 Hz), of 4.77 (1H, t, J=5.6 Hz), a 4.03 (3H, s), 3,93-3,86 (1H, m), a-3.84 (2H, s), 3,55-of 3.48 (1H, m), 3.45 points is 3.40 (1H, m), 1,72-to 1.63 (1H, m), 1,53-of 1.42 (1H, m)of 0.93 (3H, t, J=7.4 Hz); ESI-MS m/z 595 (MN+).

Example 39

Methyl 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxylate (39a)

From methyl 4-chloro-7-methoxyquinoline-6-carboxylate (synthesized as described in WO 2005/080377) (1,00 g), 2-fluoro-4-NITROPHENOL (936 mg) and N,N-diisopropylethylamine (1.35 ml) was obtained the compound 39a (1,38 g, yield: 93%).

1H-NMR (CDCl3)δ: a total of 8.74 (1H, s), 8,73 (1H, d, J=5,2 Hz), 7,54 (1H, s), 7,45-7,40 (3H, m), of 6.49 (1H, DD, J=5.0 Hz, 1.4 Hz), 4,06 (3H, s), 3,98 (3H, s); ESI-MS m/z 373 (MH+).

Methyl 4-(4-amino-2-pertenece)-7-methoxyquinoline-6-carboxylate (39b)

In a manner similar to that described for obtaining compounds 1b, compound 39a (275 mg), iron powder (206 mg) and ammonium chloride (275 mg) was obtained compound 39b (188 mg, yield: 74%).

1H-NMR (400 Hz, CDCl3) δ: 8,83 (1H, s), 8,63 (1H, d, J=5,2 Hz), of 7.48 (1H, s), 7,03 (1H, t, J=8,4 Hz), 6,56 (1H, DD, J=11,6 Hz, 2.8 Hz), 6,50 (1H, DDD, J=8,8 Hz, 2.6 Hz, 1.0 Hz), 6,41 (1H, DD, J=5.0 Hz, 1.2 Hz), Android 4.04 (3H, s), of 3.97 (3H, C)of 3.84 (2H, user.); ESI-MS m/z 343 (MN+).

4-(4-Amino-2-pertenece)-7-methoxyquinoline-6-carboxylic acid (39c)

Compound 39b (1.0 g) was added to methanol (10 ml) and then was added 4M aqueous sodium hydroxide (650 μl) and water (400 ml), then stirred at anatoy temperature for 2 hours. After completion of the reaction, to the reaction mixture was added 6N aqueous hydrochloric acid, thus setting pH 3 and the precipitate was filtered, resulting in the received connection 39c (862 mg, yield: 90%).

1H-NMR (400 Hz, DMSO-d6) δ: 8,66 (1H, d, J=5.4 Hz), 8,54 (1H, s)of 7.48 (1H, s), to 7.09 (1H, DD, J=8,8 Hz), 6,55 (1H, DD, J=13,0 Hz, 2.7 Hz), 6.48 in-to 6.43 (2H, m), of 5.55 (1H, usher.), of 3.96 (3H, s); ESI-MS m/z 329 (MN+).

4-(4-(3-(2-(2-Forfinal)acetylthiourea)-2-pertenece)-7-methoxyquinoline-6-carboxylic acid (39d)

In a manner similar to that described for obtaining the compounds 1d, from compound 39c (1,79 g), 2-pertenecer thioisocyanate (1.97 g) and a solvent mixture of N,N-dimethylacetamide (30 ml), toluene (30 ml) and ethanol (6 ml), was received carboxylic acid 39d in the form of a crude product (1.89 g, yield: 89%). The crude product was used in subsequent reactions without further purification.

4-(2-Fluoro-4-(3-(2-(2-forfinal)acetyl)touraid)phenoxy)-N-(2-hydroxy-2-methylpropyl)-7-methoxyquinoline-6-carboxamide (39)

In a manner similar to that described for obtaining compound 1, from compound 39d (126 mg), N-hydrate (DMTMM (87 mg) and 1-amino-2-methylpropan-2-ol (37 mg) was obtained is listed in the title compound 39 (89 mg, yield: 62%).

1H-NMR (400 Hz, CDCl3) δ: 12,43 (1H, s), 9,26 (1H, s), 8,67 (1H, d, J=5,1 Hz), 8,59 (1H, m), compared to 8.26 (1H, m), of 7.97 (1H, DD, J=11.5 Hz, 2.4 Hz), 7,54 (1H, s), 7,44-to 7.15 (6H, m), 6,44 (1H, DD, J=5.4 Hz, 1.2 Hz), 4,13 (3H, s), with 3.79 (2H, C)3,57 (2H, d, J=5.8 Hz), 2.57 m) (1H, C)and 1.3 (6H, C); ESI-MS m/z 595 (MN+).

Example 40

(S)-4-(2-Fluoro-4-(3-(2-(2-forfinal)acetyl)touraid)phenoxy)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide (40)

In a manner similar to that described for obtaining compound 1, from compound 39d (121 mg), N-hydrate (DMTMM (83 mg) and (S)-2-aminobutane-1-ol (28 mg) was obtained is listed in the title compound 40 (84 mg, yield: 61%).

1H-NMR (400 Hz, CDCl3) δ: to 12.44 (1H, s), a 9.25 (1H, s), 8,67 (1H, d, J=5,1 Hz)8,64 (1H, s), 8,03 (1H, d, J=7,6 Hz), of 7.97 (1H, DD, J=11,6 Hz, 2.6 Hz), 7,54 (1H, s), 7,44-7,14 (6H, m), of 6.45 (1H, DD, J=5,1 Hz, 1.2 Hz), 4,12 (3H, s), 3,86 (1H, m), with 3.79 (2H, in), 3.75 (1H, m), of 3.07 (1H, t, J=5.5 Hz), 1,82 is 1.60 (2H, m)of 1.07 (3H, t, J=7.5 Hz); ESI-MS m/z 595 (MN+).

Example 41

(S)-4-(4-Amino-2-pertenece)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide (41a)

In a manner similar to that described for obtaining compound 1, from compound 39c (300 mg), N-hydrate (DMTMM (329 mg) and (S)-2-aminobutane-1-ol (113 ml) was obtained the compound 41a (297 mg, yield: 81%).

1H-NMR (DMSO-d6) δ: 8,64 (1H, d, J=5,1 Hz), 8,56 (1H, s)to 8.12 (1H, d, J=8,3 Hz), 7,51 (1H, s), to 7.09 (1H, t, J=9.0 Hz), 6,56 (1H, DD, J=13.3 Hz, J=2.3 Hz), 6,50-to 6.43 (2H, m), 5,52 (2H, s), 4,78 (1H, t, J=5.5 Hz), 4,01 (3H, s), 3.95 to of 3.85 (1H, m), 3,56-of 3.48 (1H, m), 3.46 in-to 3.38 (1H, m), 1,74-of 1.62 (1H, m), 1,54-of 1.41 (1H, m)of 0.93 (3H, t, J=7.4 Hz); ESI-MS m/z 400 (MH+).

(S)-4-(2-Fluoro-4-(3-(2-(3-forfinal)acetyl)touraid)phenoxy)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide (41)

In a manner similar to that described for obtaining the compounds 1d, from compound 41a (100 mg) and 3-torfin lazeil thioisocyanate (73 mg) was obtained is listed in the title compound 41 (115 mg, yield: 78%).

1H-NMR (DMSO-d6) δ: to 12.44 (1H, s), 11,83 (1H, s), 8,69 (1H, d, J=5.3 Hz), to 8.57 (1H, s), 8,13 (1H, d, J=8,3 Hz), 8,03 (1H, d, J=and 12.2 Hz), to 7.59-7,49 (3H, m), 7,44 and 7.36 (1H, m), 7.23 percent-to 7.09 (3H, m), of 6.52 (1H, d, J=5.3 Hz), 4,77 (1H, t, J=5.5), the a 4.03 (3H, s), 3,93-a-3.84 (1H, m), 3,88 (2H, s), 3,54-of 3.48 (1H, m), 3.45 points-to 3.38 (1H, m), 1,72-of 1.62 (1H, m), 1,54 was 1.43 (1H, m)of 0.93 (3H, t, 7.4 Hz); ESI-MS m/z 595 (MN+).

Example 42

4-(4-Amino-2-pertenece)-N-(2-hydroxy-2-methylpropyl)-7-methoxyquinoline-6-carboxamide (42a)

In a manner similar to that described for obtaining compound 1, from compound 39c (103 mg), N-hydrate (DMTMM (104 mg) and 1-amino-2-methylpropan-2-ol (42 mg) was obtained compound 42a (to 66.3 mg, yield: 53%).

1H-NMR (400 Hz, CDCl3) δ: 9,27 (1H, s)8,64 (1H, d, J=5,2 Hz), compared to 8.26 (1H, usher.), 7,52 (1H, s), 7,02 (1H, DD, J=8,4 Hz), 6,56 (1H, DD, J=12.0 Hz, 2.8 Hz), 6,50 (1H, DDD, J=8,8 Hz, 2.8 Hz, 0.8 Hz), 6.42 per (1H, DD, J=5.4 Hz, 1.2 Hz), 4,12 (3H, s), 3,82 (1H, usher.), of 3.57 (2H, d, J=6.0 Hz), 2,70 (1H, usher.), of 1.33 (6H, s); ESI-MS m/z 400 (MH+).

4-(4-(3-(2-(4-Chlorophenyl)acetyl)touraid)-2-pertenece)-N-(2-hydroxy-2-methylpropyl)-7-methoxyquinoline-6-carboxamide (42)

In a manner similar to that described for obtaining the compounds 1d, from compound 42a (55 mg) and 4-chlorophenylacetyl thioisocyanate (43,7 mg) has been specified in the title compound 42 (41.3 mg, yield: 49%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,45 (1H, s), 11,82 (1H, s)8,71 (1H, d, J=5.4 Hz), 8,67 (1H, s), 8,35 (1H, t, J=6,1 Hz), 8,02 (1H, d, J=11,0 Hz), 7,58-7,49 (3H, m), 7,43-to 7.32 (4H, m), 6,55 (1H, d, J=5.4 Hz), Android 4.04 (3H, s), a-3.84 (2H,with), 3,36-3,30 (2H, m)to 1.98 (1H, usher.), to 1.15 (6H, s); ESI-MS m/z 611, 613 (MN+ ).

Example 43

(S)-4-(4-(3-(2-(4-Chlorophenyl)acetyl)touraid)-2-pertenece)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide (43)

In a manner similar to that described for obtaining the compounds 1d, from compound 41a (63,0 mg) and 4-chlorophenylacetyl thioisocyanate (50,1 mg) has been specified in the title compound 43 (29,9 mg, yield: 31%).

1H-NMR (400 Hz, CD3OD) δ: cent to 8.85 (1H, s), 8,63 (1H, d, J=5.6 Hz), 8,07 (1H, DD, J=12.0 Hz, 2.4 Hz), 7,52 (1H, s), 7,50-7,30 (7H, m), 6,60 (1H, DD, J=5.4 Hz, 1.0 Hz), 4,11 (3H, s), 4,08-was 4.02 (1H, m of usher.), 3,76 (2H, s)to 3.67 (2H, DD, 4.6 Hz), 3.27 to up 3.22 (1H, m), 1,80-of 1.73 (1H, m), 1,65-of 1.57 (1H, m)of 1.18 (2H, s), was 1.04 (3H, t, J=7,6 Hz); ESI-MS m/z 611, 613 (MN+).

Example 44

4-(4-(3-(2-(2,6-Differenl)acetyl)touraid)-2-pertenece)-7-methoxyquinoline-6-carboxylic acid (44a)

In a manner similar to that described for obtaining the compounds 1d, from compound 39c (98 mg), 2,6-differenetly thioisocyanate (128 mg) and a solvent mixture of N,N-dimethylacetamide (1.5 ml), toluene (1.5 ml) and ethanol (300 ml) was received connection 44a in the form of a crude product (143 mg, yield: 89%).

4-(4-(3-(2-(2,6-Differenl)acetylthiourea)-2-pertenece)-7-methoxy-N-(2-morpholinoethyl)quinoline-6-carboxamide (44)

In a manner similar to that described for obtaining compound 1, from compound 44a (143 mg), N-hydrate (DMTMM (95 mg), 2-morpholinoethyl (51 mg) and N,N-dimethylacetamide (1 ml) were specified in the title compound 44 (103 mg, yield: 60%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,5 (1H, with usher.), 11,98 (1H, usher.), to 8.70 (1H, d, J=5.3 Hz), to 8.70 (1H, s), and 8.50 (1H, t, J=5.4 Hz), 8,03 (1H, d of usher., J=13.5 Hz), EUR 7.57 (1H, s), to 7.61-7,39 (3H, m), 7.18 in-7,10 (2H, m), 6,53 (1H, d, J=5.3 Hz), 4,07 (3H, s), 3,98 (2H, s), 3,62-to 3.58 (4H, m), 3,50-3,47 (2H, m), 3,47-3,20 (4H, m), 2,50-2,47 (2H, m); ESI-MS m/z 654 (MN+).

Example 45

4-(4-(3-(2-(2,6-Differenl)acetylthiourea)-2-pertenece)-N-(2-hydroxy-2-methylpropyl)-7-methoxyquinoline-6-carboxamide (45)

In a manner similar to that described for obtaining compound 1, from compound 44a (101 mg), N,N-dimethylacetamide (600 ml), N-hydrate (DMTMM (68 mg) and 1-amino-2-methylpropan-2-ol (31 mg) was obtained is listed in the title compound 45 (74 mg, yield: 65%).

1H-NMR (400 Hz, CDCl3) δ: 12,38 (1H, s), 9,26 (1H, s), 8,69 (1H, usher.), 8,67 (1H, d, J=5.4 Hz), compared to 8.26 (1H, m), of 7.97 (1H, DD, J =11.5 Hz, 2.7 Hz), 7,54 (1H, s), 7,43-to 7.32 (2H, m),? 7.04 baby mortality-of 6.96 (3H, m), 6,44 (1H, DD, J=5,2 Hz, 1.1 Hz), 4,13 (3H, s), a-3.84 (2H, s), 3,57 (2H, d, J=5,9 Hz), of 2.58 (1H, s)of 1.33 (6H, s); ESI-MS m/z 613 (MN+).

Example 46

4-(4-Amino-2-pertenece)-7-methoxy-N-methylinosine-6-carboxamide (46a)

Compound 39b (100 mg) was dissolved in N-methylpiperidin-2-Ohe (250 μl) was added a 40%solution of methylaminoethanol (250 ml), then stirred at 40°C for 16 hours. Then to the reaction mixture was added water, and the precipitate was filtered, thus obtaining the compound 46a (63.7 mg, yield: 64%).

1H-NMR (400 Hz, CDCl3) δ: 9.28 are (1H, s), 8,63 (1H, d, J=5.4 Hz), to 7.84 (1H, usher.), to 7.50 (1H, s), 7,02 (1H, t, J=8.6 Hz), 6,56 (1H, DD, J=12.0 Hz, 2.4 Hz), 6,50 (1H, DDD, J=8,4 G is, 2,8 Hz, 0.8 Hz), to 6.43 (1H, DD, J=5,2 Hz, 1.2 Hz), 4,11 (3H, s), 3,83, of 3.80 (2H, usher.), is 3.08 (3H, d, J=5.0 Hz); ESI-MS m/z 342 (MH+).

4-(2-Fluoro-4-(3-(2-(3-methoxyphenyl)acetyl)touraid)phenoxy)-7-methoxy-N-methylinosine-6-carboxamide (46)

In a manner similar to that described for obtaining the compounds 1d, from compound 46a (50.0 mg) and 3-methoxyphenylacetyl isothiocyanate (to 45.5 mg) has been specified in the title compound 46 (40,1 mg, yield: 50%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,49 (1H, s), to 11.79 (1H, s), to 8.70 (1H, d, J=5.4 Hz), 8,59 (1H, s)of 8.37 (1H, d, J=4, 2 Hz), 8,03 (1H, DD, J=12.0 Hz, 2.4 Hz), 7,58-7,49 (3H, m), 7,42-7,33 (2H, m), 7,22-7,17 (2H, m), is 6.54 (1H, d, J=4.4 Hz), was 4.02 (3H, s), with 3.79 (2H, in), 3.75 (3H, s), and 2.83 (3H, d, J=4,8 Hz); ESI-MS m/z 549 (MN+).

Example 47

4-(2-Fluoro-4-(3-(2-(4-triptoreline)acetyl)touraid)phenoxy)-7-methoxy-N-methylinosine-6-carboxamide (47)

In a manner similar to that described for obtaining the compounds 1d, from compound 46a (50.0 mg) and 4-cryptomaterial isothiocyanate (53,9 mg) has been specified in the title compound 47 (41,2 mg, yield: 48%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,42 (1H, s), 11.87 per (1H, s), 8,69 (1H, d, J=5,2 Hz), 8,59 (1H, s), at 8.36 (1H, d, J=4,8 Hz), 8,02 (1H, DD, J=12.0 Hz, 2.0 Hz), 7,72 (2H, d, J=8,4 Hz), 7,60-7,47 (5H, m), of 6.52 (1H, d, J=5,2 Hz), was 4.02 (3H, C)of 3.96 (2H, s), and 2.83 (3H, d, J=4,8 Hz); ESI-MS m/z 587 (MN+).

Example 48

Methyl 4-(2-chloro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxylate (48a)

In a manner similar to that described for obtaining compounds 1a, from methyl 4-chloro-7-methoxyquinoline-6-carboxy is ATA (350 mg), 2-chloro-4-NITROPHENOL (240 mg), N,N-diisopropylethylamine (484 μl) and N-methylpyrrolidine-2-she (1.5 ml) was obtained the compound 48a (130 mg, yield: 24%).

1H-NMR (400 Hz, CDCl3) δ: 8,73 (1H, s), 8,73 (1H, d, J=5,2 Hz), 8,48 (1H, d, J=2,8 Hz), of 8.25 (1H, DD, J=8,8 Hz, 2.4 Hz), 7,55 (1H, s), 7,35 (1H, d, J=8,8 Hz), 6.42 per (1H, d, J=4,8 Hz), 4,07 (3H, s), 3,98 (3H, s); ESI-MS m/z 389, 391 (MN+).

Methyl 4-(4-amino-2-chlorophenoxy)-7-methoxyquinoline-6-carboxylate (48b)

In a manner similar to that described for obtaining compounds 1c, from compound 48a (111 mg), a mixture of water-methanol-tetrahydrofuran (1:1:1) (5 ml), iron powder (49,7 mg) and ammonium chloride (111 mg) was obtained compound 48b in the form of a crude product (to 31.2 mg, yield: 31%).

ESI-MS m/z 359, 361 (MN+).

4-(4-Amino-2-chlorophenoxy)-7-methoxy-N-methylinosine-6-carboxamide (48c)

In a manner similar to that described for obtaining compounds 46a, from compound 48b (29.0 mg), 40% aqueous solution of methylamine (200 μl) and N-methylpyrrolidine-2-she (200 ál) was obtained compound 48c (27,1 mg, yield: 94%).

1H-NMR (400 Hz, CDCl3) δ: of 9.30 (1H, s), 8,61 (1H, d, J=5.6 Hz), to 7.84 (1H, usher.), 7,51 (1H, s), 7,02 (1H, d, J=8,4 Hz), 6,83 (1H, d, J=2,8 Hz), only 6.64 (1H, DD, J=8,4 Hz, 2.8 Hz), 6,32 (1H, DD, J=5.4 Hz), 4,11 (3H, s), of 3.78 (2H, usher.), is 3.08 (3H, d, J=6.0 Hz); ESI-MS m/z 358, 360 (MN+).

4-(2-Chloro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-methylinosine-6-carboxamide (48)

In a manner similar to that described for obtaining the compounds 1d, from compound 48c (24,0 mg) and phenylacetyl thioisocyanate (17,8 mg)has been specified in the title compound 48 (28,1 mg, yield: 79%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,49 (1H, s), 11,85 (1H, s), to 8.94 (1H, d, J=6.0 Hz), 8,69 (1H, s), of 8.47 (1H, d, J=4,8 Hz), 8,21 (1H, d, J=1.6 Hz), 7,78 (1H, DD, J=8.6 Hz, 2.0 Hz), to 7.61 (1H, d, J=8,8 Hz), to 7.59 (1H, s), 7,35-7,13 (5H, m), 6,69 (1H, d, J=5.8 Hz), 4,07 (3H, s), 3,83 (2H, s)2,84 (3H, d, J=4.4 Hz); ESI-MS m/z 535, 537 (MN+).

Example 49

Methyl 4-(3-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxylate (49a)

In a manner similar to that described for obtaining compounds 1a, from methyl 4-chloro-7-methoxyquinoline-6-carboxylate (300 mg), 3-fluoro-4-NITROPHENOL (225 mg), N,N-diisopropylethylamine (415 μl) and N-methylpyrrolidine-2-she (1.5 ml) was obtained the compound 49a (112 mg, yield: 25%).

1H-NMR (400 Hz, DMSO-d6) δ: 8,82 (1H, d, J=5,1 Hz), to 8.45 (1H, s), to 7.67 (1H, DD, J=12,2 Hz, 2.7 Hz), to 7.59 (1H, s), 7,32 (1H, DD, J=8,8 Hz, 2.7 Hz), 6,83-6,74 (1H, m), 3,98 (3H, s), of 3.84 (3H, s); ESI-MS m/z 373 (MH+).

Methyl 4-(4-amino-3-pertenece)-7-methoxyquinoline-6-carboxylate (49b)

In a manner similar to that described for obtaining compounds 1b, compound 49a (102 mg), iron powder (76,5 mg) and ammonium chloride (100 mg) was obtained compound 49b (59,7 mg, yield: 64%).

1H-NMR (400 Hz, CDCl3) δ: 8,79 (1H, s), 8,63 (1H, d, J=5,2 Hz), 7,49 (1H, s), 6,91-to 6.80 (3H, m), 6,44 (1H, d, J=5,2 Hz), of 4.05 (3H, s), of 3.97 (3H, s), 3,78, of 3.75 (2H, user.); ESI-MS m/z 343 (MN+).

4-(4-Amino-3-pertenece)-7-methoxy-N-methylinosine-6-carboxamide (49c)

In a manner similar to that described for obtaining compounds 46a, from compound 49b (50.5 mg), 40% aqueous solution of methylamine (500 μl) and N-METI pyrrolidin-2-she (500 ml) was obtained the compound 49c (31,2 mg, yield: 62%).

1H-NMR (400 Hz, CDCl3) δ: 9,24 (1H, s), to 8.62 (1H, d, J=5.6 Hz), 7,86 (1H, usher.), to 7.50 (1H, s), 6.90 to-6,79 (3H, m), 6,46 (1H, d, J=5,2 Hz), 4,11 (3H, s), 3,76, 3,74 (2H, usher.), is 3.08 (3H, d, J=5.0 Hz); ESI-MS m/z 342 (MH+).

4-(3-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-methylinosine-6-carboxamide (49)

In a manner similar to that described for obtaining the compounds 1d, from compound 49c (25.0 mg) and phenylacetyl thioisocyanate (19.5 mg) has been specified in the title compound 49 (13.5 mg, yield: 36%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,51 (1H, s)11,89 (1H, s)8,71 (1H, d, J=4,8 Hz), 8,55 (1H, s), a 8.34 (1H, d, J=4,8 Hz), of 8.06 (1H, DD, J=8,8 Hz), 7,53 (1H, s), 7,42 (1H, DD, J=10,8 Hz, 2.8 Hz), 7,37-of 7.25 (5H, m), 7,19-to 7.15 (1H, m), 6,62 (1H, d, J=5.6 Hz), to 4.01 (3H, s), 3,83 (2H, s), 2,82 (3H, d, J=4,8 Hz); ESI-MS m/z 519 (MN+).

Example 50

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N,N-dimethylaniline-6-carboxamide (50)

In a manner similar to that described for obtaining compound 1, from compound 1e (285 mg), 50% aqueous dimethylamine (147 μl) and N-hydrate (DMTMM (174 mg) was obtained is listed in the title compound 50 (256 mg, yield: 91%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,49 (1H, s), 11,81 (1H, s), 8,66 (1H, DD, J=5.4 Hz, 1.2 Hz), of 8.06 (1H, d, J=1.0 Hz), 8,01 (1H, d, J=12,4 Hz), 7,56-7,47 (2H, m), 7,52 (1H, s), 7,38-to 7.32 (4H, m), 7,31-of 7.25 (1H, m), of 6.52 (1H, d, J=5,1 Hz), of 3.97 (3H, d, J=0.8 Hz), 3,83 (2H, s), 3,01 (3H, d, J=1.0 Hz), and 2.79 (3H, d, J=1.2 Hz); ESI-MS m/z 533 (MN+).

Example 51

N-(3-Fluoro-4-(7-methoxy-6-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)quinoline-4-yl) - Rev. XI)phenylcarbamoyl)-2-phenylacetamide (51)

In a manner similar to that described for obtaining compound 1, from compound 1e (27,6 mg), 4-(pyrrolidin-1-yl)piperidine (13,8 mg) and N-hydrate (DMTMM (18,1 mg) has been specified in the title compound 51 (14.1 mg, yield: 39%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,50 (1H, s), 11,83 (1H, s), 8,68 (1H, d, J=5,1 Hz), 8,08 (1H, d, J=14,1), 8,02 (1H, d, J=12,4 Hz), 7,58 was 7.45(2H, m), 7,53 (1H, s), 7,40-7,33 (4H, m), 7,33-7,26 (1H, m), 6,53 (1H, DD, J=4.6 Hz), and 4.40 (1H, d, J=11.7 Hz), 3,98 (3H, d, J=9.3 Hz), a-3.84 (2H, s), 3,10-2,90 (2H, m), 2,75-2,60 (4H, m), 2.05 is-of 1.92 (1H, m), 1.85 to to 1.67 (6H, m), 1.55V is 1.20 (3H, m); ESI-MS m/z 656 (MN+).

Example 52

N-(3-Fluoro-4-(6-(3-hydroxypyrrolidine-1-carbonyl)-7-methoxyquinoline-4-yloxy)phenylcarbamoyl)-2-phenylacetamide (52)

In a manner similar to that described for obtaining compound 1, from compound 1e (20.0 mg), pyrrolidin-3-ol (9,3 mg) and N-hydrate (DMTMM (11.8 mg) has been specified in the title compound 52 (15,0 mg, yield: 71%).

1H-NMR (400 Hz, DMSO-d6) δ: 12,51 (1H, s), 11,85 (1H, s), 8,93 (1H, d, J=6.4 Hz), 8,31 (1H, s), 8,10 (1H, d, J=12,4 Hz), 7,71 (1H, s), to 7.61-7,47 (2H, m), 7,40-to 7.18 (5H, m), 6.87 in (1H, d, J=6,1 Hz)to 4.33 (1H, usher.), to 4.23 (1H, usher.), a 4.03 (3H, s), 3,83 (2H, s), from 2.00 and 1.80 (4H, m), 1.77 in-1,72 (2H, m); ESI-MS m/z 575 (MN+).

Comparative example 1

4-(2-Fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-6, 7-dimethoxy-quinoline-6-carboxamide (comparative compound 1)

Specified in the title compound was synthesized as described in WO 2006/104161.

Example project 1

Test for determination of c-Met inhib is the dominant activity (in vitro)

Inhibitory activity of compounds against c-Met kinase was determined in the following ways :

Method A) analysis of inhibition of c-Met using AlphaScreenTM

As the substrate was used biotinylated peptide comprising a phosphorylated site Pyk2 (Tyr402), which was listed as bio-substrate in the document Clin. Cancer Res. vol. 8, (2), pp. 620-7 (2002). In the presence of compounds of the present invention, the substrate, c-Met (08-051, Carna bio Co., Ltd) and ATP (final concentration: 20 μm) was added to the reaction buffer (60 mm HEPES (pH: 7.5), 5 mm MgCl2, 5 mm MnCl2, 3 μm Na3VO4and 1.25 mm DTT). The mixture was left to interact at room temperature for 20 minutes. To the reaction mixture was added EDTA to a final concentration of 50 mm, thereby stopping the reaction. To the reaction mixture were added defines a liquid that is received in accordance with the AlphaScreen ProtocolTMPhosphotyrosine (P-Tyr-100) Assay Kit (phosphotyrosine-recognizing antibody-bound, 6760620C, Perkin Elmer). The reaction was carried out for one hour at room temperature. Then measured the fluorescence intensity of the reaction mixture, using multi-labeled counter (EnVisionTM, Perkin Elmer). The concentration of compound that gives 50% inhibition of the formation of phosphorylated product was identified as IC50(μm), and the results are shown in the following tables.

Method B) and the Alize inhibition of c-Met using DeskTop Profiler

A mixture of inhibitors of the enzyme dephosphorylation (PhosSTOP, #4906837, the product from the firm Roche) and a mixture of protease inhibitors (Complete, Mini, without EDTA, #1836170; the product from the firm Roche) was added to the reaction buffer (100 mm HEPES (pH: 7.5), 10 mm MgCl2, 0,003% Brij-35, 0.04% tween and 1 mm DTT). In the presence of compounds of the present invention was added to the recombinant c-Met (the purified product from the company Taiho Pharmaceutical Co., Ltd.), fluorescently labeled c-Met substrate peptide (FL-Peptide 2, #760346, Caliper Life Sciences) (final concentration: 1.5 μm)and ATP (final concentration: 43 μm), and the mixture was left to interact at a temperature of 28°C for 90 minutes. To the reaction mixture was added EDTA to a final concentration of 10 mm, thereby stopping the reaction. Using the DeskTop Profiler (#119900, Caliper Life Sciences) was determined by the fluorescence intensity of each substrate and phosphorylated product, thus determined the number of the resulting phosphorylated product. The concentration that gave 50% inhibition of the formation of phosphorylated product was identified as IC50(μm), and the results are presented in the following tables.

Table 1

Table 2

Table is CA 3

It was also investigated the comparative compound (comparative compound 1). Comparative compound 1 has a structure similar to that of the compounds of the present invention (described in examples of patent document 6), and is known for its use as a medicine (published. log Bioorg. Med. Chem. Lett., 18 (2008), 2793-2798). The study showed that the compound of the present invention exhibits inhibitory C-Met activity, which is equal to or higher than that of comparative compound 1.

Example research 2

Analysis of inhibition of cell proliferation in the cells NUGC4 (strain of cancer cells of the human stomach, in which c-Met is over-expressed and highly active), in vitro

Cell suspension NUGC4 (in 10% FBS-containing RPMI 1640 medium (product from the company Wako Pure Chemical Industries Ltd.) or FBS-containing DMEM medium (a product from the company Nacalai Tesque, Inc.)) was inoculable in each well of 96-well (flat bottom) of the microplate in an amount of 2×103cells (0.1 ml), and the plate is incubated in the incubator in an atmosphere of 5% CO2at 37°C for one day. Each connection according to the present invention and comparative compound 1 was dissolved in dimethyl-sulfoxide to a concentration of 30 mm. The solution rasb ulali 10% FBS-containing RPMI 1640 or DMEM, to the final concentrations of the studied compounds 60, 20, 6, 2, 0.6 or 0.2 μm. Thus obtained solution of tested compound was added to each well of the plate with a cell culture NUGC4 at 0.1 ml/well, and the plate is incubated in the incubator in an atmosphere of 5% CO2at 37°C for 3 days. After cultivation to each well was added 20 μl of 25% aqueous glutaraldehyde (product from the company Nacalai Tesque, Inc.), and the plate was left at room temperature for 20 minutes, whereby cells were recorded. After that the tablet was washed with tap water and dried. Then to each well was added 100 μl/well of an aqueous solution of a mixture of 0.05% crystal violet/20% methanol (product from the company Wako Pure Chemical Industries Ltd.), and the plate was left to stand at room temperature for 20 minutes, whereby the cells were stained. After that the tablet was washed with tap water and dried. To each well was added to 0.05 M NaH2PO4/ethanol (1/1=on./about.) (100 ál), thus extragere crystal violet. The absorbance of the extracted crystal violet was measured at 540 nm using a reading device for microplate, and the absorbance was used as an indicator of counting living cells. The percentage inhibition was calculated using the following equation, and races who were cityval concentration of tested compound, inhibitory 50% (IC50(μm)).

The percentage of inhibition (%)=(C-T)/C×100

T: Absorption in the hole, which was added investigated the connection.

C: Absorbance in the hole, in which the investigated compound was not added.

As can be seen from table 4, the compound of the present invention exhibits cell proliferation inhibitory activity higher than that of comparative compound 1 in respect of NUGC4 (strain of cancer cells of the human stomach, in which c-Met is over-expressed and highly active). Thus, it is confirmed that the compound of the present invention exhibits an excellent antitumor activity.

The same study in vitro the inhibition of cell proliferation was carried out in relation to low-expressing c-Met tumor cells (HCT-116), normal cells (HAOSMC (smooth muscle cells of the aorta person)) and normal cells (HMEC cells capillary endothelium of human skin). Comparative compound 1 showed IC50from 15 to 24 microns on cultures of these cells, whereas the majority of the compounds according to the present invention showed IC50≥30 µm. Thus, it was confirmed that the compounds of the present invention show inhibitory cell proliferation activity, which is equal to or lower than that of comparative compound 1 in respect of cleoc the s strains with low expression of c-Met. In other words, when comparing with the comparative compound 1, the difference (ratio) between the IC50compounds of the present invention in the cells with low expression of c-Met or normal cells and cancerous cells with overexpression of c-Met is much more. Based on this discovery, it was confirmed that the compound of the present invention exhibits cell proliferation inhibitory activity with high cell selectivity.

Example research 3

A study to determine the dose to assess antitumor activity (in vivo)

To determine the dose for the evaluation of antitumor action, each of the compounds of the present invention and comparative compound 1 is administered orally naked mice (n=3-5/group) for 14 days (once a day). The maximum tolerated dose was calculated based on the change in body weight of mice.

During the period of introduction of the compounds was calculated the percentage change of body weight of the mice (BWC%). When a decrease was observed values BWC ≥10% in the group that was administered the compound, the dose in this case was defined as a toxic dose of the drug. Thus, half the value of the toxic dose was considered as the maximum tolerated dose.

BWC for mice was calculated using the following equation, and is the change in the value of the BWC each group in the implementation process shown in Fig. 1.

BWC (%)=([(body weight of mouse on the day of measurement of weight)-(weight of the mouse in a group)]/( body weight of mice in the group))×100

As can be seen from Fig. 1, was not observed in the body weight reduction with the introduction of the group of comparative compound 1 (100 mg/kg) in the implementation process, but there was >10% reduction BWC with the introduction of the group of comparative compound 1 (200 mg/kg). Thus, the toxic dose comparative compound 1 was determined as 200 mg/kg, and the maximum tolerated dose was defined as 100 mg/kg In the sample of the study 4 (evaluation of antitumor action), dose comparative compound 1 was 100 mg/kg

Meanwhile, there was no loss of body weight in the group that was administered the compound of the present invention (200 mg/kg). Moreover, as shown in Fig. 1, was not observed loss of body weight in the group with the introduction of (400 mg/kg). Thus, the dose of compound 1 was determined as 400 mg/kg in the sample of the study 4 (evaluation of antitumor action).

Example research 4

Evaluation of antitumor activity in subcutaneous xenotransplantation models, using a strain of stomach cancer man (NUGC4) (in vivo)

Cancer cells of human stomach (NUGC4) (obtained from the firm ATCC) subcutaneously transplanted naked mice. When the amount of the formed tumors in Nude mice was achieved from about 100 to about 300 mm3mice were divided into groups (5 or group) split randomly so for the volumes of tumors in each group were equal (day 1). Each of the compounds of the present invention and comparative compound 1 was administered orally once daily for 14 days.

Based on the results of case study 3, dose comparative compound 1 was set as 100 mg/kg/day, which is the maximum tolerated dose for a 14-day period introduction to case study 4 (i.e., the maximum dose that gives <10% decrease in body mass during the period of introduction). The dose of a compound of the present invention was determined as 400 mg/kg/day.

In order to compare time-dependent changes in the profile of proliferation of the tumor to the input of the studied compounds, the relative tumor volume (RTV) in comparison with the volume of the tumor at the time of allocation to groups was calculated using the following equation. Changes in the value RTV for each group is shown in Fig. 2.

RTV=(tumor volume on the day of tumor volume)/(tumor volume in the allocation to groups)

In the case when the value of the RTV in the group, which administered the compound according to the invention, on the last day of assessment was less than in the group which introduced the comparative compound 1 and it was statistically significant (t-student test), the compound of the present invention was considered as significant what about the more effective than comparative compound 1. In Fig. 2, a statistically significant level marked with *.

As can be seen from Fig. 2, the connection of the present invention results in an effective reduction of the tumor within one week from the beginning of the introduction, showing greater antitumor activity than the comparative compound 1.

As described here and above, the compound of the present invention showed C-Met inhibitory effect, which is equal to or higher than that of comparative compound 1 (case study 1), and showed excellent specificity in inhibiting cell proliferation activity (case study 2), and this indicates that the toxicity to non-target cells, including normal cells, is small. In the study to determine the dose with the use of naked mice, the compound of the present invention did not cause weight loss, even when it was administered at a dose of 400 mg/kg, which is higher than the toxic dose (200 mg/kg) comparative compound 1, and this indicates that the connection according to the invention have a low toxicity (case study 3). In addition, the compound of the present invention can be introduced in the high dose (400 mg/kg), which is much higher than the maximum tolerated dose (100 mg/kg) comparative compound 1. Thus, the connection according to the invention shows p is elashadow regression of the tumor (antitumor activity) (case study 4).

1. Derived ulltimately represented by the formula (I):

where R1represents a hydrogen atom or a C1-3alkyl group;
R2represents a hydrogen atom, optionally substituted C1-6alkyl group, optionally substituted C6-14aromatic hydrocarbon group or optionally substituted saturated or unsaturated 5-7-membered heterocyclic group containing 1 or 2 atom(s) or nitrogen atom(s) of sulfur,
or R1and R2may form together with the nitrogen atom to which they are attached, optionally substituted nitrogen-containing saturated heterocyclic group selected from the group comprising pyrrolidinyloxy, piperidinyloxy, piperazinilnom or morpholinopropan;
where the Deputy is chosen from the group comprising halogen atom, a hydroxyl group, a cyano, a nitro-group, With1-6alkanoyloxy group1-6alkyl group, a C3-10cycloalkyl group2-6alkenylphenol group, C1-6alkoxy group, amino group, With1-6alkylamino,1-6alkanolamines, C1-6alkylaminocarbonyl group1-6alkylsulfonyl group6-14aromatic hydrocarbon group, saturated or unsaturated 5-7-membered heterocyclic GRU is PU, containing 1 to 4 atom(s) of nitrogen and/or atom(s) of oxygen, saturated or unsaturated 5-7-membered heterocyclyl-carbonyl group containing 1 or 2 atom(s) of nitrogen and/or atom(s), oxygen, and oxoprop;
R3represents a C1-6alkyl group; and
R4represents a halogen atom; R5and R6that may be the same or different from each other, represent a hydrogen atom, a halogen atom, a C1-3alkyl group which may be substituted by a halogen atom, or a C1-6alkoxygroup;
or its pharmaceutically acceptable salt.

2. Derived ulltimately according to claim 1 or its pharmaceutically acceptable salt,
where R2represents a hydrogen atom, optionally substituted C1-6alkyl group, optionally substituted C6-14aromatic hydrocarbon group or optionally substituted saturated or unsaturated 5-7-membered heterocyclic group containing 1 or 2 atom(s) or nitrogen atom(s) of sulfur,
or R1and R2may form together with the nitrogen atom to which they are attached, optionally substituted nitrogen-containing saturated heterocyclic group selected from the group comprising pyrrolidinyloxy, piperidinyloxy, piperazinilnom and morpholinopropan;
R3represents a 1-3alkyl group.

3. Derived ulltimately according to claim 2 or its pharmaceutically acceptable salt,
where R1represents a hydrogen atom or methyl group;
R2represents an optionally substituted C1-6alkyl group optionally substituted phenyl group or optionally substituted 5-7-membered heterocyclic group which contains 1 or 2 nitrogen atom or sulfur atom, or
R1and R2form together with the nitrogen atom to which they are attached, optionally substituted pyrrolidinyl group or optionally substituted piperidinyl group;
R3represents a methyl group;
R4represents a fluorine atom or a chlorine atom;
R5represents a hydrogen atom or a halogen atom; and
R6represents a hydrogen atom, halogen atom, triptorelin group or a methoxy group.

4. Derived ulltimately according to claim 3 or its pharmaceutically acceptable salt,
where R1represents a hydrogen atom;
R2represents a C1-6alkyl group which may have a Deputy, and the Deputy represents a hydroxyl group, With3-10cycloalkyl group, C1-6alkoxygroup, C1-6alkylamino, C1-6alkanolamines, C1-6 alkylsulfonyl group6-14aromatic hydrocarbon group, saturated or unsaturated 5-7-membered heterocyclic group containing 1 to 4 atom(s) of nitrogen and/or atom(s) oxygen, C1-6alkylaminocarbonyl group or a saturated or unsaturated 5-7-membered heterocyclyl-carbonyl group containing 1 or 2 atom(s) of nitrogen and/or atom(s) of oxygen;
R3represents a methyl group;
R4represents a fluorine atom or a chlorine atom;
R5represents a hydrogen atom; and R6represents a hydrogen atom, a fluorine atom or a chlorine atom.

5. Derived ulltimately according to claim 4 or pharmaceutically acceptable salt,
where R2represents a C1-4alkyl group which may have a Deputy, and the Deputy represents a hydroxyl group, tsiklogeksilnogo group, C1-3alkoxygroup, C1-6alkylamino, acetylamino, methylsulfonyl group, phenyl group, saturated or unsaturated 5-7-membered heterocyclic group containing 1 to 4 nitrogen atom and/or oxygen atom, C1-6alkylaminocarbonyl group or a saturated or unsaturated 5-7-membered heterocyclyl-carbonyl group containing 1 or 2 nitrogen atom and/or oxygen atom.

6. Derived alltimate the ins according to claim 5 or its pharmaceutically acceptable salt,
where R2represents a methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group or second-boutelou group,
where the Deputy of any of these alkyl groups is a hydroxyl group, tsiklogeksilnogo group, a methoxy group, ethoxypropan, isopropylacetate, diethylaminopropyl, acetylamino, methylsulfonyl group, phenyl group, pyrrolidinyl group, morpholinopropan, DIOXOLANYL group, tetrahydropyranyloxy group, pyridyloxy group, triazolyl group, ethylaminomethyl group, dimethylaminocarbonylmethyl group, methylbutyronitrile group, pyrrolidinylcarbonyl group or morpholinoethyl group.

7. Derived ulltimately according to claim 1 or its pharmaceutically acceptable salt, which is selected from the group consisting of:
4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-methylinosine-6-carboxamide;
4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(methoxyethyl)quinoline-6-carboxamide;
4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(2-morpholinoethyl)quinoline-6-carboxamide;
4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-7-methoxy-N-(2-morpholino-2-oxoethyl)quinoline-6-carboxamide;
4-(2-fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-N-(2-hydroxybutyl)-7-methoxyquinoline-carboxamide;
4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(2-hydroxy-2-methylpropyl)-7-methoxyquinoline-6-carboxamide;
(S)-4-(2-fluoro-4-(3-(2-phenylacetyl)touraid)phenoxy)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide;
4-(2-fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-7-methoxy-N-(2-morpholinoethyl)quinoline-6-carboxamide;
(S)-4-(2-fluoro-4-(3-(2-(4-forfinal)acetyl)touraid)phenoxy)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide;
(S)-4-(2-fluoro-4-(3-(2-(2-forfinal)acetyl)touraid)phenoxy)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide; and
(S)-4-(4-(3-(2-(4-chlorophenyl)acetyl)touraid)-2-pertenece)-N-(1-hydroxybutane-2-yl)-7-methoxyquinoline-6-carboxamide.

8. The pharmaceutical agent having inhibiting c-Met activity, containing as an active ingredient derived ulltimately according to any one of claims 1 to 7 or its pharmaceutically acceptable salt.

9. Antitumor agent containing as an active ingredient derived ulltimately according to any one of claims 1 to 7 or its pharmaceutically acceptable salt.

10. Pharmaceutical composition having inhibitory c-Met activity, containing derivative ulltimately according to any one of claims 1 to 7 or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

11. The use of derivative ulltimately according to any one of claims 1 to 7 or its pharmaceutically p is yimlamai salt to obtain an antitumor agent.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to sulphonamide compounds of formula or pharmaceutically acceptable salts thereof, wherein A is phenyl, optionally substituted with 1 or 2 halogen atoms, C1-6 alkyl group, trifluoromethyl group, C1-6 alkoxy group or -SCH3 group, thiophenyl, optionally substituted with a C1-C6 alkyl group or a halogen atom, pyridinyl, optionally substituted with a halogen atom, naphthalenyl or dihydroindenyl; R1 denotes the following formulae or [in formulae (R1a) and (R1b) Ar1 denotes the following formulae , or (each R5 and R6 independently denotes a hydrogen atom, a halogen atom, a C1-6 alkyl group optionally substituted with up to three halogen atoms, C1-6 lower alkoxy group optionally substituted with up to three halogen atoms); Ar2 denotes the following formulae , or (each R7 and R8 independently denotes a hydrogen atom, a hydroxyl group, a halogen atom, a C1-6 alkyl group optionally substituted with up to three halogen atoms or a C1-6 lower alkoxy group optionally substituted with up to three halogen atoms, an amine group, a nitro group, a C2-6 acyl group, or R7 and R8 together form -CH2CH2O-; R9 is a hydrogen atom or - J-COOR10; J is a covalent bond, alkylene containing 1 to 5 carbon atoms, alkenylene containing 2 to 5 carbon atoms or alkynylene containing 2 to 5 carbon atoms, where one carbon atom in said alkylene groups can be substituted with an oxygen atom, a sulphur atom, NR11, CONR11 or NR11CO in any chemically acceptable position; R11 is a hydrogen atom; and R10 is a hydrogen atom); and p equals 0 or 1]; R2 is a C1-6 alkyl group; each R3 and R4 is independently a C1-6 alkyl group; * denotes an asymmetric carbon atom; and m equals an integer from 1 to 3. The invention also relates to a medicinal agent for stimulating PTH secretion.

EFFECT: obtaining novel compounds which can be used in medicine to prevent or treat primary or secondary osteoporosis.

29 cl, 15 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-R- amides of (Z)-2-[(3-(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thien-2-yl)amino]-4-phenyl-4-oxobut-2-enoic acids (1-4) of general formula:

.

Acid amides (1-4) are obtained by reacting ethyl ether of 2-[(2-oxo-5-phenyl-(2H)-furanylidene)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid with R-amines in a medium of pure toluene at 25-110°C, followed by separation of the end product using known techniques.

EFFECT: obtaining novel compounds with high output, having marked analgesic activity and low toxicity.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (1) or salts thereof, where in formula (1) R1 is a lower C1-C6alkyl group, a lower C3-C6cycloalkyl group, a phenyl group, a heterocyclic group, which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom and a sulphur atom, or a phenyl(C1-C6alkyl) group; in cases when R1 is a lower C1-C6alkyl group, that lower C1-C6alkyl group can have, as substitute(s), one, two or three groups selected from a halogen atom, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one or two heteroatoms in the ring, selected from a nitrogen atom and an oxygen atom, a carboxyl group, a lower C1-C6alkoxycarbonyl group, a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a phenyl group; in cases when R1 is a phenyl group, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom or a sulphur atom, or a phenyl(C1-C6alkyl) group, that phenyl, heterocyclic or phenyl(C1-C6alkyl) group can contain, as substitute(s), one, two or three groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group or a lower C1-C6alkoxy group; R2 is a hydrogen atom or a lower C1-C6alkyl group; R3 is a hydrogen atom or a lower C1-C6alkyl group; R4 and R5 can be identical or different and are a hydrogen atom or a lower C1-C6alkyl group; R6 is a hydrogen atom or a lower C1-C6alkyl group; R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom; in cases where R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom, that phenyl or heterocyclic group can contain, as substitute(s), one or two groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group, a lower C1-C6alkoxy group and a nitro group; W is an oxygen atom or NR8; R8 is a hydrogen atom or a lower C1-C6alkyl group; X is an oxygen atom or a sulphur atom; Y is a lower C1-C6alkylene group; Z is an oxygen atom, a sulphur atom, NR9 or OCO; R9 is a hydrogen atom or a lower C1-C6alkyl group. The invention also relates to a pharmaceutical composition based on said compounds, having GR binding activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as glucocorticoid receptor modulators.

10 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

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

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

10 cl, 85 tbl, 179 ex

FIELD: chemistry.

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

EFFECT: improved efficiency.

19 cl, 6 tbl.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to substitute nicotine-amide compounds of general formula , where n=0, 1 or 2, p=0 or 1, q=0 or 1, R1 is aryl or heteroaryl or heterocyclyl, non-substitute or mono- or polysubstitute; C1-6-alkyl, C3-10-cycloalkyl, non-substitute or mono- or polysubstitute; R2 is H or C1-6-alkyl; R3 is aryl or pyridyl, non-substitute or mono- or polysubstitute; C1-6-alkyl or C3-10-cycloalkyl, in each case non-substitute or mono- or polysubstitute; R4, R5, R6 and R7 independently from each other represent H; C1-6-alkyl; R8, R9 and R10 independently from each other represent H, F, Cl, Br, CF3, C1-6-alkyl; where "substitute alkyl", "substitute heterocyclyl" and "substitute cycloalkyl" stands for substitution of hydrogen radical for F, Cl, Br, I, C1-6-alkyl, SH, S-C1-6-alkyl, O-C1-6-alkyl, O-C1-benzyl, -OH, O-C1-6-alkyl-OH, phenyl, phenoxy, morpholynyl or benzyl; and "substitute aryl" and "substitute heteroaryl stands for single or multiple substitution of one or several atoms of circular system for F, Cl, Br, I, SH, S-C1-6-alkyl, OH, O-C1-6-alkyl, O-C1-6aryl-OH, CH2SO2-phenyl, OCF3, SCF3, CF3, , , C1-6-alkyl, morpholynyl, phenoxy, phenyl or pyrazolyl; provided that if R3 is 3-trifluoromethylphenyl or 4-trifluoromethyl-2-pyridyl, R2, R4 and R5 are H, and n is 0, then R1 is not 2-pyridyl or 2-thienyl; and if R3 is or methyl, R2, R4 and R5 are H, and n is 0, then R1 is not 2-thienyl; in the form of racemate; enantiomers, diastereisomers, mixtures of enantiomers or diastereisomers or a separate enantiomer or diastereisomer; bases and/or salts of physiologically acceptable acids. Besides, the invention relates to a pain killer containing specified compounds and to application of the specified compounds for preparation of medicinal agents.

EFFECT: new compounds were produced and described, which may find their application in pain treatment.

13 cl, 150 ex, 8 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (1) or salts thereof, where in formula (1) R1 is a lower C1-C6alkyl group, a lower C3-C6cycloalkyl group, a phenyl group, a heterocyclic group, which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom and a sulphur atom, or a phenyl(C1-C6alkyl) group; in cases when R1 is a lower C1-C6alkyl group, that lower C1-C6alkyl group can have, as substitute(s), one, two or three groups selected from a halogen atom, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one or two heteroatoms in the ring, selected from a nitrogen atom and an oxygen atom, a carboxyl group, a lower C1-C6alkoxycarbonyl group, a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a phenyl group; in cases when R1 is a phenyl group, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom or a sulphur atom, or a phenyl(C1-C6alkyl) group, that phenyl, heterocyclic or phenyl(C1-C6alkyl) group can contain, as substitute(s), one, two or three groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group or a lower C1-C6alkoxy group; R2 is a hydrogen atom or a lower C1-C6alkyl group; R3 is a hydrogen atom or a lower C1-C6alkyl group; R4 and R5 can be identical or different and are a hydrogen atom or a lower C1-C6alkyl group; R6 is a hydrogen atom or a lower C1-C6alkyl group; R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom; in cases where R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom, that phenyl or heterocyclic group can contain, as substitute(s), one or two groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group, a lower C1-C6alkoxy group and a nitro group; W is an oxygen atom or NR8; R8 is a hydrogen atom or a lower C1-C6alkyl group; X is an oxygen atom or a sulphur atom; Y is a lower C1-C6alkylene group; Z is an oxygen atom, a sulphur atom, NR9 or OCO; R9 is a hydrogen atom or a lower C1-C6alkyl group. The invention also relates to a pharmaceutical composition based on said compounds, having GR binding activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as glucocorticoid receptor modulators.

10 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I and formula IV wherein the radical values are such as specified in cl. 1 and 4 of the patent claim, as well as to their therapeutically acceptable salts. Besides, the invention refers to a composition for treating cancer on the basis of the compounds of formula I, to using the compounds of formula I for preparing the therapeutic agent for treating cancer, as well as to using it for treating cancer.

EFFECT: there are prepared and described the new compounds which inhibit anti-apoptotic Bcl-2 and Bcl-x protein activity.

17 cl, 481 ex

FIELD: medicine, pharmaceutics.

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

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

10 cl, 85 tbl, 179 ex

FIELD: chemistry.

SUBSTANCE: invention relates to dispiro 1,2,4-trioxolanes of formula: , where values of R are given in claim 1.

EFFECT: disclosed compounds unexpectedly enable to treat malaria with a single dose and provide preventive action against malaria and bilharzia.

17 cl, 6 tbl, 5 ex

FIELD: chemistry.

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

EFFECT: improved efficiency.

19 cl, 6 tbl.

FIELD: medicine, pharmaceutics.

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

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

12 cl, 11 ex, 16 dwg, 11 tbl

FIELD: biotechnologies.

SUBSTANCE: invention relates to substitute nicotine-amide compounds of general formula , where n=0, 1 or 2, p=0 or 1, q=0 or 1, R1 is aryl or heteroaryl or heterocyclyl, non-substitute or mono- or polysubstitute; C1-6-alkyl, C3-10-cycloalkyl, non-substitute or mono- or polysubstitute; R2 is H or C1-6-alkyl; R3 is aryl or pyridyl, non-substitute or mono- or polysubstitute; C1-6-alkyl or C3-10-cycloalkyl, in each case non-substitute or mono- or polysubstitute; R4, R5, R6 and R7 independently from each other represent H; C1-6-alkyl; R8, R9 and R10 independently from each other represent H, F, Cl, Br, CF3, C1-6-alkyl; where "substitute alkyl", "substitute heterocyclyl" and "substitute cycloalkyl" stands for substitution of hydrogen radical for F, Cl, Br, I, C1-6-alkyl, SH, S-C1-6-alkyl, O-C1-6-alkyl, O-C1-benzyl, -OH, O-C1-6-alkyl-OH, phenyl, phenoxy, morpholynyl or benzyl; and "substitute aryl" and "substitute heteroaryl stands for single or multiple substitution of one or several atoms of circular system for F, Cl, Br, I, SH, S-C1-6-alkyl, OH, O-C1-6-alkyl, O-C1-6aryl-OH, CH2SO2-phenyl, OCF3, SCF3, CF3, , , C1-6-alkyl, morpholynyl, phenoxy, phenyl or pyrazolyl; provided that if R3 is 3-trifluoromethylphenyl or 4-trifluoromethyl-2-pyridyl, R2, R4 and R5 are H, and n is 0, then R1 is not 2-pyridyl or 2-thienyl; and if R3 is or methyl, R2, R4 and R5 are H, and n is 0, then R1 is not 2-thienyl; in the form of racemate; enantiomers, diastereisomers, mixtures of enantiomers or diastereisomers or a separate enantiomer or diastereisomer; bases and/or salts of physiologically acceptable acids. Besides, the invention relates to a pain killer containing specified compounds and to application of the specified compounds for preparation of medicinal agents.

EFFECT: new compounds were produced and described, which may find their application in pain treatment.

13 cl, 150 ex, 8 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosubstituted pyrazolon azo derivatives of formula

or pharmaceutically acceptable salts thereof, intermediate compounds of formula ,

as well as methods for production thereof, a pharmaceutical composition containing a compound of formula (II), and use thereof as a therapeutic agent, which is a thrombopoietin (TPO) mimetic, as well as use thereof as agonists of the thrombopoietin receptor. Values of substitutes in formulae (I) and (IA) are given in the claim.

EFFECT: obtaining bicyclosubstituted pyrazolon azo derivatives.

12 cl, 58 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula III which possess the properties of JAK pathway inhibitors and JAK-kinase inhibitors. In formula III: X is specified in a group consisting of C1-C10alkyl, amino, halogen, carboxyl, carboxylic acid ester, C2alkynyl, substituted tri-C1-C6alkylsilyl; R represents hydrogen; the cycle A is specified in a group consisting of C6aryl, bicycloheptene, five-and sis-member mono- or 10-member bicyclic heteroaryl including 1 to 3 heteroatoms specified in a group of heteroatoms, including N, O or S, and five- or six-member mono- or 10-member bicyclic heterocycle, including 1 to 2 heteroatoms specified in a group of heteroatoms, including N or O; p means 0, 1, 2 or 3; each of R2 is independently specified in a group consisting of C1-C6alkyl, C1-C4alkyl substituted by 1 to 3 substitutes. The other substitute and radical values are specified in the patent claim.

EFFECT: compounds may be used in preparing a therapeutic agent for T-cell mediated autoimmune disease, for treating or preventing allograft rejection in a recipient, for treating or preventing a type IV hypersensitivity reactions, which includes administering the above agent containing the compound according to cl 1-11, in an amount effective to treat the autoimmune disease or the allograft rejection or the type IV hypersensitivity.

23 cl, 7 dwg, 12 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

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