Azolyl quinoline and quinazoline derivatives, pharmaseutical composition containing the same, uses thereof and method for treatment of diseases

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

 

BACKGROUND of the INVENTION

The scope of the invention

The present invention relates to the derivatives of quinoline and derivatives hintline, which have antitumor activity. More specifically, the present invention relates to the derivatives of quinoline and derivatives hintline that are therapeutically effective for diseases such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma.

Prior art

WO 97/17329, laid claim to the Japan patent No. 328782/1997 and WO 00/43366 describe derivatives of quinoline and derivatives hintline, which have antitumor activity. However, they do not describe compounds of the present invention.

SUMMARY of INVENTION

Applicants have discovered that the group azolyl-containing derivatives of quinoline and derivatives hintline has a strong antitumor activity.

The purpose of the present invention to provide compounds with potent antitumor activity.

According to the present invention features a compound represented by the formula (I)or its pharmaceutically acceptable salt or MES:

where

X and Z each independently represents CH or N;

Y represents O Il is S;

R1, R2and R3that may be the same or different, and represent a hydrogen atom, a C1-6alkyl, C1-6alkoxy, C2-6alkenyl,2-6quinil, nitro or amino, and C1-6alkyl, C1-6CNS, With2-6alkeneamine and C2-6alkyline group optionally substituted by a halogen atom; hydroxyl; C1-4by alkyl; C1-4alkoxycarbonyl; the amino group in which one or two hydrogen atoms optionally substituted C1-4the alkyl, optionally substituted by hydroxyl or1-4alkoxy group; R12R13N-C(=O)-O-, where R12and R13that may be the same or different, represent a hydrogen atom or a C1-4alkyl, optionally substituted by hydroxyl or1-4alkoxy group; or R14-(S)m-where R14represents a saturated or unsaturated carbocyclic or heterocyclic group containing from three to seven atoms in the cycle, optionally substituted C1-4the alkyl and m is 0 or 1;

R4represents a hydrogen atom;

R5, R6, R7and R8that may be the same or different and represent a hydrogen atom, a halogen atom, a C1-4alkyl, C1-4alkoxy, C1-4alkylthio, triforma the sludge, nitro or amino group;

R9and R10that may be the same or different and represent a hydrogen atom, a C1-6alkyl or C1-4alkylsulphonyl, and the alkyl part C1-6alkyl or C1-4alkylcarboxylic group optionally substituted by a halogen atom; C1-4alkoxy; amino, optionally substituted C1-4the alkyl, optionally substituted C1-4CNS group; or a saturated or unsaturated carbocyclic or heterocyclic group containing from three to seven atoms in the cycle; and

R11represents azolyl, in which one or more hydrogen atoms optionally substituted by a halogen atom; C1-4by alkyl;

With1-4alkoxy; C1-4alkylthio; trifluoromethyl; nitro; amino group in which one or two hydrogen atoms optionally substituted C1-4alkyl(Oh) groups(Oh), which may be the same or different; C1-4alkoxycarbonyl1-4the alkyl, C1-4alkylcarboxylic or3-5cyclic alkyl.

Compounds of the present invention are therapeutically effective for diseases such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma.

A DETAILED DESCRIPTION of the INVENTION

Connection

ispolzuemye terms “With 1-6alkyl” and “C1-6alkoxy” as a group or part of a group, respectively, denote a linear or branched alkyl or CNS chain containing from 1 to 6, preferably from 1 to 4 carbon atoms.

The terms used, “2-6alkenyl” and “C2-6quinil” as a group or part of a group, respectively, denote a linear or branched alkenylphenol or alkenylphenol chain containing from 2 to 6, preferably from 1 to 4 carbon atoms.

Examples1-6of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

Examples1-6alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy group.

Examples2-6alkenyl include allyl, butenyl, pentenyl and hexenyl.

Examples2-6the quinil include 2-PROPYNYL, butynyl, pentenyl and hexenyl.

Examples3-5cyclic alkyl include cyclopropyl and cyclopentyl.

The term “halogen atom” means a fluorine atom, chlorine, bromine or iodine.

Saturated or unsaturated carbocyclic or heterocyclic ring containing from three to seven atoms in the cycle, preferably represents a saturated or unsaturated carbocyclic or heterocyclic ring is, containing from five to seven atoms in the cycle, more preferably from five to six atoms in the loop.

Examples of saturated or unsaturated carbocyclic or heterocyclic rings containing from three to seven atoms in the cycle, include phenyl, cycloheptyl, cyclohexyl and cyclopentyl.

Saturated or unsaturated heterocyclic ring containing from three to seven atoms in the cycle, contains one or more heteroatoms selected from atoms of oxygen, nitrogen and sulfur. Used in this description, the term “heteroatom” means an atom of oxygen, nitrogen or sulfur. Examples of saturated or unsaturated heterocyclic groups containing from three to seven atoms in the cycle, include pyridyl, piperidino, piperazine derivatives, morpholine, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolidinyl and pyrazolyl.

Used in this description, the term “azolyl” denotes a five-membered saturated or unsaturated heterocyclic group containing the atoms of the cycle two or more heteroatoms selected from the group consisting of nitrogen atoms, sulfur and oxygen, where at least one of the heteroatoms is a nitrogen atom.

Preferably, R1represents a hydrogen atom.

With1-6alkyl, C1-6CNS, With2-6alkeneamine and C2-6alkyline group is s, which can be represented by R1, R2and R3may not be substituted by a group R14-(S)m-.

Carbocyclic or heterocyclic group, which may be represented by R14preferably represents a saturated or unsaturated five - or six-membered carbocyclic or heterocyclic group. Carbocyclic group, more preferably represents phenyl. Heterocyclic group, more preferably represents a saturated or unsaturated five-membered heterocyclic group containing one to four nitrogen atoms, or saturated or unsaturated six-membered heterocyclic group containing one or two heteroatoms selected from nitrogen atoms and oxygen. More specifically, heteroatom, part of a six-membered heterocyclic group may be a nitrogen atom and an oxygen atom, or one or two nitrogen atoms.

When m is 0 (zero), -(S)m- represents the relationship.

Replaced With1-6CNS group, which can be represented by R1, R2and R3preferably represents a group R31-(CH2)p-O-, where R31represents a halogen atom; hydroxyl; C1-4CNS group; C1-4alkoxycarbonyl; the amino group, which one or two hydrogen atoms optionally substituted C 1-4the alkyl, optionally substituted by hydroxyl, or C1-4CNS group; R12R13N-C(=O)-O-, where R12and R13are as defined in formula (I); or R14-(S)m-where R14is the same as defined in formula (I), and p is an integer from 1 to 6, preferably from 1 to 4, more preferably 1 or 2.

R2and R3preferably represent From1-4alkoxy, more preferably methoxy.

X preferably represents N or CH, and Z preferably represents CH.

Preferably, at least one of R5, R6, R7and R8represents a halogen atom.

Preferably, at least one of R5, R6, R7and R8represents a chlorine atom or fluorine.

Preferably, at least one of R5, R6, R7and R8represents a C1-4alkyl.

Preferably, at least one of R5, R6, R7and R8represents a C1-4alkoxy.

Preferably, at least one of R5, R6, R7and R8represents a C1-4alkylthio, trifluoromethyl, nitro or amino group.

Preferably, R5and R6represent a halogen atom, more prefer is Ino atom of chlorine or fluorine, With1-4alkyl, C1-4alkoxy,

With1-4alkylthio, trifluoromethyl, nitro or amino group, and R7and R8represent a hydrogen atom.

R9and R10preferably represent a hydrogen atom.

Preferably, R11is a group (i):

where Q represents O, S or NH, and R22and R23that may be the same or different, represent a hydrogen atom; a halogen atom; C1-4alkyl; C1-4alkoxy; C1-4alkylthio; trifluoromethyl; nitro; amino in which one or two hydrogen atoms optionally substituted C1-4alkyl(s) group(s), which may be the same or different; C1-4alkoxycarbonyl1-4alkyl; C1-4alkylsulphonyl or3-5cyclic alkyl.

Preferably, R11is a group(ii):

where Q represents O, S or NH, and R22and R23that may be the same or different, represent a hydrogen atom; a halogen atom; C1-4alkyl; C1-4alkoxy; C1-4alkylthio; trifluoromethyl; nitro; amino in which one or two hydrogen atoms optionally substituted C1-4alkyl(s) group(s), which may be the same or different; the 1-4alkoxycarbonyl1-4alkyl; C1-4alkylsulphonyl or3-5cyclic alkyl.

Preferably, R11is a group(iii):

where Q represents O, S or NH, and R22and R23that may be the same or different, represent a hydrogen atom; a halogen atom; C1-4alkyl; C1-4alkoxy; C1-4alkylthio; trifluoromethyl; nitro; amino in which one or two hydrogen atoms optionally substituted C1-4alkyl(s) group(s), which may be the same or different; C1-4alkoxycarbonyl1-4alkyl; C1-4alkylsulphonyl or3-5cyclic alkyl.

Preferably, R11is a group(iv):

where Q represents O, S or NH, and R22represents a hydrogen atom; a halogen atom; C1-4alkyl; C1-4alkoxy; C1-4alkylthio; trifluoromethyl; nitro; amino in which one or two hydrogen atoms optionally substituted C1-4alkyl(s) group(s), which may be the same or different; C1-4alkoxycarbonyl1-4alkyl; C1-4alkylsulphonyl or3-5cyclic alkyl.

In groups (i) and (ii) R23preferably represents a hydrogen atom.

predpochtitelno, R11represents an optionally substituted azolyl selected from the group consisting of imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazole, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl.

A preferred group of compounds represented by formula (I)includes compounds represented by formula (Ia):

where

X represents CH or N,

R15and R16that may be the same or different and represent a1-6alkoxy,

R17, R18, R19and R20that may be the same or different and represent a hydrogen atom, a halogen atom, a C1-4alkyl, C1-4alkoxy, C1-4alkylthio, trifluoromethyl, nitro or amino group,

R21represents azolyl, in which one or more hydrogen atoms optionally substituted by a halogen atom; C1-4by alkyl;

With1-4alkoxy; C1-4alkylthio; trifluoromethyl; nitro; amino group in which one or two hydrogen atoms optionally substituted C1-4alkyl(s) group(s), which may be the same or different; C1-4alkoxycarbonyl1-4by alkyl; C1-4alkylcarboxylic or3-5cyclic alkyl.

Preferably, R15and R16represents methoxy.

Preferably, at least one of R17, R18, R19and R20represents a halogen atom.

Preferably, at least one of R17, R18, R19and R20represents a chlorine atom or fluorine.

Preferably, at least one of R17, R18, R19and R20represents a C1-4alkyl.

Preferably, at least one of R17, R18, R19and R20represents a C1-4alkoxy.

Preferably, at least one of R17, R18, R19and R20represents a C1-4alkylthio, trifluoromethyl, nitro or amino group.

Preferably, R17and R18represent a halogen atom, more preferably a chlorine atom or fluorine, With1-4alkyl, C1-4alkoxy, C1-4alkylthio, trifluoromethyl, nitro or amino group, and R19and R20represent a hydrogen atom.

Preferably, R21is a group (i), (ii), (iii) or (iv).

Preferably, R21represents an optionally substituted azolyl selected from the group consisting of imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazole, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl and 1,3,4 - oxadiazolyl.

The group of more preferred compounds is tions, represented by formula (I)includes compounds represented by formula (Ib):

where MeO represents methoxy; X represents CH or N; R17, R18and R19that may be the same or different, represent a hydrogen atom, a halogen atom, a C1-4alkyl, C1-4alkoxy, C1-4alkylthio, trifluoromethyl, nitro or amino group; and R21is a group (i), (ii), (iii) or (iv).

In the formula (Ib), preferably, R21is a group (i), where Q represents O, more preferably, R22and R23represent a hydrogen atom, or one of R22and R23represents a hydrogen atom and the other represents C1-4alkyl.

In the formula (Ib), preferably, R21is a group (iii), where Q represents S, more preferably, R22and R23represent a hydrogen atom, or one of R22and R23represents a hydrogen atom and the other represents C1-4alkyl.

Specific examples of the compounds of the present invention include compounds obtained in examples 1-75.

More preferred compounds of the present invention include the following compounds. The numerical values in brackets indicate the No. of the example.

(4) N-{2-chlor-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea;

(27) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(1,3-thiazol-2-yl)urea;

(28) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(4-methyl-1,3-thiazol-2-yl)urea and

(38) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(1,3-thiazol-2-yl)urea.

Compounds of the present invention can form pharmaceutically acceptable salts. Preferred examples of such salts include: salts of alkali metals or alkaline earth metals such as sodium, potassium or calcium salts; salts halogenation acids, such as salts of hydrofluoric acid, salts of hydrochloric acid, Hydrobromic acid salt or salt itestosterone acid; inorganic salts, such as salts of nitric acid, salts of perchloric acid, salts of sulfuric acid or salts of phosphoric acid; salts of lower alkylsulfonic acids, such as salts methansulfonate, salt triftoratsetata or salts econsultation; salt arylsulfonic acids, such as salts benzosulfimide or salt of p-toluenesulfonic acid; salts of organic acids, such as salts of fumaric acid, salts of succinic acid, salts of citric acid, salts of tartaric acid, salts of oxalic acid, salts of maleic acid, salts of acetic acid, salts of malic acid, salts of lactic acid or a salt of ascorbic acid; Sol the amino acids, such as salts of glycine, a salt of phenylalanine, and salts of glutamic acid or a salt asparginase acid.

Compounds of the present invention can be obtained, for example, according to scheme 1 and scheme 2.

where R' represents a C1-6alkyl or equivalent, and R1, R2, R3, R4, R5, R6, R7, R8and X are as defined in formula (I).

The initial compounds required for the synthesis of compounds of the present invention, are commercially available or can be easily obtained using the traditional method. For example, a derivative of 4-chlorhydrin possible to synthesize conventional method described, for example, in Org. Synth. Col. Vol. 3, 272 (1955), Acta Chim. Hung., 112, 241 (1983) or WO 98/47873.

Alternatively, a derivative of 4-chlorination you can get first (1) reaction of ester of benzoic acid with formamide to obtain a derived chinatron, and then (2) heating the derived 4-chinatron in the presence of phosphorus oxychloride, using toluene or sulfolane as solvent. Derived chinatron usually synthesized in the presence of a solvent such as an ester of benzoic acid, sodium methoxide, formamide, N,N-dimethylformamide or methanol.

Then, a derivative of 4-(aminophenoxy)quinoline or a corresponding derivative hintline you can get reactionaries derived from 4-chlorhydrin or the corresponding derivative of hintline in the presence or absence of a suitable solvent, receiving the derived 4-(nitrophenoxy)quinoline or a corresponding derivative hintline, and then mixing the derived 4-(nitrophenoxy)quinoline or a corresponding derivative hintline in a suitable solvent, for example N,N-dimethylformamide, in the presence of a catalyst, such as palladium hydroxide on charcoal, palladium on charcoal, in an atmosphere of hydrogen. Alternatively, a derivative of 4-(aminophenoxy)quinoline or a corresponding derivative hintline can be obtained by reaction of an aminophenol derived from 4-chlorhydrin or the corresponding derivative of hintline in the presence of a base such as sodium hydride.

Alternatively, a derivative of 4-(aminophenoxy)hintline can be obtained by dissolving aminophenol in aqueous sodium hydroxide solution and subjecting the solution of two-phase reaction with a solution derived 4-chlorination in an organic solvent in the presence of a phase transfer catalyst, for example bromide, Tetra-n-butylamine, or in the absence of a catalyst.

where Hal represents a halogen atom, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11and X are as defined in formula (I).

Deputy in R9you can enter the reaction of the thus obtained derivative 4-(aminophe is hydroxy)quinoline or a corresponding derivative hintline with acid chloride or acid anhydride in the presence of a base and then recovering the reaction product by socialogical or the like (stage 1A).

Alternatively, the substituent in R9you can enter by reaction of a derivative of 4-(aminophenoxy)quinoline or a corresponding derivative hintline with aldehyde or ketone, receiving the connection imine, and then carrying out the reaction between imine with mixed cyanohydrin sodium and boron or the like (stage 1B).

The compound represented by formula (I)can be obtained by reaction of a derivative having a Deputy in R9with derived isocyanate in the traditional way (stage 2) and carrying out the reaction of the reaction product with a suitable alkylating agent (R10Hal) in the presence of a base, for example sodium hydride (stage 3).

R9and R10you can also enter by reaction of a derivative of urea, where R9and/or R10represent a hydrogen atom, with a suitable alkylating agent (R10Hal) in the presence of a base such as sodium hydride, similar to stage 3 (stage 5 and 7).

A derivative of urea, where R9and/or R10represent a hydrogen atom, can be obtained by reaction of a derivative of 4-(aminophenoxy)quinoline or a corresponding derivative hintline obtained according to scheme 1, with the derived isocyanate in the traditional way, or adding triphosgene to the derived 4-(aminophenoxy)quinoline or a corresponding derivative hintline in the presence of base is, such as triethylamine, and then carrying out a reaction mixture with a suitable amine derivative (R11NH2or R10R11NH) (stages 4 and 6).

The compound represented by formula (I), where Y is S, can be obtained by reaction of a derivative aminothiophenol derived from 4-chlorhydrin or the corresponding derivative of hintline in a suitable solvent, for example chlorobenzene, according to scheme 1, receiving the derived 4-(chinaillon)aniline or a derivative of 4-(girasolereale)aniline and then forming a urea group according to scheme 2.

The use of compounds/pharmaceutical compositions

Compounds of the present invention have inhibitory against proliferation of tumor activity in vivo (pharmacological test examples 2, 3 and 4).

Further, the compounds of the present invention inhibit the in vitro autophosphorylation in the intracellular domain of the human KDR, caused by stimulation of NIH3T3 cells, which stably Express human KDR, VEGF (factor a vascular endothelial growth) (pharmacological test example 1). The binding of VEGF to KDR, VEGF receptor on the cell membrane, induces the activation MARK (mitogen activated protein kinase) or the like through autophosphorylation intracellular domain of KDR under the action of tyrosine kinase (Shibuya M., Ito N., Claesson-Welsh L., in Curr. Topics Environ. Immunol, 237, 59-83 (1999); Abedi, H., Zachary, I., J. Biol. Chem., 272, 15442-15451 (1997)). It is known that activation MARK plays an important role in cell growth of vascular endothelium during angiogenesis (Merenmies, J. et al., Cell Growth &Differ., 83 stop within 10 (1997); and Ferrara, N., and Davis-Smyth, T., Endocr. Rev., 18, 4-25 (1997)). Thus, the compounds of the present invention have inhibitory activity against angiogenesis.

Angiogenesis in pathological sections, as is well known, plays a key role in diseases such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma and metastasis of solid tumors (Folkman, J., Nature Med. 1: 27-31 (1995); Bicknell, R., Harris, A.L. Curr. Opin. Oncol. 8: 60-65 (1996)). Therefore, compounds of the present invention can be used in the treatment of these diseases.

In accordance with this invention features a pharmaceutical composition comprising the compound of the present invention. The pharmaceutical composition of the present invention can be used in the treatment of diseases such as tumors, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma and metastasis of solid tumors.

Compounds of the present invention can enter humans and other mammals orally or parenterally such routes of administration as intravenous, intramuscular entered the e, subcutaneous administration, rectal administration or percutaneous administration. Therefore, pharmaceutical compositions comprising as active ingredient the compound according to the present invention are in suitable dosage forms in accordance with the ways of introduction.

Specifically, oral preparations include tablets, capsules, powders, granules and syrups, and parenteral preparations include injections, suppositories, plasters and ointments.

These various preparations can be prepared by conventional methods, for example, commonly used pharmaceutically acceptable carriers, such as fillers, substances contributing raspadaemosti dosage forms, binders, lubricants, paints and thinners.

The fillers include, for example, lactose, glucose, corn starch, sorbitol and crystalline cellulose; substances contributing raspadaemosti dosage forms include, for example, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate and dextrin; binders include, for example, dimethylallyl, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, Arabian gum, gelatin, hydroxypropylcellulose and polyvinylpyrrolidone; lubricants include, for example, talc, magnesium stearate, polietileno the eh and hydrogenated vegetable oil.

In the preparation of injections, if necessary, you can add, for example, buferiruemoi agents, pH regulators, stabilizers, agents toychest and preservatives.

The content of compounds of the present invention in the pharmaceutical composition of the present invention may vary depending on the dosage form. However, as a rule, the content is from 0.5 to 50% mass, preferably from 1 to 20% mass of the total mass of the composition.

The dose can be appropriately determined, taking into account, for example, age, weight, gender, the difference in the disease and the severity of the condition of individual patients, and drugs can be entered, for example, in amounts of from 0.01 to 100 mg/kg, preferably from 0.1 to 50 mg/kg, This dose is administered once daily or divided doses several times per day.

The compound of the present invention can be introduced in combination with other drug(s) agent(s). In this case, the connection of the present invention can be administered simultaneously or after or before the introduction of others(CSOs) of drug(CSO) facilities(a). For example, when the disease is a malignant tumor, the compound of the present invention can act on target cells of the vascular endothelium, resulting in reduction of the tumor, followed by the introduction paragraph is tibooburra drug for the effective destruction of the tumor. Type, intervals between the doses and the same for anticancer drug can be determined depending on, for example, from the cancer type and condition of the patients. This method can be used for diseases other than cancer.

In accordance with the present invention provides the use of compounds of the present invention to obtain drugs for the treatment of diseases selected from the group comprising tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma.

Further, in accordance with the present invention proposes a method of treatment of a disease selected from the group consisting of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma, comprising a stage of introduction of a mammal such as a human, a therapeutically effective amount of the compounds of the present invention, optionally together with a pharmaceutically acceptable carrier.

Further in accordance with this invention proposes a method of inhibiting angiogenesis of blood vessels-targets, including the stage of introduction of the compounds of the present invention in contact with the cells of the vascular endothelium of the blood vessels target. Blood vessels target include krotoszynski, involved in the power supply to tissues, causing disease, such as tumors, retinopathies tissue or rheumatic tissues. Compounds of the present invention can be introduced into contact with the vascular endothelium cells, for example, a General introduction, for example, intravenous or oral introduction; local introduction, for example, transcutaneous introduction or intraarticular introduction; or Milenium the introduction of medicines, using the media, for example, a liposome, a lipid microsphere or polymeric forms of the drug.

EXAMPLES

Further, the present invention is illustrated by the following examples which are not intended to limit the invention.

Example 1: N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(3-isoxazolyl)urea

3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (20 mg) dissolved in chlorobenzene (2 ml) and N,N-diisopropylethylamine (0.2 ml)to give solution. Then to this solution was added a solution of triphosgene (18 mg) in chlorobenzene (0.5 ml) and the mixture is stirred at room temperature for 30 minutes Then add 3-isoxazolin (10 mg) and the mixture is stirred at 110°With during the night. The reaction solution are on hard-shelled earth, impregnated (saturated) saturated aqueous sodium bicarbonate, then SL is blowing the extraction with chloroform. The solvent is removed from the extract by distillation. The residue is purified HPLC using for the manifestation of a mixture of chloroform/methanol, getting mentioned in the title compound (2 mg, yield 8%).

1H-NMR (CDCl3, 400 MHz): 4,06 (s, 3H), 4,07 (s, 3H), 6.35mm (d, J=5.4 Hz, 1H), 6,37 (user., 1H), 7.23 percent (d, J=8,8 Hz, 1H), 7,45 (s, 1H), 7,51 (DD, J=2,4, 8,8 Hz, 1H), 7,60 (s, 1H), of 7.90 (d, J=2.4 Hz, 1H), 8,29 (d, J=2.0 Hz, 1H), 8,49 (d, J=5.4 Hz, 1H)

Mass spectrometry (ERI-MS, m/z): 441 (M++1)

Example 2: N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(3-methyl-5-isoxazolyl)urea

3-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (20 mg) dissolved in chlorobenzene (2 ml) and N,N-diisopropylethylamine (0.2 ml)to give solution. Then to this solution was added a solution of triphosgene (18 mg) in chlorobenzene (0.5 ml) and the mixture is stirred at room temperature for 30 minutes Then add 3-methyl-5-isoxazolone (12 mg) and the mixture is stirred at 110°With during the night. The reaction solution are on hard-shelled earth, impregnated with a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The solvent is removed from the extract by distillation. The residue is purified HPLC using for the manifestation of a mixture of chloroform/methanol, getting mentioned in the title compound (5 mg, yield 18%).

1H-NMR (CDCl3, 400 MHz): δ of 2.28 (s, 3H), a 4.03 (s, 3H), 4,06 (s, 3H), 6,09 (s, 1H), 6,33 (d, J=5.4 Hz, 1H), 7,17 (who, J=8,8 Hz, 1H), 7,38 (DD, J=2.7, and an 8.8 Hz, 1H), 7,43 (s, 1H), to 7.61 (s, 1H), 7,73 (d, J=2.7 Hz, 1H), of 8.47 (d, J=5.4 Hz, 1H), 8,48 (user., 1H)

Mass spectrometry (ERI-MS, m/z): 455 (M++1)

Example 3: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-forfinal}-N'-(3-isoxazolyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-3-ftoranila (800 mg) is dissolved in chloroform (20 ml) and triethylamine (1.0 ml)to give solution. Then to this solution was added a solution of triphosgene (378 mg) in chloroform and the mixture is stirred at room temperature for 10 minutes Then add 3-aminoethoxy (252 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added ice water and the mixture extracted with chloroform. The organic layer is washed with water, saturated salt solution and then dried over anhydrous sodium sulfate. The dried organic layer was filtered and then concentrated. To the residue for crystallization add ether. Crystalline material is collected by filtration. Assembled crystalline substance purified by chromatography (chloroform:acetone=2:1). The cleaning product to add a 10% solution of hydrogen chloride in methanol, followed by concentration. The resulting crystalline material was washed with ether, receiving 554 mg of the connection specified in the connection header.

1H-NMR (DMSO-d6, 400 MHz): δ of 4.05 (3H, s), 406 (3H, C)6,86 (1H, d, J=1.7 Hz), of 6.99 (1H, d, J=6.3 Hz), was 7.36 (1H, DD, J=1.5 Hz, J=9.0 Hz), 7,55 (1H, t, J=9.0 Hz), a 7.62 (1H, s), 7,78 (1H, s), 7,83 (1H, DD, J=2.4 Hz, J=12.9 Hz), 8,77 (1H, d, J=1.5 Hz), cent to 8.85 (1H, d, J=6.6 Hz), made up 9.77 (1H, s), 9,96 (1H, s)

Mass spectrometry (ERI-MS, m/z): 498 (M++1)

Example 4: N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 3-amino-5-methylisoxazole (38 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 78 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ to 2.42 (3H, s), was 4.02 (3H, s), a 4.03 (3H, s), 6,00 (1H, usher.), of 6.49 (1H, d, J=5.4 Hz), 7,11 (1H, DD, J=2.7 Hz, J=9.0 Hz), 7.23 percent-7,27 (1H, m), 7,41 (1H, s), 7,49 (1H, s), at 8.36 (1H, d, J=9.0 Hz), 8,44 (1H, users), and 8.50 (1H, d, J=5.4 Hz), of 9.51 (1H, users)

Mass spectrometry (ERI-MS, m/z): 453, 455 (M+-1)

Example 5: N-{2-chloro-4-(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(3-methyl-5-isoxazolyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 5-amino-3-methylisoxazole (32 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 53 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,46 (1H, d, J=5,1 Hz), 8,23 (1H, d, J=8,8 Hz), of 7.70 (1H, s), the 7.43 (1H, s), 7,37 (1H, s), to 7.15 (1H, d, J=2.7 Hz), 7,07-7,11 (1H, m), to 6.43 (1H, d, J=5,1 Hz), of 5.99 (1H, s), of 3.97 (6H, s), 2,22 (3H, s)

Mass spectrometry (ERI-MS, m/z): 453 (M+-1)

Example 6: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(3-methyl-5-isoxazolyl)urea

2-Fluoro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then d is billaut 5-amino-3-methylisoxazole (37 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 53 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ and 8.50 (1H, d, J=5.4 Hz), to 8.20 (1H, d, d, J=9.0 Hz, J=9.0 Hz), 7,73 (1H, s), 7,49 (1H, s), 7,42 (1H, s), 6,99? 7.04 baby mortality (1H, m), 6,93 (1H, DD, J=2.7 Hz, J=11.2 Hz), 6,50 (1H, d, J=5.4 Hz), 6,05 (1H, s), was 4.02 (6H, s), and 2.27 (3H, s)

Mass spectrometry (ERI-MS, m/z): 437 (M+-1)

Example 7: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-forfinal}-N'-(3-methyl-5-isoxazolyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-3-ftoranila (800 mg) is dissolved in chloroform (20 ml) and triethylamine (1.0 ml)to give solution. Then to this solution was added a solution of triphosgene (378 mg) in chloroform and the mixture is stirred at room temperature for 10 minutes Then add 5-amino-3-methylisoxazole (294 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added ice water and the mixture extracted with chloroform. The organic layer is washed with water, saturated salt solution and then dried over anhydrous sodium sulfate. The dried organic layer was filtered and then the end of tryout. To the residue for crystallization add ether and the crystalline material is collected by filtration. Assembled crystalline substance purified by chromatography (chloroform:acetone=2:1). The cleaning product to add a 10% solution of hydrogen chloride in methanol, followed by concentration. The resulting crystalline material was washed with ether, receiving 669 mg specified in the connection header.

1H-NMR (DMSO-d6, 400 MHz): δ to 2.18 (3H, s), Android 4.04 (3H, s), of 4.05 (3H, s), of 5.99 (1H, s), 6,93 (1H, d, J=6.6 Hz), of 7.36-7,39 (1H, m), 7,53 (1H, t, J=8,8 Hz), EUR 7.57 (1H, s), of 7.75 (1H, s), 7,81 (1H, DD, J=2.7 Hz, J=13,2 Hz), 8,81 (1H, d, J=6.6 Hz), being 9.61 (1H, s), 10,44 (1H, s)

Mass spectrometry (ERI-MS, m/z): 439 (M++1)

Example 8: the hydrochloride of N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-forfinal}-N'-(5-methyl-3-isoxazolyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-3-ftoranila (800 mg) is dissolved in chloroform (20 ml) and triethylamine (1.0 ml)to give solution. Then to this solution was added a solution of triphosgene (378 mg) in chloroform and the mixture is stirred at room temperature for 10 minutes Then add 3-amino-5-methylisoxazole (294 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added ice water and the mixture extracted with chloroform. The organic layer is washed with water, saturated salt solution and then dried over anhydrous sulfate intothree is. The dried organic layer was filtered and then concentrated. To the residue for crystallization add ether and the crystalline material is collected by filtration. Collected solid is purified by chromatography (chloroform:acetone=2:1). The cleaning product to add a 10% solution of hydrogen chloride in methanol, followed by concentration. The resulting crystalline material was washed with ether, receiving 598 mg specified in the connection header.

1H-NMR (DMSO-d6, 400 MHz): δ of 2.38 (3H, s), of 4.05 (3H, s)4,06 (3H, s), 6,56 (1H, s), 7,01 (1H, d, J=6.6 Hz), 7,34-7,37 (1H, m), 7,55 (1H, t, J=9.0 Hz), 7,63 (1H, s), 7,78 (1H, s), 7,83 (1H, DD, J=2.4 Hz, J=13.1 Hz), cent to 8.85 (1H, d, J=6.6 Hz), of 9.75 (1H, s), 9,80 (1H, s)

Mass spectrometry (ERI-MS, m/z): 439 (M++1)

Example 9: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(5-methyl-3-isoxazolyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (800 mg) is dissolved in chloroform (20 ml) and triethylamine (1.0 ml)to give solution. Then to this solution was added a solution of triphosgene (378 mg) in chloroform and the mixture is stirred at room temperature for 10 minutes Then add 3-amino-5-methylisoxazole (270 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added ice water and the mixture extracted with chloroform. The organic layer is washed with water, saturated salt solution, and C is the dried over anhydrous sodium sulfate. The dried organic layer was filtered and then concentrated. To the residue for crystallization add ether and the crystalline material is collected by filtration. Assembled crystalline substance purified by chromatography (mixture of chloroform:acetone=2:1), receiving 636 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 2,43 (3H, d, J=0.7 Hz), of 4.05 (3H, s), of 4.05 (3H, s), 5,96 (1H, usher.), 6,53 (1H, d, J=5,1 Hz), 7,00-7,02 (2H, m), the 7.43 (1H, s), 7,51 (1H, s), with 8.05 (1H, usher.), 8,29 (1H, t, J=8.5 Hz), charged 8.52 (1H, d, J=5.4 Hz), 9,44 (1H, user.)

Mass spectrometry (ERI-MS, m/z): 439 (M++1)

Example 10: N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (40 mg) dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml)to give solution. Then to this solution was added a solution of triphosgene (20 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 3-amino-5-methylisoxazole (15 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and the residue purified by chromatography (chloroform:acetone=2:1), obtaining mentioned in the title compound (20.0 mg, yield of 35.2%).

1H-NMR (DMSO-d6, 400 MHz): δ is 2.37 (s, 3H), 3,98 (d, J=5.4 Hz, 6H), 6,55 (s, 1H), 7,24 (d, J=8,8 Hz, 2H), 7,38 (s, 1H) rate of 7.54 (d, J=9.0 Hz, 2H), 7,56 (s, 1H), 8,54 (s, 1H), 9,01 (user., 1H), 9,56 (user., 1H)

Mass spectrometry (ERI-MS, m/z): 420 (M+-1)

Example 11: N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(3-methyl-5-isoxazolyl)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (40 mg) dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml)to give solution. Then to this solution was added a solution of triphosgene (20 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 5-amino-3-methylisoxazole (15 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and the residue is then purified by chromatography (chloroform:acetone=2:1), obtaining mentioned in the title compound (9.8 mg, yield of 17.3%).

1H-NMR (CDCl3-di, 400 MHz): δ and 2.27 (s, 3H), 4,07 (d, J=2,9 Hz, 6H), 6,04 (s, 1H), 7,24 (d, J=8,8 Hz, 2H), 7,33 (s, 1H), 7,49 (DD, J=2.2 Hz, 9.0 Hz, 2H), 7,55 (s, 1H), 8,61 (s, 1H)

Mass spectrometry (ERI-MS, m/z): 420 (M+-1)

Example 12: N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (43 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml)to give solution. Then to this solution was added a solution of triphosgene (20 mg) in chloroform and the mixture is stirred at room temperature is round within 5 minutes Then add 3-amino-5-methylisoxazole (15 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and the residue is then purified by chromatography (chloroform:acetone=2:1), obtaining specified in the header connection (19,0 mg, yield 32%).

1H-NMR (DMSO-d6, 400 MHz): δ is 2.37 (s, 3H), 3,98 (d, J=6.8 Hz, 6H), 6,51 (s, 1H), 7,32 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,39 (s, 1H), 7,55 (s, 1H), EUR 7.57 (d, J=2.7 Hz, 1H), to 8.20 (DD, J=2,69, 9.0 Hz, 1H), 8,56 (s, 1H), 8,75 (user., 1H), 10,14 (user., 1H)

Mass spectrometry (ERI-MS, m/z): 454 (M+-1)

Example 13: N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(3-methyl-5-isoxazolyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (43 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml)to give solution. Then to this solution was added a solution of triphosgene (20 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 5-amino-3-methylisoxazole (15 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and the residue is then purified by chromatography (chloroform:acetone=2:1), obtaining specified in the header connection (18,1 mg, yield 31%).

1H-NMR (DMSO-d6 , 400 MHz): δ to 2.18 (s, 3H), 3,98 (d, J=6.8 Hz, 6H), 5,98 (s, 1H), 7,33 (DD, J=2,4, and 9.0 Hz, 1H), 7,40 (s, 1H), 7,55 (s, 1H), 7,58 (d, J=2.7 Hz, 1H), 8,17 (DD, J=3,9, 9.0 Hz, 1H), to 8.57 (s, 1H)

Mass spectrometry (ERI-MS, m/z): 454 (M+-1)

Example 14: N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea

3-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (42 mg) dissolved in chloroform (2.0 ml) and triethylamine (0,13 ml)to give solution. Then to this solution was added a solution of triphosgene (19 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 3-amino-5-methylisoxazole (14 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and evaporated to the dry state. To the resulting solid substance is added diethyl ether and the solution is filtered. The filtrate is concentrated and to the residue add methyl alcohol. The resulting crystalline material is collected by filtration, getting mentioned in the title compound (8,8 mg, yield 15%).

1H-NMR (DMSO-d6, 400 MHz): δ of 2.38 (s, 3H), 3,99 (d, J=5,9 Hz, 6H), 6,55 (s, 1H), 7,40-7,42 (m, 3H), EUR 7.57 (s, 1H), 7,84-7,86 (m, 1H), 8,55 (s, 1H), remaining 9.08 (user., 1H), 9,60 (user., 1H)

Mass spectrometry (ERI-MS, m/z): 454 (M+-1)

Example 15: N-{3-chloro-4-[(6,7-dimethoxy-4-hin zainil)oxy]phenyl}-N'-(3-methyl-5-isoxazolyl)urea

3-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (84 mg) dissolved in chloroform (2.5 ml) and triethylamine (0.25 ml)to give solution. Then to this solution was added a solution of triphosgene (38 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 5-amino-3-methylisoxazole (27 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and evaporated to the dry state. To the resulting solid substance is added diethyl ether and the solid is collected by filtration, and then washed with methyl alcohol, getting mentioned in the title compound (34,2 mg, 30%yield).

1H-NMR (DMSO-d6, 400 MHz): δ to 2.18 (s, 3H), 3,99 (d, J=5,9 Hz, 6H), of 5.99 (s, 1H), 7,41 (s, 1H), 7,42 was 7.45 (m, 2H), EUR 7.57 (s, 1H), 7,84-7,86 (m, 1H), 8,54 (s, 1H), 9,17 (user., 1H), 10,31 (user., 1H)

Mass spectrometry (ERI-MS, m/z): 454 (M+-1)

Example 16: N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(3-methyl-5-isothiazolin)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (40 mg) dissolved in chloroform (1.2 ml) and triethylamine (0.2 ml)to give solution. Then to this solution was added a solution of triphosgene (20 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 5-amino-3-metalis the thiazole hydrochloride (22 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and the residue is then purified by chromatography (chloroform:acetone=2:1), obtaining mentioned in the title compound (17.5 mg, yield 29,7%).

1H-NMR (CDCl3, 400 MHz): δ of 2.38 (s, 3H), 4,07 (d, J=4.4 Hz, 6H), 6,40 (s, 1H), 7,21-7,25 (m, 2H), 7,33 (s, 1H), 7,47 (d, J=8,8 Hz, 2H), 7,55 (s, 1H), at 8.60 (s, 1H)

Mass spectrometry (ERI-MS, m/z): 436 (M+-1)

Example 17: N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(3-methyl-5-isothiazolin)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (43 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.2 ml)to give solution. Then to this solution was added a solution of triphosgene (20 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 5-amino-3-metalization hydrochloride (22 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and the residue is then purified by chromatography (chloroform:acetone=2:1), obtaining specified in the header connection (13,7 mg, yield 22%).

1H-NMR (DMSO-d6, 400 MHz): δ of 2.30 (s, 3H), 3,99 (d, J=6.6 Hz, 6H), of 6.68 (s, 1H), 7,34 (DD, J=2.7, and 9.0 Hz, 1H), 7,40 (s, 1H), 7,56 (s, 1H), to 7.59 (d, J=2.7 Hz, 1H), 8,13-8,17 (m, 1H), to 8.57 (s, 1H), 8,77 (user., 1H), 10,94 (user., 1H)

Mass SPECT is ometry (ERI-MS, m/z): 470 (M+-1)

Example 18: N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(3-methyl-5-isothiazolin)urea

3-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (84 mg) dissolved in chloroform (2.5 ml) and triethylamine (0,50 ml)to give solution. Then to this solution was added a solution of triphosgene (38 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 5-amino-3-metalization (38 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and evaporated to the dry state. To the residue is added diethyl ether, the solid is collected by filtration and washed with methyl alcohol, getting mentioned in the title compound (32,2 mg, yield 27%).

1H-NMR (DMSO-d6, 400 MHz): δ of 2.30 (s, 3H), 3,99 (d, J=5,61 Hz, 6H), of 6.68 (s, 1H), 7,41 (s, 1H), 7,44 (s, 1H), of 7.48 (DD, J=2,4 Hz and 8.8 Hz, 1H), 7,58 (s, 1H), a 7.85 (d, J=2,4, 1H), 8,55 (s, 1H), 9,46 (user., 1H), 10,59 (user., 1H)

Mass spectrometry (ERI-MS, m/z): 470 (M+-1)

Example 19: N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(1H-5-pyrazolyl)urea

3-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (20 mg) dissolved in chlorobenzene (2 ml) and N,N-diisopropylethylamine (0.2 ml)to give solution. Then to this solution was added a solution of triphosgene (18 mg) in 0.5 ml of chlorobenzene and the mixture is stirred at room temperature for 30 minutes Then add 1H-5-pyrazolin (10 mg) and the mixture is stirred at 110°With during the night. The reaction solution are on hard-shelled earth, impregnated with a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The solvent is removed from the extract by distillation. The residue is purified HPLC using for the manifestation of a mixture of chloroform/methanol, getting mentioned in the title compound (1 mg, yield 4%).

1H-NMR (CDCl3, 400 MHz): δ of 4.05 (s, 3H), 4,07 (s, 3H), to 5.93 (d, J=2.4 Hz, 1H), 6,34 (d, J=5,1 Hz, 1H), 7,20 (d, J=8,8 Hz, 1H), 7,43 (s, 1H), 7,52 (d, J=2.4 Hz, 1H), 7,55 (DD, J=2.7 Hz, 8,8 Hz, 1H), to 7.61 (s, 1H), 7,86 (d, J=2.4 Hz, 1H), 8,48 (d, J=5.4 Hz, 1H)

Mass spectrometry (ERI-MS, m/z): 440 (M++1)

Example 20: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(1H-5-pyrazolyl)urea

4-[(6,7-dimethoxy-4-chinolin)oxy]-2-ftoranila (20 mg) dissolved in chlorobenzene (1.5 ml) and N,N-diisopropylethylamine (0.15 ml)to give solution. Then to this solution was added a solution of triphosgene (19 mg) in chlorobenzene (0.5 ml) and the mixture is stirred at room temperature for 30 minutes Then add 1H-5-pyrazolin (10 mg) and the mixture is stirred at 100°With during the night. The reaction solution are on hard-shelled earth, impregnated with a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The solvent and the extract is removed by distillation. The residue is purified HPLC using for the manifestation of a mixture of chloroform/methanol, getting mentioned in the title compound (3 mg, yield 11%).

Mass spectrometry (ERI-MS, m/z): 424 (M++1)

Example 21: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(5-methyl-1,3-thiazol-2-yl)urea hydrochloride

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (300 mg) dissolved in chloroform (6 ml) and triethylamine (0.3 ml)to give solution. Then to this solution was added a solution of triphosgene (142 mg) in chloroform and the mixture is stirred at room temperature for 10 minutes Then add 2-amino-5-methylthiazole (119 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added ice water and the mixture extracted with chloroform. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The dried organic layer was filtered and then concentrated. To the residue is added ether for crystallization and crystalline material is collected by filtration. The crystalline substance is purified by chromatography (chloroform:acetone=2:1). To a purified crystalline substance added 10% solution of hydrogen chloride in methanol and then the solution concentrated. The resulting crystalline material was washed with ether, receiving 380 mg specified in the zag is lowke connection.

1H-NMR (CDCl3/400 MHz): δ 2,47 (3H, d, J=1.5 Hz), 4,11 (3H, s), 4,19 (3H, s), PC 6.82 (1H, d, J=6.6 Hz), 7,08-to 7.15 (2H, m), 7,16 (1H, d, J=1.5 Hz), 7,63 (1H, s), 8,03 (1H, s), of 8.27 (1H, t, J=8.5 Hz), 8,63 (1H, d, J=6,6 Hz)

Mass spectrometry (ERI-MS, m/z): 453 (M+-1)

Example 22: N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(4-methyl-1,3-thiazol-2-yl)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (10 ml) and piperidine (0.1 ml)to give solution. Then to this solution was added a solution of triphosgene (45 mg) in chloroform and the mixture is stirred at room temperature for 10 minutes Then add 2-amino-4-methylthiazole (38 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added ice water and the mixture extracted with chloroform. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The dried organic layer was filtered and then concentrated. To the residue is added ether for crystallization and crystalline material is collected by filtration. The crystalline substance is purified by chromatography (chloroform:acetone=2:1)to give 90 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ to 2.40 (3H, d, J=0.7 Hz), of 4.05 (3H, s), of 4.05 (3H, s), 6,44 (1H, d, J=1.0 Hz), 6,51 (1H, d, J=5,1 Hz), to 7.15 (1H, DD, J=2.7 Hz, J=9.0 Hz), 7,28 (1H, d, J=2.7 Hz), the 7.43 (1H, s), 7,52 (1H, ), and 8.50 (1H, d, J=9.0 Hz), charged 8.52 (1, d, J=5,1 Hz)

Mass spectrometry (ERI-MS, m/z): 469 (M+-1)

Example 23: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (95 mg) was dissolved in chloroform (3 ml) and pyridine (0.2 ml)to give solution. Then to this solution was added a solution of triphosgene (45 mg) in chloroform and the mixture is stirred at room temperature for 10 minutes Then add 2-amino-4,5-dimethylthiazole hydrochloride (54 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added ice water and the mixture extracted with chloroform. The organic layer is washed with water and saturated saline and then dried over anhydrous sodium sulfate. The dried organic layer was filtered and then concentrated. To the residue is added ether for crystallization and crystalline material is collected by filtration. The crystalline substance is purified by chromatography (chloroform:acetone=2:1)to give 29 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ and 2.27 (3H, s), of 2.28 (3H, s), Android 4.04 (3H, s), of 4.05 (3H, s), 6,51 (1H, d, J=5.4 Hz), 6,97-7,02 (2H, m), the 7.43 (1H, s), 7,51 (1H, s), 8,39 (1H, t, J=8,8 Hz), 8,51 (1H, d, J=5.4 Hz)

Mass spectrometry (ERI-MS, m/z): 469 (M++1)

Example 24: N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea

2-Chloro-4-[(6,7-dime the XI-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml), getting a solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-4,5-dimethylthiazole hydrochloride (55 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 62 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,49 (1H, d, J=5,2 Hz), 8,46 (1H, d, J=9.0 Hz), to 7.50 (1H, s), 7,41 (1H, s), 7.24 to 7,26 (1H, m), 7,11 (1H, DD, J=2.7 Hz, J=9.0 Hz), 6.48 in (1H, d, J=5,1 Hz), a 4.03 (3H, s), a 4.03 (3H, s), 2.26 and (3H, s), 2,24 (3H, s)

Mass spectrometry (ERI-MS, m/z): 483, 485 (M+-1)

Example 25: N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea

3-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-4,5-dimethylthiazole hydrochloride (55 mg) and the mixture of paramashiva the t at room temperature over night. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 29 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,46 (1H, d, J=5.4 Hz), 7,88 (1H, d, J=2.4 Hz), to 7.59 (1H, s)of 7.48 (1H, DD, J=2.4 Hz, J=8,8 Hz), the 7.43 (1H, s), 7.23 percent-7,26 (1H, m), 7,17 (1H, d, J=8,8 Hz), of 6.31 (1H, d, J=5.4 Hz), of 4.05 (3H with), a 4.03 (3H, in), 2.25 (3H, s), are 2.19 (3H, s)

Mass spectrometry (ERI-MS, m/z): 483, 485 (M+-1)

Example 26: N-[4-[(6,7-dimethoxy-4-chinolin)oxy]-2-(trifluoromethyl)phenyl]-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-(trifluoromethyl)aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-4,5-dimethylthiazole hydrochloride (55 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. Organic is Loy concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 43 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ and 8.50 (1H, d, J=5.4 Hz), compared to 8.26 (1H, d, J=8.6 Hz), to 7.50 (1H, s), 7,42-7,46 (2H, m), 7,35 (1H, DD, J=3.0 Hz, J=9.0 Hz), 6.48 in (1H, d, J=5.4 Hz), Android 4.04 (3H, s), a 4.03 (3H, in), 2.25 (3H, s), 2,21 (3H, s)

Mass spectrometry (ERI-MS, m/z): 517 (M+-1)

Example 27: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(1,3-thiazol-2-yl)urea hydrochloride

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (12 g) dissolved in chloroform (350 ml) and triethylamine (50 ml)to give solution. Then to this solution was added a solution of triphosgene (12 g) in chloroform and the mixture is stirred at room temperature for 30 minutes Then add 2-aminothiazol (4.77 g) and the mixture is stirred at room temperature overnight. To the reaction solution was added ice water and the mixture extracted with chloroform. The organic layer is washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The dried organic layer was filtered and then concentrated, to the residue is added ether for crystallization, and then collected by filtration of the resulting crystalline substance. Next, the crystalline substance is washed with methanol and collected by filtration. To assembled crystalline substance, add a solution of hydrogen chloride in methanol and the solution concentrated. Obrazovavsheesya resulting crystalline material was washed with a mixed solution, consisting of ether and ethanol, getting 11.5g specified in the connection header.

1H-NMR (DMSO-d6, 400 MHz): δ Android 4.04 (s, 3H), of 4.05 (s, 3H), 7,00 (d, J=6,8 Hz, 1H), 7,17 (d, J=3,7 Hz, 1H), 7,27-7,32 (m, 1H), 7,41 (d, J=3,7 Hz, 1H), 7,55 -7,60 (m, 1H), to 7.67 (s, 1H), to 7.77 (s, 1H), 8,30-of 8.37 (m, 1H), cent to 8.85 (d, J=6,6 Hz, 1H), 9,35 (users, 1H)

Mass spectrometry (ERI-MS, m/z): 441 (M++1)

Example 28: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(4-methyl-1,3-thiazol-2-yl)urea hydrochloride

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (10 g) dissolved in chloroform (300 ml) and triethylamine (40 ml)to give solution. Then to this solution was added a solution of triphosgene (10 g) in chloroform and the mixture is stirred at room temperature for 30 minutes Then add 2-amino-4-methylthiazole (4,36 g) and the mixture is stirred at room temperature overnight. To the reaction solution was added ice water and the mixture extracted with chloroform. The organic layer is washed with water and saturated saline and then dried over anhydrous magnesium sulfate. The dried organic layer was filtered and then concentrated, to the residue is added ether for crystallization, and then collected by filtration of the resulting crystalline substance. The crystalline substance is purified by chromatography (chloroform:acetone=2:1). The cleaning product to add a 10% solution of hydrogen chloride in methanol, the donkey which should concentration. The resulting crystalline material was washed with ether, receiving 6.0 g specified in the connection header.

1H-NMR (DMSO-d6, 400 MHz): δ 2,24 (s, 3H), Android 4.04 (s, 3H), of 4.05 (s, 3H), of 6.71 (s, 1H), 7,00 (d, J=6,8 Hz,1H), 7,26-7,31 (m, 1H), 7,55-of 7.60 (m, 1H), 7,68 (s, 1H), 7,76 (s, 1H), 8,29-at 8.36 (m, 1H), 8,84 (d, J=6,8 Hz, 1H)

Mass spectrometry (ERI-MS, m/z): 455 (M+-1)

Example 29 Ethyl-2-{2-[({4-[(6,7-dimethoxy-4-chinolin)oxy]-2-foronline}carbonyl)amino]-1,3-thiazol-4-yl)acetate

4-[(6,7-dimethoxy-4-chinolin)oxy]-2-ftoranila (30 mg) dissolved in chloroform (3 ml)to give solution. Then to the solution is added triethylamine (0.3 ml) and the solution triphosgene (27 mg) in chloroform (0.2 ml) and the mixture is stirred at room temperature for 30 minutes Then add a solution of ethyl-(2-amino-4-thiazolyl)acetate (76 mg) in chloroform (0.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The extract was washed with saturated saline solution and dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified by chromatography on silica gel using for the manifestation of a mixture of chloroform/acetone, receiving 22 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ of 1.29 (t, 3H, J=7,1 Hz), 3,76 (s, 2H), Android 4.04 (s, 3H), of 4.05 (s, 3H), 4,23 (square, 2H, J=7,1 Hz), 73 (s, 1H), of 6.52 (d, 1H, J=5.4 Hz), 6,97-7,02 (m, 2H), 7,44 (s, 1H), 7,51 (s, 1H), 8,35 (t, 1H, J=9.0 Hz), charged 8.52 (d, 1H, J=5.4 Hz)

Mass spectrometry (ERI-MS, m/z): 525 (M+-1)

Example 30: N-[4-(tert-butyl)-1,3-thiazol-2-yl]-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}urea

4-[(6,7-dimethoxy-4-chinolin)oxy]-2-ftoranila (30 mg) dissolved in chloroform (3 ml)to give solution. Then to the solution is added triethylamine (0.3 ml) and the solution triphosgene (27 mg) in chloroform (0.2 ml) and the mixture is stirred at room temperature for 30 minutes Then add a solution of 2-amino-4-tert-butylthiazole (64 mg) in chloroform (0.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The extract was washed with saturated saline solution and dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified by chromatography on silica gel using for the manifestation of a mixture of chloroform/acetone, receiving 26 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ of 1.36 (s, 9H), 4,06 (s, 3H), 4,06 (s, 3H), 6,41 (s, 1H), is 6.54 (d, 1H, J=5.4 Hz), 7,00? 7.04 baby mortality (m, 2H), 7,45 (s, 1H), 7,53 (s, 1H), 8,48 (t, 1H, J=8.5 Hz), 8,53 (d, 1H, J=5,1 Hz)

Mass spectrometry (ERI-MS, m/z): 495 (M+-1)

Example 31 Ethyl-2-{2-[({2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline}carbonyl)amino]-1,3-thiazol-4-yl}acetate

2-Chloro-4-[(6,7-is metoxy-4-chinolin)oxy]aniline (30 mg) dissolved in chloroform (3 ml), getting a solution. Then to the solution is added triethylamine (0.3 ml) and the solution triphosgene (27 mg) in chloroform (0.2 ml) and the mixture is stirred at room temperature for 30 minutes Then add a solution of ethyl-(2-amino-4-thiazolyl)acetate (76 mg) in chloroform (0.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The extract was washed with saturated saline solution and dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified by chromatography on silica gel using for the manifestation of a mixture of chloroform/acetone, receiving 23 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ of 1.23 (t, 3H, J=7,1 Hz), 3,76 (s, 2H), of 4.05 (s, 3H), of 4.05 (s, 3H), 4,21 (square, 2H, J=7,1 Hz), 6,51 (d, 1H, J=5.4 Hz), 6.75 in (s, 1H), 7,14 (DD, 1H, J=2.7 Hz, J=9.0 Hz), 7,27 (d, 1H, J=2.7 Hz), 7,44 (s, 1H), 7,51 (s, 1H), 8,46 (d, 1H, J=9.0 Hz), charged 8.52 (d, 1H, J=5.4 Hz)

Mass spectrometry (ERI-MS, m/z): 541 (M+-1)

Example 32: N-(5-bromo-1,3-thiazol-2-yl)-N'-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (30 mg) dissolved in chloroform (3 ml)to give solution. Then to the solution is added triethylamine (0.3 ml) and the solution triphosgene (27 mg) in chloroform (0.2 ml) and the mixture is stirred at room temperature for 30 minutes Then add Aut a solution of 2-amino-5-brotizolam (106 mg) in chloroform (0.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The extract was washed with saturated saline solution and dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified by chromatography on silica gel using for the manifestation of a mixture of chloroform/acetone, receiving 6 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): Android 4.04 (s, 3H), Android 4.04 (s, 3H), 6.48 in (d, 1H, J=5.4 Hz), 7,16 (DD, 1H, J=2.7 Hz, J=9.0 Hz), 7,26 (d, 1H, J=2.7 Hz), 7,35 (s, 1H), 7,43 (s, 1H), 7,50 (s, 1H), to 8.41 (d, 1H, J=9.0 Hz), 8,51 (d, 1H, J=5.4 Hz)

Mass spectrometry (ERI-MS, m/z): 534 (M+-1)

Example 33: N-[4-(tert-butyl)-1,3-thiazol-2-yl]-N'-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}moonvine-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (30 mg) dissolved in chloroform (3 ml)to give solution. Then to the solution is added triethylamine (0.3 ml) and the solution triphosgene (27 mg) in chloroform (0.2 ml) and the mixture is stirred at room temperature for 30 minutes Then add a solution of 2-amino-4-tert-butylthiazole (64 mg) in chloroform (0.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The extract was washed with saturated saline solution and dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure ostatok purify by chromatography on silica gel using for the manifestation of a mixture of chloroform/acetone, receiving 14 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ of 1.36 (s, 9H), of 4.05 (s, 3H), 4,06 (s, 3H), 6.42 per (s, 1H), is 6.54 (d, 1H, J=5,1 Hz), to 7.15 (DD, 1H, J=2.7 Hz, J=9.0 Hz), 7,28 (d, 1H, J=2.7 Hz), 7,45 (s, 1H), 7,52 (s, 1H), 8,40 (d, 1H, J=9.0 Hz), 8,53 (d, 1H, J=5,1 Hz)

Mass spectrometry (ERI-MS, m/z): 511 (M+-1)

Example 34: N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-chloro-1,3-thiazol-2-yl)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (30 mg) dissolved in chloroform (3 ml)to give solution. Then to the solution is added triethylamine (0.3 ml) and the solution triphosgene (27 mg) in chloroform (0.2 ml) and the mixture is stirred at room temperature for 30 minutes Then add a solution of 2-amino-5-chlorothiazole (70 mg) in chloroform (0.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The extract was washed with saturated saline solution and dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified by chromatography on silica gel using for the manifestation of a mixture of chloroform/acetone, receiving 6 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): Android 4.04 (s, 3H), of 4.05 (s, 3H), of 6.50 (d, 1H, J=5.4 Hz), to 7.15 (DD, 1H, J=2.7 Hz, J=9.0 Hz), 7,26-7,27 (m, 2H), 7,44 (s, 1H), 7,50 (s, 1H), scored 8.38 (t, 1H, J=9.0 Hz), charged 8.52 (d, 1H, J=5.4 Hz)

Mass spectrometry (ERI-MS, m/z: 489, 491 (M+-1)

Example 35: N-(5-bromo-1,3-thiazol-2-yl)-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (30 mg) dissolved in chloroform (3 ml)to give solution. Then to the solution is added triethylamine (0.3 ml) and the solution triphosgene (27 mg) in chloroform (0.2 ml) and the mixture is stirred at room temperature for 30 minutes Then add a solution of 2-amino-5-bromothiazole bromate (106 mg) in chloroform (0.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The extract was washed with saturated saline solution and dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified by chromatography on silica gel using for the manifestation of a mixture of chloroform/acetone, receiving 5 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): 3,93 (s, 3H), of 3.95 (s, 3H), 6,56 (d, 1H, J=5,1 Hz), 7,13 (d, 1H, J=7.8 Hz), 7,37-7,49 (m, 4H), 8,16 (t, 1H, J=9,3 Hz)and 8.50 (d, 1H, J=4.9 Hz), 8,99 (user., 1H), 11,02 (user., 1H)

Mass spectrometry (ERI-MS, m/z): 518, 520 (M+-1)

Example 36: N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (30 mg) dissolved in chloroform (3 ml)to give solution. Then to the solution was added tri the ylamine (0.3 ml) and the solution triphosgene (27 mg) in chloroform (0.2 ml) and the mixture is stirred at room temperature for 30 minutes Then add a solution of 5-acetyl-2-amino-4-methylthiazole (64 mg) in chloroform (0.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The extract was washed with saturated saline solution and dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified by chromatography on silica gel using for the manifestation of a mixture of chloroform/acetone, receiving 6 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 2,47 (s, 3H), of 2.56 (s, 3H), 3,93 (s, 3H), of 3.95 (s, 3H), to 6.57 (d, 1H, J=4.9 Hz), 7,14 (d, 1H, J=8,3 Hz), 7,38-7,41 (m, 1H), 7,49 (s, 1H), 7,80 (s, 1H), 8,17 (t, 1H, J=9.0 Hz), 8,51 (d, 1H, J=5.4 Hz), 9,17 (s, 1H), 11,23 (user., 1H)

Mass spectrometry (ERI-MS, m/z): 495 (M+-1)

Example 37: N-(5-chloro-1,3-thiazol-2-yl)-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (30 mg) dissolved in chloroform (3 ml)to give solution. Then to the solution is added triethylamine (0.3 ml) and the solution triphosgene (27 mg) in chloroform (0.2 ml) and the mixture is stirred at room temperature for 30 minutes Then add a solution of 2-amino-5-chlorothiazole (70 mg) in chloroform (0.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture share extracti the th chloroform. The extract was washed with saturated saline solution and dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified by chromatography on silica gel using for the manifestation of a mixture of chloroform/acetone, receiving 12 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ of 3.94 (s, 3H), of 3.95 (s, 3H), to 6.57 (d, 1H, J=5.4 Hz), 7,13-to 7.15 (m, 1H), 7,37-7,40 (m, 1H), 7,41 (s, 1H), 7,44 (s, 1H), 7,49 (s, 1H), 8,16 (t, 1H, J=9.0 Hz), 8,51 (d, 1H, J=5,1 Hz), 9,00 (s, 1H), br11.01 (user., 1H)

Mass spectrometry (ERI-MS, m/z): 473 (M+-1)

Example 38: N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(1,3-thiazol-2-yl)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-aminothiazol (49 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 31 mukozalnogo in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,61 (1H, s), of 8.47 (1H, d, J=9.0 Hz), 7,51 (1H, s), 7,44 (1H, d, J=3.6 Hz), was 7.36 (1H, d, J=2.7 Hz), 7,31 (1H, s), 7.18 in-7,24 (1H, m)6,91 (1H, d, J=3,7 Hz), of 4.05 (3H, s), of 4.05 (3H, s)

Mass spectrometry (ERI-MS, m/z): 456 (M+-1)

Example 39: N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-1,3-thiazol-2-yl)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-methylthiazole (58 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 18 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,56 (1H, s), to 8.41 (1H, d, J=9.0 Hz), 7,45 (1H, s), 7,29 (1H, d, J=2.7 Hz), 7,26 (1H, s), 7,13 (1H, DD, J=2.7 Hz, J=9.0 Hz), 7,00 (1H, d, J=1.4 Hz), of 4.00 (3H, s)to 3.99 (3H, s), of 2.34 (3H, d, J=1.0 Hz)

Mass spectrometry (ERI-MS, m/z): 470 (M+-1)

Example 40: N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]Fe is Il}-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-4,5-dimethylthiazole hydrochloride (50 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 33 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,61 (1H, s), 8,48 (1H, d, J=9.0 Hz), 7,51 (1H, s), 7,34 (1H, d, J=2.7 Hz), 7,31 (1H, s), 7,17 (1H, DD, J=2.7 Hz, J=9.0 Hz), of 4.05 (3H, s), of 4.05 (3H, s), and 2.26 (3H, s), 2,24 (3H, s)

Mass spectrometry (ERI-MS, m/z): 484 (M+-1)

Example 41: N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(4-methyl-1,3-thiazol-2-yl)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature during the course the e 15 minutes Then add 2-amino-4-methylthiazole (60 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 15 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ to 8.57 (1H, d, J=3.0 Hz), 8,43 (1H, d, J=9.0 Hz), 7,46 (1H, s), 7,30-to 7.35 (1H, m), 7.24 to 7,28 (1H, m), 7,10-7,20 (1H, m), 6.35mm (1H, s), 4.00 points (6H, s), 2,31 (3H, d, J=1.0 Hz)

Mass spectrometry (ERI-MS, m/z): 470 (M+-1)

Example 42: N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(1,3-thiazol-2-yl)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (40 mg) dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml)to give solution. Then to this solution was added a solution of triphosgene (20 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 2-aminothiazol (15 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and then the residue purified by chromatography (chloroform:acetone=2:1), obtaining the decree of the TES in the title compound (19,0 mg, the output of 33.4%).

1H-NMR (DMSO-d6, 400 MHz): δ 3,99 (d, J=4,88 Hz, 6H), 7,12 (user., 1H), 7,26 (d, J=8,78 Hz, 2H), 7,37 -7,39 (m, 2H), 7,55-to 7.59 (m, 3H), 8,54 (s, 1H)

Mass spectrometry (ERI-MS, m/z): 422 (M+-1)

Example 43: N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-1,3-thiazol-2-yl)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (40 mg) dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml)to give solution. Then to this solution was added a solution of triphosgene (20 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 2-amino-5-methylthiazole (17 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and then the residue purified by chromatography (chloroform:acetone=2:1), obtaining specified in the header connection (22,5 mg, yield of 38.2%).

1H-NMR (CDCl3, 400 MHz): δ of 2.38 (d, J=1.2 Hz, 3H), 4,07 (s, 6H), of 6.96 (d, J=1.5 Hz, 1H), 7,21 (DD, J=2.2 Hz, 9.0 Hz, 2H), 7,32 (s, 1H), 7,56 (s, 1H), to 7.61 (DD, J=2,20, 9,03 Hz, 2H), at 8.60 (s, 1H)

Mass spectrometry (ERI-MS, m/z): 436 (M+-1)

Example 44: N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(4-methyl-1,3-thiazol-2-yl)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (40 mg) dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml)to give solution. Then to this solution add a solution is ribogene (20 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 2-amino-4-methylthiazole (17 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and then the residue purified by chromatography (chloroform:acetone=2:1), obtaining mentioned in the title compound (11.8 mg, yield of 20.0%).

1H-NMR (CDCl3, 400 MHz): δ of 2.38 (d, J=0,97 Hz, 3H), 4,07 (d, J=1.2 Hz, 6H), 6,41 (d, J=1.0 Hz, 1H), 7.23 percent-7,27 (m, 2H), 7,32 (s, 1H), 7,56 (s, 1H), to 7.64 (d, J =8,8 Hz, 2H), to 8.62 (s, 1H)

Mass spectrometry (ERI-MS, m/z): 436 (M+-1)

Example 45: N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (40 mg) dissolved in chloroform (1.2 ml) and triethylamine (0.2 ml)to give solution. Then to this solution was added a solution of triphosgene (20 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 2-amino-4,5-dimethylthiazole hydrochloride (24 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and then the residue purified by chromatography (chloroform:acetone=2:1), obtaining specified in the header of the connection (from 25.8 mg, yield 42,0%).

1H-NMR (DMSO-d6, 400 MHz): δ a 2.12 (s, 3H), of 2.21 (s, 3H), 3,98 (d,J=5,1 Hz, 6H), 7,24 (d, J=8,8 Hz, 2H), 7,38 (s, 1H), 7,56 (s, 1H), EUR 7.57 (d, J=7,3 Hz, 2H), 8,54 (s, 1H)

Mass spectrometry (ERI-MS, m/z): 450 (M+-1)

Example 46: N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(1,3-thiazol-2-yl)urea

3-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (84 mg) dissolved in chloroform (2.5 ml) and triethylamine (0.25 ml)to give solution. Then to this solution was added a solution of triphosgene (38 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 2-aminothiazol (28 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and evaporated to the dry state. Then to the solid residue is added diethyl ether and the solid collected by filtration. Next, the collected solid washed with methyl alcohol, getting mentioned in the title compound (77,5 mg, yield 66%).

1H-NMR (DMSO-d6, 400 MHz): δ 3,99 (d, J=5.4 Hz, 6H), 7,13 (user., 1H), 7,38 (d, J=3,7 Hz, 1H), 7,41 (s, 1H), 7,43 (s, 1H), 7,46 (DD, J=2.2 Hz, 8,8 Hz, 1H), 7,58 (s, 1H), 7,89 (d, J=1.7 Hz, 1H), 8,54 (s, 1H)

Mass spectrometry (ERI-MS, m/z): 456 (M+-1).

Example 47: N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-1,3-thiazol-2-yl)urea

3-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (84 mg) dissolved in chloroform (2.5 ml) and the retinamide (0.25 ml), getting a solution. Then to this solution was added a solution of triphosgene (38 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 2-amino-5-methylthiazole (32 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and evaporated to the dry state. Then to the solid residue is added diethyl ether and the solid collected by filtration. Next, the collected solid washed with methyl alcohol, getting mentioned in the title compound (81,5 mg, yield 70%).

1H-NMR (DMSO-d6, 400 MHz): δ 2,32 (s, 3H), 3,99 (d, J=5.6 Hz, 6H),? 7.04 baby mortality (user., 1H), 7,40-7,47 (m, 3H), 7,58 (s, 1H), 7,88 (user., 1H), 8,55 (s, 1H)

Mass spectrometry (ERI-MS, m/z): 470 (M+-1)

Example 48: N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(4-methyl-1,3-thiazol-2-yl)urea

3-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (84 mg) dissolved in chloroform (2.5 ml) and triethylamine (0.25 ml)to give solution. Then to this solution was added a solution of triphosgene (38 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 2-amino-4-methylthiazole (32 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and MES separated by extraction with chloroform. The organic layer is concentrated and evaporated to the dry state. Then to the solid residue is added diethyl ether and the solid collected by filtration. Next, the collected solid washed with methyl alcohol, getting listed at the beginning of the connection (to 78.3 mg, yield 68%).

1H-NMR (DMSO-d6, 400 MHz): δ of 2.23 (s, 3H), 3,99 (d, J=5,61 Hz, 6H), 6,64 (User., 1H), 7,39-of 7.48 (m, 3H), 7,58 (s, 1H), 7,89 (user., 1H), 8,54 (s, 1H)

Mass spectrometry (ERI-MS, m/z): 470 (M+-1)

Example 49: N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea

3-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline (84 mg) dissolved in chloroform (2.5 ml) and triethylamine (0,50 ml)to give solution. Then to this solution was added a solution of triphosgene (38 mg) in chloroform and the mixture is stirred at room temperature for 5 minutes Then add 2-amino-4,5-dimethylthiazole hydrochloride (42 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added water and the mixture is separated by extraction with chloroform. The organic layer is concentrated and evaporated to the dry state. Then to the solid residue is added diethyl ether and the solid collected by filtration. Next, the collected solid washed with methyl alcohol, getting listed at the beginning of the connection (to 86.4 mg, yield 68%).

1H-NMR (DMSO-d6, 400 MHz): δ to 2.13 (s, 3H), of 2.20 (s, 3H), 3,99 (d, J=5,9 Hz, 6H), 7,38-7,49 (m, 3H), EUR 7.57 (s, 1H), 7,88 (user., 1H), 8,54 (s, 1H)

Mass spectrometry (ERI-MS, m/z): 484 (M+-1)

Example 50: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (70 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 43 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,45-and 8.50 (1H, m), 7,53-7,56 (1H, m), of 7.48-7,52 (1H, m), 7,39-the 7.43 (1H, m), 7,00-7,24 (2H, m), 6.42 per-6,48 (1H, m), a 4.03 (6H, s)

Mass spectrometry (ERI-MS, m/z): 490 (M+-1)

Example 51: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]moonvine-[(6,7-dimethoxy-4-chinolin)oxy]-2-f Oranien (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml), getting a solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (70 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 62 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ charged 8.52 (1H, d, J=5.4 Hz), to 8.20 (1H, DD, J=8,9 Hz, J=8,9 Hz), of 7.48 (1H, s), 7,44 (1H, s), 7,00-was 7.08 (2H, m), 6,53 (1H, d, J=5,1 Hz), Android 4.04 (3H, s), a 4.03 (3H, s)

Mass spectrometry (ERI-MS, m/z): 508 (M+-1)

Example 52: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-forfinal}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-3-ftoranila (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (70 mg) and the mixture was stirred at room is the temperature during the night. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 72 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,30 at 8.60 (1H, m), 7,00-of 7.70 (5H, m), 6.30-in-6,50 (1H, m), of 4.05 (3H, s), a 4.03 (3H, s)

Mass spectrometry (ERI-MS, m/z): 508 (M+-1)

Example 53: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (68 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the roadline mixture of chloroform/acetone, receiving 70 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ to 8.40 (1H, d, J=6.6 Hz), 7,60-the 7.65 (1H, m), 7,55 (1H, s), 7,39 (1H, s), of 6.99 (1H, d, J=8,8 Hz), 6,24 (1H, d, J=5.4 Hz), to 4.01 (3H, s)to 3.99 (3H, s), is 2.30 (3H, s)a 2.12 (3H, s)

Mass spectrometry (ERI-MS, m/z): 518 (M+-1)

Example 54: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-methyl-1,3,4-thiadiazole-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-methyl-1,3,4-thiadiazole (47 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 49 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ to 8.41 (1H, d, J=5.4 Hz), 7,56 (2H, d, J=8.6 Hz), to 7.50 (1H, s), 7,35 (1H, s), 7,20-of 7.25 (2H, m), 7,07 (2H, d, J=9.0 Hz), 6,38 (1H, d, J=5,1 Hz), 3,98 (6H, s)to 2.46 (3H, s)

Mass spectrometry (ERI-MS, m/z): 436 (M+-1)

Example 55: N-{4-[(6,7-dimethoxy-4-hin is a Lil)oxy]-2-were}-N'-(5-methyl-1,3,4-thiadiazole-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-methylaniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-methyl-1,3,4-thiadiazole (49 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 40 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,46 (1H, d, J=5.4 Hz), 8,03-of 8.15 (1H, m), 7,54 (1H, s), 7,40 (1H, s), 6,95 -7,07 (3H, m), 6,46 (1H, d, J=5,2 Hz), a 4.03 (6H, s), of 2.51 (3H, s), of 2.28 (3H, s)

Mass spectrometry (ERI-MS, m/z): 450 (M+-1)

Example 56: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-were}-N'-(5-methyl-1,3,4-thiadiazole-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-3-methylaniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes the ZAT is added 2-amino-5-methyl-1,3,4-thiadiazole (49 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 58 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ scored 8.38 (1H, d, J=5.4 Hz), 7,53 (1H, s)of 7.48 (1H, s), of 7.36 (1H, s), 7,15-7,21 (2H, m), and 6.25 (1H, d, J=5.4 Hz), of 4.00 (3H, s)to 3.99 (3H, s), 2,43 (3H, s)to 2.06 (3H, s)

Mass spectrometry (ERI-MS, m/z): 450 (M+-1)

Example 57: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N'-(5-methyl-1,3,4-thiadiazole-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-methyl-1,3,4-thiadiazole (43 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue PTS who participate HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 52 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ at 8.36 (1H, d, J=8.5 Hz), 7,71 (1H, d), 7,55 (1H, s), of 7.36 (1H, s), of 7.90-7,00 (2H, m), 6,21 (1H, d, J=5,1 Hz), of 4.00 (3H, s), 3,98 (3H, s), a 2.45 (3H, s)to 2.18 (3H, s), is 2.05 (3H, s)

Mass spectrometry (ERI-MS, m/z): 464 (M+-1)

Example 58 N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(5-methyl-1,3,4-thiadiazole-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-methyl-1,3,4-thiadiazole (52 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 52 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,46 (1H, d, J=5.4 Hz), 8,20-8,30 (1H, m), 7,44-7,46 (1H, m), 7,37 (1H, s), 6.90 to-7,00 (2H, m), 6,47 (1H, d, J=5.4 Hz), 3,99 (3H, s), 3,98 (3H, s)of 2.64 (3H, s)

Mass spectrometry (ERI-MS, m/z): 454 (M+-1)

Example 59: N-{4-[(6,7-dimetix the-4-chinolin)oxy]phenyl}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-ethyl-1,3,4-thiadiazole (45 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 72 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): 6 8,43 (1H, d, J=5.4 Hz), 7,63 (2H, d, J=8,8 Hz), 7,51 (1H, s), 7,37 (1H, s), 7,11 (2H, d, J=9.0 Hz), 6,41 (1H, d, J=5,1 Hz)to 3.99 (3H, s)to 3.99 (3H, s), 3,03 (2H, square, J=7,6 Hz)of 1.41 (3H, t, J=7,6 Hz)

Mass spectrometry (ERI-MS, m/z): 450 (M+-1)

Example 60: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-were}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-methylaniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature in them is giving 15 minutes Then add 2-amino-5-ethyl-1,3,4-thiadiazole (42 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 68 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): 6 8,43 (1H, d, J=5.4 Hz), of 7.90 (1H, d, J=8.0 Hz), 7,49 (1H, s), 7,37 (1H, s), 6,98-7,05 (2H, m), 6,44 (1H, d, J=5.4 Hz), 3,99 (6H, s), 2,98 (2H, square, J=7,6 Hz), 2,39 (3H, s)of 1.36 (3H, t, J=7,6 Hz)

Mass spectrometry (ERI-MS, m/z): 464 (M+-1)

Example 61: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-were}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-3-methylaniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-ethyl-1,3,4-thiadiazole (43 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer is washed us is pregnant with brine and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 71 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,39 (1H, d, J=5.4 Hz), 8,17 (1H, s), 7,53 (1H, s)of 7.48 (1H, d, J=2.2 Hz), was 7.36 (1H, s), 7.18 in-7,30 (2H, m), 6,28 (1H, d, J=5,2 Hz), of 4.00 (3H, s)to 3.99 (3H, s), 2,90 (2H, square, J=7,6 Hz)that is 2.09 (3H, s)of 1.27 (3H, t, J=7,6 Hz)Mass spectrometry (ERI-MS, m/z): 464 (M+-1)

Example 62: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-ethyl-1,3,4-thiadiazole (44 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 53 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ scored 8.38 1H, d, J=5,1 Hz), to 7.64 (1H, d, J=8.5 Hz), 7,56 (1H, s), 7,37 (1H, s), 6,97 (1H, d, J=8,8 Hz), 6,24 (1H, d, J=5,1 Hz)to 4.01 (3H, s)to 3.99 (3H, s)to 2.99 (2H, square, J=7,6 Hz), 2,32 (3H, s)of 2.10 (3H, s), 1,36 (3H, t, J=7,6 Hz)

Mass spectrometry (ERI-MS, m/z): 478, 479 (M+-1)

Example 63 N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of three phosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-ethyl-1,3,4-thiadiazole (43 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 49 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,46 (1H, d, J=5.4 Hz), by 8.22 (1H, square, J=9.1 Hz), 7,45 (1H, s), 7,37 (1H, s), 6,92-7,00 (2H, m), 6,47 (1H, d, J=5.4 Hz), 3,99 (3H, s), 3,98 (3H, s), 3,01 (2H, square, J=7,6 Hz)to 1.38 (3H, t, J=7,6 Hz)

Mass spectrometry (ERI-MS, m/z): 468, 469 (M+-1)

Example 64: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-forfinal}-N'-(5-the Teal-1,3,4-thiadiazole-2-yl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-3-ftoranila (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-ethyl-1,3,4-thiadiazole (41 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 53 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,44 (1H, d, J=5,1 Hz), compared to 8.26 (1H, bc), of 7.68 (1H, DD, J=2.4 Hz, J=12.0 Hz), 7,53 (1H, s), 7,37 (1H, s), 7,28-7,33 (1H, m), 7,15-7,22 (2H, m), 6,37 (1H, DD, J=1.0 Hz, J=5.4 Hz), of 4.00 (3H, s), to 3.99 (3H, s), 3.04 from (2H, square, J=7.5 Hz), of 1.41 (3H, t, J=7,6 Hz)

Mass spectrometry (ERI-MS, m/z): 468 (M+-1)

Example 65: N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture re eshivot at room temperature for 15 minutes Then add 2-amino-5-ethyl-1,3,4-thiadiazole (41 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 21 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,46 (1H, d, J=5,2 Hz), of 8.25 (1H, d, J=9.0 Hz), 7,45 (1H, s), 7,37 (1H, s), 7,22 (1H, d, J=2.7 Hz), to 7.09 (1H, DD, J=2.7 Hz, J=9.0 Hz), 6,46 (1H, d, J=5,2 Hz)to 3.99 (3H, s), 3,98 (3H, ), to 2.99 (2H, square, J=7,6 Hz)to 1.37 (3H, t, J=7,6 Hz)

Mass spectrometry (ERI-MS, m/z): 484 (M+-1)

Example 66 N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea

3-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-ethyl-1,3,4-thiadiazole (41 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. Org the organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 48 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,48 (1H, d, J=5.4 Hz), 7,92 (1H, d, J=2.7 Hz), to 7.59 (1H, s), 7,45-7,52 (2H, m), 7,17 (1H, d, J=8,8 Hz), 6,33 (1H, d, J=5.4 Hz), of 4.05 (3H, s), Android 4.04 (3H, s), 3,01 (2H, square, J=7,6 Hz), 1,40 (3H, t, J=7,6 Hz)

Mass spectrometry (ERI-MS, m/z): 484, 486 (M+-1)

Example 67 N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-cyclopropyl-1,3,4-thiadiazole-2-yl)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-cyclopropyl-1,3,4-thiadiazole (55 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 32 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): ; 8,51 (1H, d, J=5.4 Hz), 8,29 (1H, d, J=9.0 Hz), to 7.50 (1H, s), 7,42 (1H, s), 7,27 (1H, d, J=2.7 Hz), 7,14 (1H, d, d, J=2.7 Hz, J=9.0 Hz), 6,51 (1H, d, J=5,1 Hz), Android 4.04 (3H, s), a 4.03 (3H, s), 2,23-2,31 (1H, m), 1,07 is 1.23 (4H, m)

Mass spectrometry (ERI-MS, m/z): 496, 498 (M+-1)

Example 68: N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-cyclopropyl-1,3,4-thiadiazole-2-yl)urea

3-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-cyclopropyl-1,3,4-thiadiazole (55 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 42 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,43 (1H, d, J=5.4 Hz), of 8.37 (1H, users), 7,81 (1H, d, J=2.4 Hz), 7,54 (1H, s)to 7.50 (1H, DD, J=8,8 Hz, J=2.7 Hz), 7,37 (1H, s), 7,16 (1H, d, J=8,8 Hz), 6,28 (1H, d, J=5.4 Hz), 4,01 (3H, ), to 3.99 (3H, s), 2,22-2,31 (1H, m), 1,15-1,22 (2H, m), 1,12-1,08 (2H, m)

Mass spectrometry (ERI-MS, m/z): 496 (M+-1)

the example 69 N-(5-cyclopropyl-1,3,4-thiadiazole-2-yl)-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimethylaniline (100 mg) dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-cyclopropyl-1,3,4-thiadiazole (55 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 55 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): 8,40 (1H, d, J=5.4 Hz), 7,80 (1H, c), 7,54 (1H, s), 7,37 (1H, s)6,91 (1H, s), 6,21 (1H, d, J=5.4 Hz), 5,27 (1H, users), of 4.00 (3H, s)to 3.99 (3H, s), of 2.34 (3H, s), 2,13-of 2.27 (1H, m), 2,11 (3H, s), of 1.10-1.20 (2H, m), 0,98-1,08 (2H, m)

Mass spectrometry (ERI-MS, m/z): 490 (M+-1)

Example 70: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-[5-(ethylsulfonyl)-1,3,4-thiadiazole-2-yl]urea

4-[(6,7-dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture premesis the Ute at room temperature for 15 minutes Then add 2-amino-5-ethylthio-1,3,4-thiadiazole (55 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 31 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ to 8.45 (1H, d, J=5,1 Hz), 8,18 (1H, DD, J=9.1 Hz, J=9.1 Hz), of 8.09 (1H, users), 7,44 (1H, s), 7,37 (1H, s), 6.90 to-7,00 (2H, m), 6,47 (1H, d, J=5,2 Hz)to 3.99 (3H, s), 3,98 (3H, s), and 3.16 (2H, square, J=7,3 Hz)to 1.37 (3H, t, J=7,3 Hz)Mass spectrometry (ERI-MS, m/z): 500 (M+-1)

Example 71: N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N'-[5-(ethylsulfonyl)-1,3,4-thiadiazole-2-yl]urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-ethylthio-1,3,4-thiadiazole (60 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform is m The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 53 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ scored 8.38 (1H, d, J=5.4 Hz), 7,56 (1H, s), 7,52 (1H, d, J=8,8 Hz), 7,37 (1H, s), to 6.95 (1H, d, J=8.6 Hz), 6,23 (1H, d, J=5.4 Hz), to 4.01 (3H, s)to 3.99 (3H, s), of 3.13 (2H, square, J=7,3 Hz), 2,28 (3H, (C), of 2.08 (3H, s)to 1.37 (3H, t, J=7,3 Hz)

Mass spectrometry (ERI-MS, m/z: 510 (M+-1)

Example 72 N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (65 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/and Eton, receiving 48 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): charged 8.52 (1H, d, J=5,2 Hz), of 8.28 (1H, d, J=9.0 Hz), to 7.93 (1H, s)of 7.48-rate of 7.54 (1H, m), 7,38-7,44 (1H, m), 7,29 (1H, d, J=2.7 Hz), 7,10-7,20 (1H, m), of 6.52 (1H, d, J=5,2 Hz), Android 4.04 (3H, s), a 4.03 (3H, s)

Mass spectrometry (ERI-MS, m/z): 524 (M+-1)

Example 73: N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]urea

3-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (65 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 63 mg specified in the connection header 30.

1H-NMR (CDCl3, 400 MHz): δ 8,42 (1H, d, J=5.4 Hz), to 7.84 (1H, users), to 7.67 (1H, d, J=2.7 Hz), 7,55 (1H, s), of 7.36 (1H, s), 7,30 (1H, DD, J=2.7 Hz, J=8,8 Hz), 7,12 (1H, d, J=8,8 Hz), 6,28 (1H, d, J=5.4 Hz), of 4.00 (3H, ), of 3.97 (3H, s)

Mass spectrometry (ERI-MS m/z): 524 (M +-1)

Example 74 N-[5-(tert-butyl)-1,3,4-thiadiazole-2-yl)-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution was added a solution of triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-tert-butyl-1,3,4-thiadiazole (65 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 49 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,51 (1H, d, J=5.4 Hz), 8,30 (1H, DD, J=8,9 Hz, J=8,9 Hz)to 7.50 (1H, s), 7,42 (1H, s), 6,97? 7.04 baby mortality (2H, m), 6,53 (1H, d, J=5,1 Hz), Android 4.04 (3H, s), a 4.03 (3H, s)of 1.39 (9H, s)

Mass spectrometry (ERI-MS, m/z): 496 (M+-1)

Example 75 N-[5-(tert-butyl)-1,3,4-thiadiazole-2-yl)-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (100 mg) dissolved in chloroform (5 ml) and triethylamine (0.5 ml)to give solution. Then to this solution is dobavlaut solution triphosgene (100 mg) in chloroform and the mixture is stirred at room temperature for 15 minutes Then add 2-amino-5-tert-butyl-1,3,4-thiadiazole (65 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added distilled water and the mixture is separated by extraction with chloroform. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The organic layer is concentrated under reduced pressure and the residue purified HPLC using for the manifestation of a mixture of chloroform/acetone, receiving 28 mg specified in the connection header.

1H-NMR (CDCl3, 400 MHz): δ 8,43 (1H, d, J=5,2 Hz), 7,66 (1H, d, J=8.5 Hz), to 7.61 (1H, s), 7,42 (1H, s), 7,01 (1H, d, J=8,8 Hz), of 6.29 (1H, d, J=5,1 Hz), of 4.05 (3H, s), Android 4.04 (3H, s), is 2.37 (3H, s), and 2.14 (3H, s), 1,38 (9H, s)

Mass spectrometry (ERI-MS, m/z): 506 (M+-1)

Structures of the compounds obtained in examples 1-75, can be represented as follows.

A: ethoxycarbonylmethyl, tBu: tert-butyl, AC: acetyl, Et: ethyl, cPr: cyclopropyl and EtS: atillio.

Pharmacological test example 1: measurement of inhibitory activity against the phosphorylation of KDR method ELYSA

Cells NIH 3T3 engaged in the expression of KDR man (A. Sawano et al., Cell Growth &Differentiation, 7, 213-221 (1996), “Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelal growth factor”), obtained by transfection of KDR gene man, grown in DMEM containing 10% fetal calf serum (purchased from GIBCO BRL), in an incubator with 5% carbon dioxide until the merge (confluence) from 50 to 70%. Collected cells seeded in the wells of 96-well flat-bottomed tablet coated with collagen, each of which contains the same environment, number 1,5x104on the hole, and then grown at 37°With during the night. Then the medium is replaced by DMEM containing 0.1% fetal calf serum. To each well add a solution of test compound in dimethyl sulfoxide and cultivation continued at 37°C for one hour. Add human recombinant growth factor vascular endothelial (hereinafter, referred to as “VEGF”) to a final concentration of 100 ng/ml and carry out the stimulation of the cells at 37°C for 2 minutes, Remove the medium and cells are washed with saline phosphate buffer (pH 7.4) and then to add 50 µl of buffer solution to solubilize (20 mm HEPES (pH of 7.4), 150 mm NaCl, and 0.2% Triton X-100, 10% glycerol, 5 mm ortho-unadilla sodium, 5 mm and 2 dinitrilotetraacetic mm Na4P2O7). The mixture was shaken at 4°C for 2 hours, getting a cell extract.

Separately in the microplate for ELISA (Maxisorp; purchased from NUNC) add salt solution with phosphate buffer 50 ál, pH 7.4)containing 5 μg/ml antiphospho-the tyrosine antibody (PY20; purchased from Transduction Laboratories), and then incubated at 4°during the night with the formation of the solid phase to the wells. After washing tablet add 300 µl of blocking solution and then incubated at room temperature for 2 hours for blocking. After washing all the amount of cellular extract is transferred into the wells and the tablet then incubated at 4°With during the night. After washing carry out the reaction with anti-KDR antibody (purchased from Santa Cruz) at room temperature for one hour and after washing carry out the reaction with antibodies against rabbit Ig peroxidase labeled (purchased from Amersham) at room temperature for one hour. After washing, add the chromophore substrate to peroxidase (purchased from Sumitomo Bakelite Co., Ltd)to initiate the reaction. After the appropriate level of display colors, add a solution to complete the reaction, to stop the reaction and measure the absorbance at 450 nm using a tablet reader. The activity of KDR phosphorylation for each well determined, assuming that the absorption with the addition of VEGF and without the addition of a medicinal product is 100% activity of KDR phosphorylation and absorption without adding drugs and VEGF 0% activity phosphorylase is of KDR. The concentration of the tested compounds vary on several levels, for each case determine the inhibition (%) of KDR phosphorylation and calculate the concentration of test compound required for 50% inhibition of KDR phosphorylation (IC50).

Inhibitory activity against the phosphorylation of KDR for typical examples of groups of compounds of the present invention shown in table 2.

Table 2
IC50, mcm
Example 10,0023
Example 20,002
Example 3<0,001
Example 4<0,001
Example 5<0,001
Example 6<0,001
Example 9is 0.0002
Example 100,0036
Example 110,0093
Example 12<0,001
Example 130,0022
Example 140,0044
Example 150,0134
Example 160,0549
Example 170,0049
Example 180,0697
Example 19 0,0175
Example 200,0042
Example 210,0004
Example 22<0,001
Example 23<0,001
Example 240,001
Example 250,0019
Example 260,005
Example 270,0003
Example 280,0003
Example 290,0494
Example 300,0286
Example 310,0339
Example 320,0037
Example 330,0211
Example 340,0028
Example 350,0019
Example 360,0012
Example 370,0019
Example 38<0,001
Example 39<0,001
Example 40<0,001
Example 420,0047
Example 43<0,001
Example 440,0011
Example 45<0,001
Example 460,0074
Example 470,0028
Example 480,0044
Example 490,0031
Example 500,0063
Example 510,0037
Example 520,013
Example 530,0012
Example 58being 0.036
Example 590,0013
Example 60<0,001
Example 620,0015
Example 63<0,001
Example 640,0015
Example 65<0,001
Example 660,0037
Example 670,0024
Example 680,018
Example 690,0041
Example 700,0022
Example 710,0031
Example 720,0029
Example 730,021
Example 740,003
Example 750,0045

Pharmacological test example 2: measurement of antitumor activity against cells of human lung cancer (LC-6)

Human cell lung cancer (LC-6) (obtained from Central Laboratories for Experimental Animals transplanted bare (Nude) mice. When tumor volume reaches the example is about 100 mm 3mice are grouped so that each group consisted of four mice and the mean tumor volume in the groups was equal. The test compound is administered orally a dose of 20 mg/kg of the test groups every day once a day for 9 days, while the control group injected with only the solvent in the same manner as the test groups. The rate of inhibition of tumor growth (TGIR) calculated as follows: rate of inhibition of tumor growth (TGIR)=(1 - TX/CX) x 100, where CX represents the tumor volume on day X for the control group, when the tumor volume on the first day of introduction to be equal to 1; and t represents tumor volume for teams that enter the test connection.

The rate of inhibition of tumor growth for typical examples of compounds in this connection are shown in table 3.

td align="center"> 39,8
Table 3
TGIR, %
Example 339,5
Example 455,4
Example 529,5
Example 629,3
Example 963,5
Example 2166,6
Example 2243,8
Example 2351,7
Example 24
Example 2518,8
Example 28to 66.3
Example 2966,1
Example 3892,0
Example 3964,0
Example 4034,2
Example 5011,9
Example 5145,6
Example 5220,7
Example 5314.4V
Example 58the 13.4
Example 6923,3

Pharmacological test example 3: measurement of antitumor activity against cells of human lung cancer (LC-6) using Nude rats

Human cell lung cancer (LC-6) (obtained from Central Laboratories for Experimental Animals transplanted Nude rats. When tumor volume reaches approximately 700 mm3, rats are grouped so that each group consisted of four rats, and the mean tumor volume in the groups was equal. The test compound is administered oral doses of 0.2; 0.5, 1.0 and 5.0 mg/kg of the test groups every day once a day for 14 days, while the control group injected with only the solvent in the same manner as the test groups. The rate of inhibition of tumor growth (TGIR) calculated as follows: speed and is generowania tumor growth (TGIR)=(1 - TX/CX) x 100, where CX represents the tumor volume on day X for the control group, when the tumor volume on the first day of introduction to be equal to 1; and t represents tumor volume for teams that enter the test connection.

The rate of inhibition of tumor growth for typical examples of compounds in this connection are shown in table 4.

Table 4
ConnectionDose, mg/kgTGIR, %
40,262
40,580
4188
27582
28559
38578

Pharmacological test example 4: measurement of antitumor activity of compound 4 with respect to the cells of human lung cancer (A549) or cancer cells of the colon of a person (LS174T) using Nude mice

Cancer cells of the colon of a person (LS174T) (obtained from American Type Culture Collection) or cells of human lung cancer (A549) (obtained from RIKEN Cell Bank) transplanted Nude mice. When tumor volume reaches approximately 150 mm3mice are grouped so that each of the group consisted of four mice and the mean tumor volume in the groups was equal. The test compound is administered orally in doses of 5 and 20 mg/kg of the test groups every day once a day for 9 days, while the control group injected with only the solvent in the same manner as the test groups. The rate of inhibition of tumor growth (TGIR) calculated as follows: rate of inhibition of tumor growth (TGIR)=(1 - TX/CX) x 100, where CX represents the tumor volume on day X for the control group, when the tumor volume on the first day of introduction to be equal to 1; and t represents tumor volume for teams that enter the test connection.

The rate of inhibition of tumor growth for typical examples of the compounds of the present invention shown in table 5.

Table 5
Cancer cellsDose, mg/kgTGIR, %
LS17565
A5492065

1. The compound represented by formula (I)or its pharmaceutically acceptable salt or MES

where X and Z each independently represents CH or N;

Y represents O;

R1, R2and R3that may be the same or different and represent the volume of hydrogen, C1-6alkoxy;

R4represents a hydrogen atom;

R5, R6, R7and R8that may be the same or different and represent a hydrogen atom, a halogen atom, a C1-4alkyl, trifluoromethyl;

R9and R10represent hydrogen atoms; and

R11is a group (i)

where Q represents O, and R22and R23that may be the same or different, represent a hydrogen atom, a C1-4alkyl;

or group (ii)

where Q represents O, S or NH, and R22and R23that may be the same or different, represent a hydrogen atom, a C1-4alkyl;

or group (iii)

where Q represents S, and R22and R23that may be the same or different and represent a hydrogen atom, a halogen atom, a C1-4alkyl, C1-4alkoxycarbonyl C1-4alkyl, C1-4alkylsulphonyl;

or group (iv)

where Q represents S, and R22represents a hydrogen atom, a C1-4alkyl, C1-4alkylthio, trifluoromethyl or3-5a cycle is a mini-alkyl.

2. The compound according to claim 1, where X represents N or CH, and Z represents CH.

3. The compound according to claim 1, which is represented by formula (Ia)

where X represents CH or N;

R15and R16that may be the same or different, represent a C1-6alkoxy;

R17, R18, R19and R20that may be the same or different, represent a hydrogen atom, a halogen atom, a C1-4alkyl or trifluoromethyl;

R21is a group (i)

where Q represents O, and R22and R23that may be the same or different, represent a hydrogen atom, a C1-4alkyl;

or group (ii):

where Q represents O, S or NH, and R22and R23that may be the same or different, represent a hydrogen atom, a C1-4alkyl;

or group (iii)

where Q represents S, and R22and R23that may be the same or different and represent a hydrogen atom, a halogen atom, a C1-4alkyl, C1-4alkoxycarbonyl C1-4alkyl, C1-4alkylsulphonyl;

or group (iv)

where Q represents S, and R22represents a hydrogen atom, a C1-4alkyl, C1-4alkylthio, trifluoromethyl or3-5cyclic alkyl.

4. The compound according to claim 3, where R15and R16represent methoxy.

5. The compound according to claim 3, where at least one of R17, R18, R19and R20represents a halogen atom.

6. The compound according to claim 3, where at least one of R17, R18, R19and R20represents a chlorine atom or a fluorine atom.

7. The compound according to claim 3, where at least one of R17, R18, R19and R20represents a C1-4alkyl.

8. The compound according to claim 3, where at least one of R17, R18, R19and R20represents trifluoromethyl.

9. The compound represented by formula (Ia)

where X represents CH or N;

R15and R16that may be the same or different, represent a C1-6alkoxy;

R17, R18, R19and R20that may be the same or different, represent a hydrogen atom or a halogen atom;

R21represents isoxazolyl substituted by one or two C1-4alkilani.

10. The connection p is 9, where R15and R16represent methoxy.

11. The connection according to claim 9, where at least one of R17, R18, R19and R20represents a halogen atom.

12. The connection according to claim 9, where at least one of R17, R18, R19and R20represents a chlorine atom or fluorine.

13. The connection according to claim 9, where R21is a group (i)

where Q represents O, and R22and R23that may be the same or different, represent a hydrogen atom, a C1-4alkyl.

14. The connection indicated in paragraph 13, where R23represents a hydrogen atom.

15. The compound according to claim 1, which is represented by formula (Ib)

where MeO represents methoxy;

X represents CH or N;

R17, R18and R19that may be the same or different, represent a hydrogen atom or a halogen atom; and

R21is a group (i)

where Q represents O, and R22and R23that may be the same or different, represent hydrogen atoms; or one of R22and R23represents a hydrogen atom and the other represents C1-4and the keel.

16. The connection indicated in paragraph 15, where X represents CH.

17. Connection P16, where R22and R23represent hydrogen atoms.

18. Connection P16, where R22and R23represent a hydrogen atom, a halogen atom, which is represented by R17, R18or R19represents a fluorine atom.

19. Connection P16, where R22and R23represent a hydrogen atom, a halogen atom, which is represented by R17, R18or R19represents a chlorine atom.

20. Connection P16, where R22represents a C1-4alkyl, and R23represents a hydrogen atom.

21. Connection P16, where R22represents a C1-4alkyl, R23represents a hydrogen atom, a halogen atom, which is represented by R17, R18or R19represents a fluorine atom.

22. Connection P16, where R22represents a C1-4alkyl, R23represents a hydrogen atom, a halogen atom, which is represented by R17, R18or R19represents a chlorine atom.

23. The connection indicated in paragraph 15, where X represents N.

24. Connection item 23, where R22represents a C1-4alkyl, and R23represents a hydrogen atom.

25. Connection item 23, where R22represents a C1-4alkyl, R23predstavljaet a hydrogen atom, and the halogen atom which is represented by R17, R18or R19represents a chlorine atom.

26. Connection PP,16, 20-25, where C1-4alkyl, representing R22and R23represents methyl.

27. The compound according to claim 1, which is a compound selected from the group consisting of the following, or its pharmaceutically acceptable salt or MES:

N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(3-isoxazolyl)urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(3-methyl-5-isoxazolyl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-forfinal}-N'-(3-isoxazolyl)urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl }-N'-(3-methyl-5-isoxazolyl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(3-methyl-5-isoxazolyl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-forfinal}-N'-(3-methyl-5-isoxazolyl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(5-methyl-3-isoxazolyl)urea;

N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea;

N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(3-methyl-5-isoxazolyl)urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea;

p num="533"> N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(3-methyl-5-isoxazolyl)urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(3-methyl-5-isoxazolyl)urea;

N-{4-[(6,7-dimethoxy-4-hintline)oxy] phenyl}-N'-(3-methyl-5-isothiazolin)urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(3-methyl-5-isothiazolin)urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(3-methyl-5-isothiazolin)urea;

N-{3-chloro-4- [(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(1H-5-pyrazolyl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy] -2-forfinal}-N'-(1H-5-pyrazolyl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(5-methyl-1,3-thiazol-2-yl)urea hydrochloride;

N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(4-methyl-1,3-thiazol-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea;

N-[4-[(6,7-dimethoxy-4-chinolin)oxy]-2-(trifluoromethyl)phenyl]-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(1,3-thiazol-2-yl)urea is hydrochlorid;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(4-methyl-1,3-thiazol-2-yl)urea hydrochloride;

Ethyl-2-{2-[({4-[(6,7-dimethoxy-4-chinolin)oxy]-2-foronline}carbonyl)amino]-1,3-thiazol-4-yl)acetate;

N-[4-(tert-butyl)-1,3-thiazol-2-yl]-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal} urea;

Ethyl-2- {2- [({2-chloro-4- [(6,7-dimethoxy-4-chinolin)oxy]aniline }carbonyl)amino]-1,3-thiazol-4-yl} acetate;

N-(5-bromo-1,3-thiazol-2-yl)-N'-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy] phenyl} urea;

N-[4-(tert-butyl)-1,3-thiazol-2-yl]-N'-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy] phenyl} urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-chloro-1,3-thiazol-2-yl)urea;

N-(5-bromo-1,3-thiazol-2-yl)N'-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal} urea;

N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy] -2-forfinal} urea;

N-(5-chloro-1,3-thiazol-2-yl)-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal} urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(1,3-thiazol-2-yl)urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-1,3-thiazol-2-yl)urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy] phenyl}-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(4-methyl-1,3-thiazol-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-hintline)is XI]phenyl}-N'-(1,3-thiazol-2-

yl)urea;

N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-1,3-thiazol-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(4-methyl-1,3-thiazol-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(4,5-dimethyl-1,3-thiazol-2-yl)urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(1,3-thiazol-2-yl)urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(5-methyl-1,3-thiazol-2-yl)urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N'-(4-methyl-1,3-thiazol-2-yl)urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N-(4,5-dimethyl-1,3-thiazol-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-forfinal}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-methyl-1,3,4-thiadiazole-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-were}-N'-(5-methyl-1,3,4-thiadiazole-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-were}-N'-(5-methyl-1,3,4-thiadiazole-2-yl)urea;

N-{4-[(6,7-dimetix the-4-chinolin)oxy]-2,3-dimetilfenil}-N'-(5-methyl-1,3,4-thiadiazole-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(5-methyl-1,3,4-thiadiazole-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-were}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-were}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-(5-ethyl-l,3,4-thiadiazole-2-yl)urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-3-forfinal}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-ethyl-1,3,4-thiadiazole-2-yl)urea;

N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-cyclopropyl-1,3,4-thiadiazole-2-yl)urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy] phenyl}-N'-(5-cyclopropyl-1,3,4-thiadiazole-2-yl)urea;

N-(5-cyclopropyl-1,3,4-thiadiazole-2-yl)-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy] -2,5-dimetilfenil} urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N'-[5 -(ethylsulfonyl)-1,3,4-thiadiazole-2-yl]urea;

N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N'-[5-(ethylsulfonyl)-1,3,4-thiadiazole-2-yl]urea;

N-{2-the ENT-4- [(6,7-dimethoxy-4-chinolin)oxy] phenyl}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]urea;

N-{3-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]urea;

N-[5-(tert-butyl)-1,3,4-thiadiazole-2-yl)-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy] -2-forfinal} urea;

N-[5-(tert-butyl)-1,3,4-thiadiazole-2-yl)-N'-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea.

28. N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea or its pharmaceutically acceptable salt or MES.

29. Pharmaceutical composition having inhibitory activity against KDR phosphorylation, comprising as active ingredient a compound according to any one of claims 1 to 28 or its pharmaceutically acceptable salt or MES.

30. The pharmaceutical composition according to clause 29, which is used for the treatment of a disease selected from the group comprising tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma.

31. The use of compounds according to any one of claims 1 to 28 or its pharmaceutically acceptable salt or MES, for the manufacture of a medicinal product for the treatment of diseases selected from the group comprising tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma.

32. The method of treatment of a disease selected from the group comprising tumor, diabetic retinopathy, chronic roar of atism, psoriasis, atherosclerosis, and Kaposi's sarcoma, comprising the administration to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 28 or its pharmaceutically acceptable salt or MES.

33. Method of inhibiting angiogenesis of blood vessels-targets, including the stage of introduction into contact with the cells of the vascular endothelium of the blood vessels of target compounds according to any one of claims 1 to 28, or its pharmaceutically acceptable salt or MES.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, chemical technology, medicine, endocrinology.

SUBSTANCE: invention relates to a method for preparing an antidiabetic agent pioglitazone of the formula (I): . Method involves condensation of 4-substituted phenol or phenolate of the general formula (II): wherein R represents organic radical comprising amino-group and chosen from group comprising group of the general formula: -NHRa (IIa) wherein Ra means hydrogen atom or protective group that is removed before the following treatment, and group of the general formula: wherein Rb represents carboxyl group as free acid or as salt or ester; M represents hydrogen atom or alkaline metal with pyridine base of the general formula (III): wherein Z means a removing group distinguishing from halogen atom and wherein the following steps are carried out: (a) diazotization reaction of amino-group as a moiety of organic radical R; (b) conversion of diazotized radical R to derivative of 2-halogenpropionate or 2-halogenpropionitrile of the formula: wherein Rb is determined above; X represents halogen atom; (c) cyclization of derivative of 2-halogenpropionate or 2-halogenpropionitrile with thiourea, and (d) hydrolysis of imine prepared. In case when R represents group of the formula (IIa) method involves firstly carrying out the condensation reaction followed by carrying out steps (a)-(d) to obtain agent of the formula (I); or in case when R represents group of the formula (IIb) then method involves firstly carrying out steps (a)-(d) followed by condensation with pyridine base of the general formula (III) to obtain agent of the formula (I). Also, invention describes compounds of the formula (V): wherein Ra represents a protective group chosen from group comprising acyl, n-alkoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-cyanoethoxycarbonyl as an intermediate substance in synthesis of compound of the formula (I).

EFFECT: improved preparing method of agent.

12 cl, 5 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, cosmetics, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means radical of the following formulae: (a) or (b) wherein R2 and R3 are similar or different and mean hydrogen atom, alkyl with 10-12 carbon atoms, aryl, radical -OR7; X means a binding fragment of the following formula: -(CH2)m-(Z)n-(CO)p-(W)q- wherein a binding fragment can be read from the left to the right or inversely; R4 means alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl; Y means radical -CH2 or sulfur atom; R5 means hydroxyl, alkoxyl with 1-6 carbon atoms, radical -NH-OH or radical -N(R8)(R9); R6 means alkyl with 1-12 carbon atoms, radical -OR10 or radical -(CH2)r-COR11; R7 means hydrogen tom or aralkyl; Z means oxygen atom or radical -NR12; W means oxygen atom, radical -NR13 or radical -CH2; m, n, p and q are similar or different and can mean 0 or 1 under condition that the sum (m + n + p + q) = 2 or above, and when p = 0 then n or q = 0; R8 means hydrogen atom; R9 means hydrogen atom or aryl; r means 0 or 1; R10 means alkyl with 1-12 carbon atoms; R11 means hydroxyl or radical -OR14; R12 means hydrogen atom or alkyl with 1-12 carbon atoms; R13 means hydrogen atom or alkyl with 1-12 carbon atoms; R14 means alkyl with 1-12 carbon atoms; and optical and geometric isomers of abovementioned compounds of the formula (I), and their salts also. These compounds are useful as activating agents of receptors of type PPAR-γ in pharmaceutical compositions designated for using in medicine, in particular, in dermatology, in treatment of cardiovascular diseases and related to immunity of diseases and/or diseases associated with lipid metabolism, and in cosmetic compositions also.

EFFECT: valuable properties of compounds and compositions.

19 cl, 1 tbl, 2 dwg, 37 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of mycophenolate mofetil. Method involves the direct esterification of mycophenolic acid and 2-morpholinoethanol. The esterification reaction is carried out by boiling in ethers medium as a solvent of the general formula R3OR4 wherein R3 and R4 mean independently alkyl. Method involves using from 1.01 to 3.0 mole equivalents of 2-morpholinoethanol. The initial temperature of reaction is in the range 130-138°C and the final temperature of reaction is in the range 140-145°C, and the reaction period is from 5 to 50 h. The ratio of mycophenolic acid to solvent is in the range from 1 g/2 ml to 1 g/5 ml. Invention avoids problems associated with coloring mycophenolate mofetil, low solubility of product in higher ethers.

EFFECT: improved method of synthesis.

8 cl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivative of phenylpiperazine mesylate of the formula: possessing preferable properties as compared with form of a free base of the same compound. Also, invention describes a pharmaceutical composition and a method for inhibition of activity of dopamine D2-receptors and site of serotonin reuptake.

EFFECT: valuable pharmacological properties of derivatives.

3 cl, 1 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine that are partial agonists of D2 receptors and can be used in treatment of the central nervous system disorders, in particular, Parkinson's disease. Invention describes derivatives of benzoxazolone of the formula (1): wherein R means group of the formula (a) or (b) , and their salts. Also, invention describes a method for preparing compounds of the formula (1), pharmaceutical composition based on compounds of the formula (1), method for treatment of Parkinson's disease and method for treatment of the central nervous system disorders, such as schizophrenia, anxiety state and depression based on compounds of the formula 91). Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: improved methods for treatment, valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 1 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means phenyl or naphthyl comprising the following substitutes: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl (-CF3), phenyl or heteroaryl representing aromatic 5-membered ring that comprises sulfur atom; each among R2, R3, R4 and R6 and independently of one another means hydrogen atom, hydroxy-group, (lower)-alkenyl, halogen atom, (lower)-alkyl or (lower)-alkoxy-group wherein at least one radical among R2, R3, R4 and R6 doesn't mean hydrogen atom, or R3 and R4 are bound and also bound with carbon atoms to which they are bound and form ring, and R3 and R4 mean in common -CH=CH-S-, -S-CH=CH-, -CH=CH-O-, -O-CH=CH-, -CH=CH-CH=CH-, -(CH2)3-5-, -O-(CH2)2-3 or -(CH2)2-3-O- wherein R2 and R6 have above given values; R5 means (lower)-alkoxy-, (lower)-alkenyloxy-group, or ; R7 means hydrogen atom or (lower)-alkyl; R8 means (lower)-alkyl; R9 means hydrogen atom; R10 means phenyl or naphthyl that can be mono- or poly-substituted with -CF3; n means 1, 2 or 3, and wherein the bond between Ca carbon atom and Cb carbon atom represents carbon-carbon single or double bond, and to their pharmaceutically acceptable salts and esters also. Indicated compounds can be used as therapeutically active substances in treatment and/or prophylaxis of diseases mediated by agonists of PPAR-α and/or PPAR-γ receptors, for example, in treatment of diabetes.

EFFECT: valuable medicinal properties of compounds.

24 cl, 167 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted glutarimides of the general formula (I): wherein X means group of the formula -(CH2)n-(CR8R9)p-Z-(CR8R)m wherein Z means sulfur (S) or oxygen (O) atom, SO- or SO2-group, residue -NR8 (optionally as N-oxide) or the group -CR8R9; m and p mean 0 or 1; n means 0, 1, 2 or 3, and m, n and p can't mean 0 simultaneously; R1 and R2 mean carboxyl, ester or acyl group and others; R3 means hydrogen atom, hydroxyl group and others; R4 means hydrogen atom, (C1-C3)-alkyl group, fluorine atom, trifluoromethyl group; R8 and R9 means hydrogen atom, benzyl, alkyl and others, and to their physiologically acceptable salts also. Compounds of the formula (I) possess immunomodulating effect and can be used in treatment of angiopathy and/or oncohematological diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

15 cl, 1 tbl, 20 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to piperidine- and piperazine-substituted N-hydroxyformamides of the general formula (I) or their pharmaceutically acceptable salts wherein B represents phenyl group monosubstituted at 3- or 4-position with halogen atom or trifluoromethyl group or bisubstituted at 3- and 4-position with halogen atom (that can be similar or distinct); or B represents 2-pyridyl or 2-pyridyloxy-group monosubstituted at 4-, 5- or 6-position with halogen atom, trifluoromethyl group, cyano-group or (C1-C4)-alkyl; or B represents 4-pyrimidinyl group possibly substituted with halogen atom or (C1-C4)-alkyl at 6-position; X represents carbon or nitrogen atom; R1 represents trimethyl-1-hydantoin-(C2-C4)-alkyl or trimethyl-3-hydantoin-(C2-C4)-alkyl group; or R1 represents phenyl or (C2-C4)-alkylphenyl monosubstituted at 3- or 4-position with halogen atom, trifluoromethyl group, thio-group, (C1-C3)-alkyl or (C1-C3)-alkoxy-group; or R1 represents phenyl-SO2NH-(C2-C4)-alkyl; or R1 represents 2-pyridyl or 2-pyridyl-(C2-C4)-alkyl; or R1 represents 3-pyridyl or 3-pyridyl-(C2-C4)-alkyl; or R1 represents 2-pyrimidine-SCH2CH2; or R1 represents 2- or 4-pyrimidinyl-(C2-C4)-alkyl possibly monosubstituted with one of the following substitutes: halogen atom, trifluoromethyl, (C1-C3)-alkyl, (C1-C3)-alkoxy-group, 2-pyrazinyl possibly substituted with halogen atom, or 2-pyrazinyl-(C2-C4)-alkyl possibly substituted with halogen atom. Also, invention describes a method for synthesis (variants) of compounds of the formula (I) and a pharmaceutical composition. Compounds can be used as inhibitors of metalloproteinases and useful in such morbidity states as inflammatory and allergic ones.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical compositions.

12 cl, 1 tbl, 10 ex

Up!