Quinoline and quinazoline derivatives

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

 

BACKGROUND of INVENTION

The scope of the invention

The present invention relates to quinoline and hinazolinam derivative with antitumor activity. More specifically, the present invention relates to quinoline and hinazolinam derived that can be used for the treatment of diseases such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma.

The level of technology

In WO 97/17329 described quinoline and hintline derivatives with antitumor activity. However, in WO 97/17329 not described the impact of these quinoline and khinazolinov derivatives on zitomers or compounds of the present invention.

SUMMARY of INVENTION

The authors of the present invention discovered that a group of quinoline and khinazolinov derivatives and antitumor activity and, at the same time, no significant effect on zitomers. Activity, leading to increased size of the cells may relate to activity, inducing tissue disorders.

The object of the present invention are compounds having antitumor activity, and, at the same time, do not have a major impact on zitomers.

In accordance with the present invention, the proposed compound is expressed by formula (I), or its pharmaceutically acceptable salt or MES:

where X and Z each represent CH or N;

R1, R2and R3that may be the same or different, represent a hydrogen atom, a C1-6alkyl, C1-6alkoxy, C2-6alkenyl,2-6quinil, nitro or amino, and C1-6alkyl, C1-6alkoxy, C2-6alkenyl and C2-6quinil optionally substituted by a halogen atom; hydroxyl; C1-4alkoxy, C1-4alkoxycarbonyl; the amino group, one or two hydrogen atoms which is optionally substituted C1-4alkyl, optionally substituted by hydroxyl or C1-4alkoxy; a group of R12R13N-C(=O)-O-, where R12and R13that may be the same or different, represent a hydrogen atom or a C1-4alkyl, and alkyl optionally substituted by hydroxyl or C1-4alkoxy; or R14-(S)m-where R14denotes a saturated or unsaturated carbocyclic or heterocyclic group having in the cycle of three to seven atoms, optionally substituted C1-4the alkyl and m is 0 or 1;

R4denotes a hydrogen atom;

R5, R6, R7and R8that may be the same or different, represent a hydrogen atom, a halogen atom, a C1-4alkyl, C1-4alkoxy, C-4 alkylthio, nitro or amino, provided that R5, R6, R7and R8do not simultaneously denote a hydrogen atom;

R9and R10that may be the same or different, represent a hydrogen atom, a C1-6alkyl or C1-4alkylsulphonyl, and the alkyl fragment data C1-6the alkyl or C1-4alkylsulphonyl optionally substituted by a halogen atom; C1-4alkoxy; amino, which is optionally substituted C1-4the alkyl, optionally substituted C1-4alkoxy; or a saturated or unsaturated carbocyclic or heterocyclic group having in the cycle of three to seven atoms; and

R11represents C1-6alkyl, C2-6alkenyl or2-6quinil (each C1-6alkyl, C2-6alkenyl and C2-6quinil optionally substituted by a halogen atom or C1-6alkoxy), or R15-(CH2)n-where n is an integer from 0 to 4, and R15denotes a saturated or unsaturated carbocyclic or heterocyclic group having in the cycle of three to seven atoms, which is optionally substituted by a halogen atom, a C1-6the alkyl or C1-6alkoxy, and optionally condensed with another saturated or unsaturated carbocyclic or heterocyclic structure having a cycle of three to seven atoms, with images is of a bicyclic structure.

Connection in accordance with the present invention can be applied, for example, for the treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma solid tumors.

DETAILED description of the INVENTION

Connection

As used here, the term "C1-6alkyl" and "C1-6alkoxy" as a group or fragment groups, respectively, denotes alkyl with straight or branched-chain alkoxy having from 1 to 6, preferably from 1 to 4 carbon atoms.

As used here, the term "C2-6alkenyl" and "C2-6quinil" as a group or fragment groups, respectively, denotes alkenyl straight or branched chain and quinil having from 2 to 6, preferably from 2 to 4 carbon atoms.

Examples of C1-6of alkyl include methyl, ethyl, n-propyl, ISO-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

Examples of C1-6alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

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

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

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

Saturated or unsaturated carbocycles the traveler or heterocyclic structure, having in a cycle of three to seven atoms, preferably represents a five-semicolony, more preferably five - or six-membered, saturated or unsaturated carbocyclic or heterocyclic structure.

Examples of saturated or unsaturated carbocyclic groups having in the cycle of three to seven atoms include phenyl, cycloheptyl, cyclohexyl and cyclopentyl.

Saturated or unsaturated heterocyclic structure having a cycle of three to seven atoms, contains at least one heteroatom selected from atoms of oxygen, nitrogen and sulfur. The term "heteroatom"as used here, denotes oxygen, nitrogen or sulfur atom. Examples of saturated or unsaturated heterocyclic groups having in the cycle of three to seven atoms include pyridyl, piperidine, piperazine, morpholine, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolidinyl and pyrazolyl.

Saturated or unsaturated heterocyclic group, which may be represented by R15and R32may be condensed with another saturated or unsaturated heterocyclic structure with the formation of the bicyclic ring. Such condensed cyclic group include naphthyl, indanyl, chinosol and hintline.

R1preferably represents a hydrogen atom.

R2and R3 preferably represent an optionally substituted C 1-6alkoxy.

C1-6alkyl, C1-6alkoxy, C2-6alkenyl and C2-6quinil, which can be represented by R1, R2and R3may be substituted by a group R14-(S)m-.

Carbocyclic or heterocyclic group, which may be represented by R14preferably denotes 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 (preferably pyridyl), containing one or two heteroatoms selected from nitrogen atoms and oxygen. More specifically, the heteroatom that is part of a six-membered heterocyclic group may be one nitrogen atom and one oxygen atom or one or two nitrogen atom.

If m is equal to 0 (zero), -(S)mrefers to the relationship.

Substituted C1-6CNS group, which may be represented by R1, R2and R3preferably represented by the group R31-(CH2)p-O-, where R31denotes a halogen atom, hydroxyl, C1- alkoxy, C1-4alkoxycarbonyl, the amino group in which one or each of the two hydrogen atoms optionally substituted C1-4alkyl, optionally substituted by hydroxyl or C1-4CNS group, the group R12R13N-C(=O)-O-, where R12and R13are as defined in formula (I), or a group R14-(S)m-where R14may be the same as defined in formula (I); p is an integer from 1 to 6, preferably from 1 to 4, more preferably p is 1 or 2, particularly preferably 1.

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

compounds in which R1denotes a hydrogen atom, and R2and R3denote C1-4CNS group, preferably metaxylene;

compounds in which R1denotes a hydrogen atom, R2denotes a substituted C1-4CNS group, preferably the group R31-(CH2)p-O-, and R3denotes unsubstituted C1-4CNS group, preferably metaxylene, and

compounds in which R1denotes a hydrogen atom, R2denotes unsubstituted C1-4CNS group, preferably metaxylene, and R3denotes a substituted C1-4CNS group, preferably the group R31-(CH2)p-O-.

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

compounds in which at least one of R5, R6, R7and R8denotes a halogen atom, preferably a chlorine atom or a fluorine atom;

compounds in which at least one of R5, R6, R7and R8represents C1-4alkyl;

compounds in which two of R5, R6, R7and R8denote methyl and the other two represent a hydrogen atom;

compounds in which at least one of R5, R6, R7and R8denote nitro, amino, C1-4alkoxy or C1-4alkylthio;

compounds in which R5, R7and R8represent a hydrogen atom, and R6denotes a halogen atom, more preferably a chlorine atom or a fluorine atom;

compounds in which R5and R6denote C1-4alkyl, more preferably methyl, and R7and R8represent a hydrogen atom;

compounds in which R5and R8represent a hydrogen atom, and R6and R7denote C1-4alkyl, more preferably methyl; and

compounds in which R5, R7and R8represent a hydrogen atom, and R6represents C1-4alkyl, C1-4alkoxy, C1-4alkylthio, nitro or amino.

In R9and R10rich is or unsaturated carbocyclic or heterocyclic group, having from three to seven atoms in the cycle, as Deputy preferably represents a saturated or unsaturated five - or six-membered carbocyclic or heterocyclic group.

R9and R10preferably denote a hydrogen atom, methyl, ethyl, propyl, methoxymethyl, formyl, acetyl, benzyl or phenethyl.

The next group of preferred compounds represented by formula (I)includes:

compounds in which R1, R9and R10represent a hydrogen atom; and

compounds in which R1denotes a hydrogen atom, and any one of R9and R10or they both represent a group other than hydrogen atom.

In the group R15-(CH2)n-that may be represented by R11n preferably represents an integer from 0 to 2, more preferably 0 or 1. Preferred examples of R15include optionally substituted saturated or unsaturated six-membered carbocyclic group, more preferably phenyl, and optionally substituted saturated or unsaturated six-membered heterocyclic group, more preferably pyridyl. Heteroatom(s), part of a six-membered heterocyclic group, particularly, may include one nitrogen atom, or one nitrogen atom and one oxygen atom.

The next group is as preferred compounds, represented by formula (I)includes compounds in which X represents N or CH, a, Z represents CH.

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

where X represents CH or N;

R21and R22that may be the same or different, represent an unsubstituted C1-6alkoxy, or the group R31-(CH2)p-O-, where R31denotes a halogen atom, hydroxyl, C1-4alkoxy, C1-4alkoxycarbonyl, the amino group in which one or two hydrogen atoms optionally substituted C1-4the alkyl, optionally substituted by hydroxyl or C1-4alkoxy group, R12R13N-C(=O)-O-, where R12and R13that may be the same or different, represent a hydrogen atom or a C1-4alkyl, and alkyl optionally substituted by hydroxyl or C1-4alkoxy, or the group R14-(S)m-where R14denotes a saturated or unsaturated carbocyclic or heterocyclic group having in the cycle of three to seven atoms, optionally substituted C1-4the alkyl and m is 0 or 1, and p is an integer from 1 to 6;

R23, R24, R25and R26that may be the same or different, pre whom represent a hydrogen atom, halogen atom, a C1-4alkyl, C1-4alkoxy, C1-4alkylthio, nitro or amino, provided that R23, R24, R25and R26simultaneously denote a hydrogen atom;

R27and R28that may be the same or different, represent a hydrogen atom, a C1-6alkyl or C1-4alkylsulphonyl, alkyl fragment data C1-6the alkyl or C1-4alkylsulphonyl optionally substituted by halogen atom; C1-4alkoxy; amino, which is optionally substituted C1-4the alkyl, optionally substituted C1-4alkoxy; or a saturated or unsaturated carbocyclic or heterocyclic group, having from three to seven atoms in the cycle; and

R29represents a C1-6alkyl, C2-6alkenyl or2-6quinil (each of these C1-6of alkyl, C2-6alkenyl or2-6the quinil optionally substituted by a halogen atom or C1-4alkoxy), or R32-(CH2)q-where q is an integer from 0 to 4, and R32represents a saturated or unsaturated six-membered carbocyclic or heterocyclic group which is optionally substituted by a halogen atom, a C1-4the alkyl or C1-4alkoxy and is optionally condensed with another saturated or unsaturated five - or six-membered ka is bollicelli or heterocyclic structure with the formation of the bicyclic structure.

R21and R22can be an unsubstituted C1-6alkoxy, preferably methoxy.

Any of R21and R22can be an unsubstituted C1-6CNS group, preferably metaxylene, and the other represents a group R31-(CH2)p-O-.

In the group R31-(CH2)p-O-, R is preferably equal to the number of from 1 to 4, more preferably 1 or 2, particularly preferably 1.

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

compounds in which at least one of R23, R24, R25and R26represents a halogen atom, preferably a chlorine atom or a fluorine atom;

compounds in which at least one of R23, R24, R25and R26represents a C1-4alkyl;

compounds in which two of R23, R24, R25and R26represent methyl and the other two represent a hydrogen atom;

compounds in which at least one of R23, R24, R25and R26represents nitro, amino, C1-4alkoxy, or C1-4alkylthio;

compounds in which R23, R25and R26represent a hydrogen atom and R24represents a halogen atom, more preferably a chlorine atom or atom f is ora;

compounds in which R23and R24represents a C1-4alkyl, more preferably methyl, and R25and R26represent a hydrogen atom;

compounds in which R23and R26represent a hydrogen atom, a R24and R25represents a C1-4alkyl, more preferably methyl; and

compounds in which R23, R25and R26represent a hydrogen atom, and R24represents a C1-4alkyl, C1-4alkoxy, C1-4alkylthio, nitro or amino.

Another group of preferred compounds represented by formula (Ia)include compounds in which R27and R28represent a hydrogen atom.

Another group of preferred compounds represented by formula (Ia)include compounds in which any one of R27and R28or both, represent a group other than hydrogen atom.

In the group R32-(CH2)q-that may be represented by R29q preferably represents an integer from 0 to 2, more preferably 0 or 1. Examples of preferred R32include optionally substituted phenyl and optionally substituted saturated or unsaturated six-membered heterocyclic group, more preferably pyridyl. Heteroatom(s)included in the composition of the pole is membered heterocyclic group, in particular, can include one nitrogen atom or one nitrogen atom and one oxygen atom. Saturated or unsaturated six-membered carbocyclic or heterocyclic group, which may be represented by R32, is preferably condensed with a saturated or unsaturated six-membered carbocyclic or heterocyclic structure with the formation of the bicyclic ring.

The next group of preferred compounds represented by formula (Ia)include:

connections

X represents CH or N, R21and R22represent unsubstituted C1-4alkoxy,

R23, R25and R26represent a hydrogen atom,

R24represents a halogen atom, a C1-4alkyl, C1-4alkoxy or nitro,

R27and R28represent a hydrogen atom, and

R29represents a C1-6alkyl, C2-6alkenyl or C2-6quinil (each of C1-6of alkyl, C2-6alkenyl and C2-6the quinil optionally substituted by a halogen atom or C1-4alkoxy), or -(CH2)q-R32where q is an integer of 0 or 1, and R32represents phenyl, pyridyl or naphthyl, and phenyl, pyridyl and naphthyl are optionally substituted by a halogen atom, a C1-4the alkyl Il is C 1-4alkoxy;

connections

X represents CH or N,

R21and R22represent unsubstituted C1-4alkoxy, R23, R25and R26represent a hydrogen atom,

R24represents a halogen atom, a C1-4alkyl, C1-4alkoxy or nitro,

any of R27and R28or both, represent a group other than hydrogen atom, and

R29represents a C1-6alkyl, C2-6alkenyl or2-6quinil (each of C1-6of alkyl, C2-6alkenyl and C2-6the quinil optionally substituted by a halogen atom or C1-4alkoxy), or -(CH2)q-R32where q is an integer of 0 or 1, and R32represents phenyl, pyridyl or naphthyl, and phenyl, pyridyl and naphthyl optionally substituted by a halogen atom, a C1-4the alkyl or C1-4alkoxy;

connections

X represents CH or N,

R21and R22represent unsubstituted C1-4alkoxy,

R23, R25and R26represent a hydrogen atom,

R24represents a halogen atom, a C1-4alkyl, C1-4alkoxy or nitro,

R27represents a hydrogen atom,

R28represents a group other than hydrogen atom, and

R29p is ecstasy a C 1-6alkyl, C2-6alkenyl or2-6quinil (each of C1-6of alkyl, C2-6alkenyl and C2-6the quinil optionally substituted by a halogen atom or C1-4alkoxy), or - (CH2)q-R32where q is an integer of 0 or 1, and R32represents phenyl, pyridyl or naphthyl, and phenyl, pyridyl and naphthyl optionally substituted by a halogen atom, a C1-4the alkyl or C1-4alkoxy;

connections

X represents CH or N,

any of R21and R22represents unsubstituted C1-4alkoxy and the other represents a group R31-(CH2)p-O-, preferably R21represents unsubstituted C1-4alkoxy, and R22represents a group R31-(CH2)p-O-,

R23, R25and R26represent a hydrogen atom,

R24represents a halogen atom, a C1-4alkyl, C1-4alkoxy or nitro,

R27and R28represent a hydrogen atom, and

R29represents a C1-6alkyl, C2-6alkenyl or2-6quinil (each of C1-6of alkyl, C2-6alkenyl and C2-6the quinil optionally substituted by a halogen atom or C1-4alkoxy), or -(CH2)q-R32where q is an integer, aunoe 0 or 1, and R32represents phenyl, pyridyl or naphthyl, and phenyl, pyridyl and naphthyl optionally substituted by a halogen atom, a C1-4the alkyl or C1-4alkoxy;

connections

X represents CH or N,

any of R21and R22represents unsubstituted C1-4alkoxy and the other represents a group R31-(CH2)p-O-, preferably R21represents unsubstituted C1-4alkoxy, and R22represents a group R31-(CH2)p-O-,

R23, R25and R26represent a hydrogen atom,

R24represents a halogen atom, a C1-4alkyl, C1-4alkoxy or nitro,

any of R27and R28represents a group other than hydrogen atom, and

R29represents a C1-6alkyl, C2-6alkenyl or2-6quinil (each of C1-6of alkyl, C2-6alkenyl and C2-6the quinil optionally substituted by a halogen atom or C1-4alkoxy), or -(CH2)q-R32where q is an integer of 0 or 1, and R32represents phenyl, pyridyl or naphthyl, and phenyl, pyridyl and naphthyl optionally substituted by a halogen atom, a C1-4the alkyl or C1-4alkoxy;

connections

X represents CH or N,

any of R21and R22represents unsubstituted C1-4alkoxy and the other represents a group R31-(CH2)p-O-, preferably R21represents unsubstituted C1-4alkoxy, and R22represents a group R31-(CH2)p-O-,

R23, R25and R26represent a hydrogen atom,

R24represents a halogen atom, a C1-4alkyl, C1-4alkoxy or nitro,

R27represents a hydrogen atom,

R28represents a group other than hydrogen atom, and

R29represents a C1-6alkyl, C2-6alkenyl or2-6quinil (each of C1-6of alkyl, C2-6alkenyl and C2-6the quinil optionally substituted by a halogen atom or C1-4alkoxy), or -(CH2)q-R32where q is an integer of 0 or 1, and R32represents phenyl, pyridyl or naphthyl, and phenyl, pyridyl and naphthyl optionally substituted by a halogen atom, a C1-4the alkyl or C1-4alkoxy;

connections

X represents CH or N,

any of R21and R22represents unsubstituted C1-4alkoxy and the other represents a group R31-(CH2)p-O-, preferably R21represents unsubstituted what th C 1-4alkoxy, and R22represents a group R31-(CH2)p-O-,

R23and R26represent a hydrogen atom,

R24and R25represents a halogen atom, a C1-4alkyl, C1-4alkoxy or nitro,

R27and R28represent a hydrogen atom, and

R29represents a C1-6alkyl, C2-6alkenyl or2-6quinil (each of C1-6of alkyl, C2-6alkenyl and C2-6the quinil optionally substituted by a halogen atom or C1-4alkoxy), or -(CH2)q-R32where q is an integer of 0 or 1, and R32represents phenyl, pyridyl or naphthyl, and phenyl, pyridyl and naphthyl optionally substituted by a halogen atom, a C1-4the alkyl or C1-4alkoxy.

Examples of preferred compounds in accordance with the present invention include compounds described in the examples 1-186.

Other examples of preferred compounds in accordance with the present invention include the following compounds:

N-{2-chloro-4-[(6,7-dimethyl-4-hintline)oxy]-phenyl}-N’-isobutylamine;

N-(4-{[7-(benzyloxy)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N’-proprotein;

N-(4-{[6-(benzyloxy)-7-methoxy-4-hintline]oxy}-2-chlorophenyl)-N’-proprotein;

N-(2-chloro-4-{[7-methoxy-6-(3-morpholinopropan-4-hintline]oxy}phenyl)-N’-proprotein;

N-[2-chloro-4-({6-methoxy-7-[2-(lH-1-imidazolyl)ethoxy]-4-hintline}oxy)phenyl]-N’-atilmotin;

N-[2-chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)ethoxy]-4-hintline}oxy)phenyl]-N’-atilmotin;

N-[2-chloro-4-({6-methoxy-7-[3-(1H-1,2,3-triazole-1-yl)-propoxy]-4-hintline}oxy)phenyl]-N’-atilmotin;

N-[2-chloro-4-({6-methoxy-7-[2-(4-methylpiperazine)-ethoxy]-4-hintline}oxy)phenyl]-N’-atilmotin;

N-(2-chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-atilmotin;

N-(2-chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-atilmotin;

N-[2-chloro-4-({6-methoxy-7-[2-(dimethylamino)-ethoxy]-4-hintline}oxy)phenyl]-N’-atilmotin;

N-[2-chloro-4-({6-methoxy-7-[2-(1H-1-imidazolyl)-ethoxy]-4-hintline}oxy)phenyl]-N’-proprotein;

N-[2-chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)ethoxy]-4-hintline}oxy)phenyl]-N’-proprotein;

N-[2-chloro-4-({6-methoxy-7-[3-(1H-1,2,3-triazole-1-yl)propoxy]-4-hintline}oxy)phenyl]-N’-proprotein;

N-(2-chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-proprotein;

N-[2-chloro-4-({6-methoxy-7-[2-(dimethylamino)ethoxy]-4-hintline}oxy)phenyl]-N’-proprotein;

N-[2-chloro-4-({6-methoxy-7-[2-(1H-1-imidazolyl)ethoxy]-4-hintline}oxy)phenyl]-N’-mutilation;

N-[2-chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)-ethoxy]-4-hintline}oxy)phenyl]-N’-mutilation;

N-[2-chloro-4-({-methoxy-7-[3-(1H-1,2,3-triazole-1-yl)-propoxy]-4-hintline}oxy)phenyl]-N’-mutilation;

N-[2-chloro-4-({6-methoxy-7-[2-(4-methyl-piperazino)ethoxy]-4-hintline}oxy)phenyl]-N’-mutilation;

N-(2-chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-mutilation;

N-(2-chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-mutilation;

N-[2-chloro-4-({6-methoxy-7-[2-(dimethylamino)ethoxy]-4-hintline}oxy)phenyl]-N’-mutilation; and

N-[2-chloro-4-({6-methoxy-7-[2-(dimethylamino)ethoxy]-4-chinolin}oxy)phenyl]-N’-proprotein.

Examples of particularly preferred compounds in accordance with the present invention include:

(13) N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N’-proprotein;

(51) N-(2-chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-chinolin]-oxy}phenyl)-N’-(2,4-differenl)

(62) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-phenyl}-N’-proprotein;

(76) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-phenyl}-N’-atilmotin;

(117) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-phenyl}-N’-metalmachine;

(119) N-(2-chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-proprotein;

(135) N-(2-chloro-4-{[6-methoxy-7-(3-piperidinyloxy)-4-hintline]oxy}phenyl)-N’-proprotein;

(142) N-(2-chloro-4-{[6-methoxy-7-(3-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-proprotein;

(143) N-(2-chloro-4-{[6-methoxy-7-(4-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-proprotein;

(144) N-(2-chloro-4-{[6-methods the si-7-(2-morpholinoethoxy)-4-chinolin]oxy}phenyl)-N’-proprotein;

(145) N-[2-chloro-4-([6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)ethoxy]-4-chinolin}oxy)phenyl]-N’-proprotein;

(146) N-[2-chloro-4-((7-[2-(1H-1-imidazolyl)ethoxy]-6-methoxy-4-chinolin]oxy)phenyl]-N’-proprotein;

(148) N-[2-chloro-4-({6-methoxy-7-[2-(4-methylpiperazine)-ethoxy]-4-chinolin}oxy)phenyl]-N’-proprotein;

(149) N-(2-chloro-4-{[7-(2-hydroxyethoxy)-6-methoxy-4-chinolin]oxy}phenyl)-N’-proprotein;

(151) N-(2-chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-chinolin]oxy}phenyl)-N’-proprotein;

(152) N-[2-chloro-4-(6-methoxy-7-{[3-(4-methylpiperazin)-propoxy]-4-chinolin}oxy)phenyl]-N’-proprotein;

(153) N-[2-chloro-4-(6-methoxy-7-{[3-(1H-1,2,3-triazole-1-yl)propoxy]-4-chinolin}oxy)phenyl]-N’-proprotein;

(157) N-{2-chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]-propoxy}-6-methoxy-4-chinolin)oxy]-phenyl}-N’-proprotein;

(159) N-{2-chloro-4-[(6-methoxy-7-{[5-(1H-1,2,3-triazole-1-yl)pentyl]oxy}-4-chinolin)oxy]phenyl}-N’-proprotein;

(160) N-[2-chloro-4-({7-[4-(1H-1-imidazolyl)butoxy]-6-methoxy-4-chinolin}oxy)phenyl]-N’-proprotein;

(162) N-(2-chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-(2,4-differenl)urea;

(163) N-(2-chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-(2,4-differenl)urea;

(164) N-[2-chloro-4-({6-methoxy-7-[3-(4-methylpiperazine)-propoxy]-4-hintline]oxy)phenyl]-N’-(2,4-differenl)-urea;

(165) N-{2-chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)is Mino]-propoxy}-6-methoxy-4-hintline)oxy]-phenyl}-N’-(2,4-differenl)urea;

(168) N-(2-chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea;

(169) N-(2-chloro-4-{[6-methoxy-7-(3-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea;

(170) N-[2-chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)ethoxy]-4-chinolin}oxy)phenyl]-N’-(2,4-differenl)urea;

(184) N-(2-chloro-4-{[6-methoxy-7-(3-piperidinyloxy)-4-hintline]oxy}phenyl)-N’-metalmachine;

(185) N-(2-chloro-4-{[6-methoxy-7-(3-piperidinyloxy)-4-hintline]oxy}phenyl)-N’-atilmotin; and

(186) N-(2-chloro-4-{[6-methoxy-7-(4-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea.

Examples of preferred compounds in accordance with the present invention include the following compounds:

(62) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-phenyl}-N’-proprotein;

(142) N-(2-chloro-4-{[6-methoxy-7-(3-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-proprotein; and

(169) N-(2-chloro-4-{[6-methoxy-7-(3-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea.

Compounds in accordance with the present invention can form pharmaceutically acceptable salts. Preferred examples of such salts include: salts of alkaline or alkaline-earth metals, such as salts of sodium, potassium or calcium; salts of halogen acids, such as hydrohloride, hydrochloride, hydrobromide or hydroiodide; salt reorgan the ical acids, such as salts of nitric acid, perchloro acid, sulfuric acid or phosphoric acid; salts of lower alkylsulfonic acids, such as salts methanesulfonic acid, triftormetilfullerenov acid or econsultancy acid; salts arylsulfonic acids, such as salts of benzosulfimide acid or p-toluensulfonate acid; organic acid salts such as salts of fumaric, succinic, citric, tartaric, oxalic, maleic, acetic, malic, lactic, or ascorbic acid; and salts formed with amino acids, such as salts of glycine, phenylalanine, glutamic acid or aspartic acid.

In addition, the compounds in accordance with the present invention may include a solvate (e.g. hydrate).

Getting connections

Compounds in accordance with the present invention can be obtained, for example, according to scheme 1 or 2.

The initial compounds required for the synthesis of compounds in accordance with the present invention may be commercially available or, alternatively, can be obtained in the usual way. For example, 4-chloridoideae derivative can be synthesized in the usual way, as described in Org. Synth. Col. Vol. 3, 272 (1955), Acta Chim. Hung., 112, 241 (1983) or WO 98/47873. 4-Chlorination derivative can be synthesized normal pic is BOM, as described in J. Am. Chem. Soc., 68, 1299 (1946) or J. Am. Chem. Soc., 68, 1305 (1946).

Alternatively, 4-chlorination derivative can be obtained by using a method which involves the following stages: (1) first, the interaction of the ester of benzoic acid with formamide with getting chineselanguage derivative (see example obtain 34), and (2) then heating the 4-chineselanguage derived using toluene or sulfolane as a solvent in the presence of phosphorus oxychloride (see examples obtain 35 and 36). Chineselanguage derivative normally synthesized in the presence of an ester of benzoic acid, sodium methoxide, formamide and a solvent such as DMF or methanol. At the stage (1) the reaction proceeds in a system where there are only the ester of benzoic acid and formaldehyde. The advantage is that the synthesis can be performed using small amounts of starting compounds. 4-Chineselanguage usually derived halogenous by heating chineselanguage derived and phosphorus oxychloride. In this case, often, due to the high reactivity of chineselanguage derived solvent causes the conversion chineselanguage derived in the initial connection and, therefore, makes it impossible for completion of the reaction. At stage (2) the reaction is completed in the presence of toluene or sulfolane and such about what atom, has the advantage from the point of view of increasing output.

Next, 4-chloridoideae derivative or a corresponding hintline derivative is subjected to interaction with NITROPHENOL in the presence of a suitable solvent or in the absence of solvent, in order to synthesize 4-(nitrophenoxy)quinoline derivative or a corresponding hintline derivative, which is then stirred in a suitable solvent, for example N,N-dimethylformamide, in the presence of a catalyst such as palladium hydroxide on coal or palladium on charcoal, in an atmosphere of hydrogen to obtain 4-(aminophenoxy)quinoline derivative or corresponding chineselanguage derived. Alternatively, 4-chloridoideae derivative or a corresponding hintline derivative can be subjected to interaction with aminophenol in the presence of a base such as a hydride nitria, to obtain the 4-(aminophenoxy)quinoline derivative or corresponding chineselanguage derived.

Alternatively, a 4-(aminophenoxy)quinoline derivative or a corresponding hintline derivative can also be obtained in the following way: the aminophenol is dissolved in aqueous sodium hydroxide solution and then the solution is subjected to two-phase interaction with solution of 4-chlorinating derivative, or with the subsequent chineselanguage derivative, in an organic solvent in the presence of a catalyst phase transfer, or in the absence of catalyst (see examples get 37 and 38). In this reaction, for example, phenol remains unreacted, and the product of the decomposition of 4-chlorination remains in the water layer, while the target product present in the organic layer. That is, the organic layer contains only the target product. Therefore, the procedure, the following processing is mostly simple. In addition, obtaining N-alkylenedioxy-hintline as a by-product can be advantageously suppressed.

Thus obtained 4-(aminophenoxy)quinoline derivative or a corresponding hintline derived can interact with the acid chloride of the acid or acid anhydride in the presence of base, followed by reduction, for example, using lithium aluminum hydride, to the introduction of the substituent in R9(stage 1A).

Alternatively, a 4-(aminophenoxy)quinoline derivative or a corresponding hintline derived can interact with the aldehyde or ketone with getting imine, followed by reduction, for example, using barcenoletta sodium, for the introduction of the substituent in R9(stage 1B).

Derived from the Deputy entered in R9/sup> interacts with isocyanate derivative (O=C=N-R11) in the usual way (stage 2), and a suitable alkylating reagent (R10Hal) interact in the presence of a base, for example, hydride nitria (stage 3), to obtain the compounds of formula (I).

Alternative, R9and R10can also be introduced by reacting a suitable alkylating agent (R9Hal, R10Hal) with a derivative of urea, where R9and/or R10represent a hydrogen atom, in the presence of a base, for example, hydride nitria (stages 5 and 7).

A derivative of urea, where R9and/or R10represent a hydrogen atom, can be obtained by the interaction of isocyanate derived from 4-(aminophenoxy)quinoline derivative or corresponding hinazolinam derivative obtained according to scheme 1, a conventional method, or by adding triphosgene to the 4-(aminophenoxy)quinoline derivative or corresponding hinazolinam derived in the presence of a base, such as triethylamine, and then the interaction of the mixture with a suitable alkylamino (R11NH2, R10R11NH) (stages 4 and 6).

Derivative having a specific substituent at the 7-position of the quinoline cycle can be obtained, for example, according to scheme 3.

Approaching the third Deputy (for example, benzyl) can interact with commercially available 4’-hydroxyacetophenone derived for the protection of the hydroxyl group and subsequent interaction with nitrious agent (for example, nitric acid, acetic acid) for the introduction of a nitro group.

Then the nitro-group can be restored to the amino group, which then reacts with the ester of formic acid in the presence of a base with the formation of quinolone cycle with subsequent interaction with gloriouse agent such as phosphorus oxychloride, to obtain 4-chlorinating derived.

Thus obtained 4-chloridoideae derived can interact with the aminophenol in the presence of a base such as a hydride nitria, to obtain the 4-(aminophenoxy)quinoline derivative.

Fragment of urea can be synthesized by reacting isocyanate derivative (O=C=N-R29with thus obtained derivative usual method, or by treating the derivative with triphosgene, and then the interaction of the aromatic amine or alkylamine (R29NH2with processed derivatives.

Next, the protective group (PG) of the hydroxyl group at the 7-position of the quinoline cycle can be removed, followed by reaction with alkylhalogenide (R22’Hal, where R22’ is alkylene the fragment, if R22represents alkoxy) in the presence of base, or with an alcohol derivative (R22’OH) conventional method, for example, by the Mitsunobu reaction, to obtain the compounds of the present invention, having CNS group in 7-position of the quinoline series.

Alkylhalogenide used in the substitution reaction may be commercially available or can be obtained according to the method described, for example, in J. Am. Chem. Soc., 1945, 67, 736.

Alcohol derivative used in the substitution reaction may be commercially available or can be obtained according to the method described, for example, in J. Antibiot. (1993), 46(1), 177 and Ann. Pharm. Fr. 1977, 35, 503.

Derivative having a specific substituent in the 6-position of the quinoline cycle, can be obtained using 3’-hydroxyacetophenone derivative as a starting compound according to the method shown in scheme 3.

Derivative having a specific substituent in the 7 position chineselanguage cycle, can be obtained by the method shown in scheme 4.

Derived ether 2-aminobenzoic acid can be obtained by esterifying derivative of 2-nitrobenzoic acid, synthesized by the method described, for example, in J. Med. Chem. 1977, 20, 146, for example, using dimethyl-sulfuric acid in the presence of a base, nab the emer potassium carbonate, and then nitrogroup reduction, for example using iron/acetic acid.

Next, the thus obtained compound interacts with formamide in the presence of a base with the formation of 4-chineselanguage cycle, with subsequent interaction with gloriouse agent such as phosphorus oxychloride, to obtain 4-chlorinating derived.

Thus obtained 4-chlorination derived interacts with aminophenol derivative in the presence of a base such as a hydride nitria, to obtain the 4-(aminophenoxy)chineselanguage derived.

Fragment of urea can be synthesized by reacting isocyanate derivative (O=C=N-R29with thus obtained derived using the traditional method or by reacting the derivative with triphosgene and then the interaction of the aromatic amine or alkylamine (R29NH2with processed derivatives.

Next, the protective group (PG) of the hydroxyl group at the 7 position chineselanguage cycle can be removed, followed by reaction with alkylhalogenide (R22’Hal, where R22’ represents an alkyl fragment, if R22represents alkoxy) in the presence of base, or with an alcohol derivative (R22’OH) using the traditional method, such as the Mitsunobu reaction, the obtaining compounds of the present invention, having CNS group in the 7 position chineselanguage cycle.

Alkylhalogenide and alcohol derivative used in the substitution reaction may be commercially available or can be obtained according to the method described in the literature, in accordance with the description of the scheme 3.

Derivative having a specific substituent in the 6 position chineselanguage cycle, can be obtained using 3-hydroxybenzaldehyde derived as parent compound, in accordance with scheme 4.

The use of compounds/pharmaceutical composition

Compounds in accordance with the present invention have inhibitory activity against the proliferation of tumors in vivo (see example pharmacological test 4).

In addition, the compounds in accordance with the present invention inhibit the in vitro activation MARK (mitogenactivated protein kinase), caused by stimulation of vascular endothelial cells under the action of VEGF (factor vascular endothelial growth) (see examples of pharmacological tests 1 and 2). Upon stimulation of endothelial cells of blood vessels under the action of VEGF MARK is activated through a system of signal transmission, after the receptor, and subsequently there is an increase in phosphorylated MARK (Abedi, H. and Zachary, I., J.Biol. Chem., 272, 15442-15451 (1997)). It is known that the activation MARK plays important is th role in the growth of endothelial cells of blood vessels in 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)). Therefore, the compounds in accordance with the present invention have inhibitory activity against angiogenesis.

Angiogenesis in pathological areas associated mainly with diseases such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma, and metastatic solid tumors (Forkman, J., Nature Med. 1: 27-31 (1995); Bicknell, R., Harris, A.L. Curr. Opin. Oncol. 8: 60-65 (1996)). Therefore, the compounds in accordance with the present invention can be used in the treatment of diseases such as tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma, and metastatic solid tumors.

Compounds in accordance with the present invention does not have a significant impact on zitomers (see pharmacological test 3). Therefore, the introduction of living organisms compounds in accordance with the present invention is largely safe.

In accordance with the present invention is provided a pharmaceutical composition comprising the compound of the present invention. The pharmaceutical composition in accordance with the present invention can be used in the treatment of diseases such as tumor, diabeticheski the retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma, and metastatic solid tumors.

In addition, in accordance with the present invention, 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 the mammals of the compounds of the present invention together with farmatsevticheskii acceptable carrier.

Compounds of the present invention can be administered to the human and animal oral or parenteral use of such routes of administration, such as intravenous, intramuscular, subcutaneous, rectal, or intradermal. Therefore, the pharmaceutical composition comprising as active ingredient a compound of the present invention are in suitable dosage forms, appropriate to the route of administration.

Namely, preparations for oral administration include tablets, capsules, powders, granules and syrups and preparations for parenteral administration include injectable solutions, suppositories, cassettes and ointments.

These various preparations can be obtained using conventional methods, for example, using traditionally used components, such as excipients, loosening means, the connecting means, nazyvausia means, dyes and thinners.

Excipients include, for example, lactose, glucose, corn starch, sorbitol and crystalline cellulose. Loosening tools 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, gum Arabic, gelatin, hydroxypropylcellulose and polyvinylpyrrolidone. Lubricants include, for example, talc, magnesium stearate, polyethylene glycol, and hydrogenated vegetable oil.

Preparation of solutions for injection, if necessary, can be added, for example, buffers, means for establishing pH, stabilizers, tonics and conservatives.

The content of compounds of the present invention in the pharmaceutical composition in accordance with the present invention may vary accordingly dosage form. Mostly, however, the content is from 0.5 to 50%, preferably from 1 to 20% by weight of the total composition.

The dose may be, respectively, determined by taking into account, for example, age, weight, gender, differences in disease and severity of condition of patients, and the drug can be introduced, for example, in quantities of 0.1 to 100 mg/kg, preferably from 1 to 5 mg/kg This dose is administered daily in one dose or divided into several doses per day.

The compound of the present invention may be introduced in combination with other drug(s) agent(s). In this case, the connection of the present invention can be administered simultaneously with the introduction of one or more other medicines, or before or after administration of other medicines. For example, if the disease is a malignant tumor, provide impact compounds of the present invention to target cells of the vascular endothelium, causing regression of the tumor, then enter cancerostatic agent for the effective elimination of the tumor. Method, frequency of injection, etc. for cancerostatic agent can be determined depending on, for example, the type of cancer and the condition of the patients. This method is correct for the treatment of diseases other than cancer.

Further, in accordance with the present invention provides a method of inhibiting angiogenesis target blood vessel, comprising a stage of bringing the compounds of the present invention in contact with the endothelial cells of the target blood vessel. Target blood vessels include blood vessels involved in the supply of tissues affected by the disease (in the example, tumor tissues, retinopathies tissue or rheumatic tissue). The compound of the present invention can be brought into contact with the endothelial cells of blood vessels, for example, in the General introduction (e.g., intravenous or oral administration), local administration (e.g., cutaneous or intra-articular injection), or target delivery of drugs using media (for example, liposomes, lipid microspheres or polymeric forms of drugs).

EXAMPLES

The present invention is hereinafter described with reference to the following examples, although it is not limited to only these examples.

Example a 1: 2-Chloro-4-[(6,7-dimethoxy-4-chinolin)-oxy]aniline

Sodium hydride (60 wt.%, 0,72 g) are added to a dimethyl sulfoxide (10 ml). The mixture was stirred at 50°C for 30 min and then cooled to room temperature. To the cooled mixture hydrochloride 4-amino-3-chlorophenol (1,61 g), and the mixture is stirred at room temperature for 10 minutes Then add 4-chloro-6,7-dimethoxyaniline (1,00 g), and the mixture was stirred at 100°With during the night. To the reaction solution was added water, and then extracted with chloroform. Then the chloroform layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. Races shall foretell removed by distillation under reduced pressure, and to the residue add methanol. The precipitated crystals are collected by filtration with suction, getting to 0.89 g (yield 60%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 4.05 (s, 3H), of 4.05 (s, 3H), 4,08 (s, 2H), 6,44 (d, J=5.4 Hz, 1H), 6,85 (d, J=8.5 Hz, 1H), 6,93-of 6.96 (m, 1H), 7,15 (d, J=2.7 Hz, 1H), 7,41 (s, 1H), 7,54 (s, 1H), 8,48 (d, J=5,1 Hz, 1H).

Example of getting a 2: 4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline

Sodium hydride (60 wt.%, 0,72 g) are added to a dimethyl sulfoxide (10 ml). The mixture was stirred at 50°C for 30 min and then cooled to room temperature. To the cooled mixture hydrochloride 4-amino-2,3-dimethylphenol (1.55 g), and the mixture is stirred at room temperature for 10 minutes Then add 4-chloro-6,7-dimethoxyaniline (1,00 g), and the mixture was stirred at 100°With during the night. To the reaction solution was added water, and then extracted with chloroform. Then the chloroform layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and to the residue is added methanol. The precipitated crystals are collected by filtration with suction, getting to 0.94 g (yield 65%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,07 (s, 3H), of 2.15 (s, 3H), 3,62 (s, 2H), of 4.05 (s, 3H), 4,07 (s, 3H), and 6.25 (d, J=5.4 Hz, 1H) 6,64 (d, J=8.5 Hz, 1H), 6,83 (d, J=8.5 Hz, 1H), 7,42 (s, 1H), to 7.64 (s, 1H), 8,42 (d, J=5.4 Hz, 1H).

Example for the preparation of 3: 4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimethylaniline

Sodium hydride (60 wt.%, 0.36 g) are added to a dimethyl sulfoxide (10 ml), the mixture was stirred at 50°C for 30 min and then cooled to room temperature. To the cooled mixture is added 4-amino-2,5-dimethylphenol (1,23 g), and the mixture is stirred at room temperature for 10 minutes Then add 4-chloro-6,7-dimethoxyaniline (1,00 g), and the mixture was stirred at 100°With during the night. To the reaction solution was added water, and then extracted with chloroform. The chloroform layer is then washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and the residue purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (1/1), receiving specified in the header of the connection.

Example 4: 3,5-Dichloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline

Sodium hydride (60 wt.%, 0.36 g) are added to a dimethyl sulfoxide (10 ml), the mixture was stirred at 50°C for 30 min and then cooled to room temperature. To the cooled mixture is added 4-amino-2,6-dichlorophenol (1,59 g), and the mixture is stirred at room temperature for 10 minutes Then add 4-chloro-6,7-dimethoxyaniline (1,g), and the mixture was stirred at 100°With during the night. To the reaction solution was added water, and then extracted with chloroform. The chloroform layer is then washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and the residue purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (1/1)to give 0.35 g (yield 22%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 3.84 (s, 2H), of 4.05 (s, 3H), 4,08 (s, 3H), 6,28 (d, J=5.4 Hz, 1H), 6,74 (s, 2H), 7,43 (s, 1H), to 7.64 (s, 1H), 8,48 (d, J=5.4 Hz, 1H).

Example of getting a 5: 4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-nitroaniline

Sodium hydride (60 wt.%, 0,54 g) are added to a dimethyl sulfoxide (15 ml), the mixture was stirred at 70°C for 30 min and then cooled to room temperature. To the cooled mixture is added 4-amino-3-NITROPHENOL (2,07 g), and the mixture is stirred at room temperature for 10 minutes Then add 4-chloro-6,7-dimethoxyaniline (1.50 g), and the mixture was stirred at 100°C for 4 h To the reaction solution was added water, and then extracted with chloroform. The chloroform layer is then washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and who headed the remainder of purify by chromatography on silica gel, elwira a mixture of chloroform/acetone (1/1), receiving of 0.53 g (yield 23%) specified in the connection header.

Example of getting 6: 1-[2-Amino-4-(benzyloxy)-5-methoxyphenyl]-1-alanon

1-(4-Hydroxy-3-methoxyphenyl)-1-Etalon (20 g), potassium carbonate (18.3 g), iodide, Tetra-n-butylamine (4,45 g) and benzylbromide (17.3 ml) dissolved in N,N-dimethylformamide (300 ml)and the reaction allowed to proceed at 100°C for one hour. The solvent is removed by distillation under reduced pressure, to the residue water is added, then extracted with ethyl acetate. An ethyl acetate layer is dried over sodium sulfate. Then the solvent is removed by distillation under reduced pressure. Balance and fuming nitric acid (12,47 ml) dissolved in acetic acid (120 ml)and the reaction left to proceed at room temperature for 2 hours the Reaction solution is neutralized at 0°by adding an aqueous solution of sodium hydroxide, then extracted with chloroform. The chloroform layer is dried over sodium sulfate. Then the solvent is removed by distillation under reduced pressure. The residue is dissolved in ethanol (1160 ml) and water (120 ml) under heating. Add ammonium chloride (19.2 g) and zinc (101,7 g). The mixture is heated under reflux for 3 hours, the Reaction solution is filtered through Celite, then washed with a mixture of chloroform/methanol (3/1). The solvent UD is given by distillation under reduced pressure, the residue is alkalinized with an aqueous solution of sodium hydroxide, and the alkaline solution extracted with chloroform. The chloroform layer is dried over sodium sulfate. The solvent is removed by distillation under reduced pressure, and the residue purified by chromatography on silica gel, elwira a mixture of chloroform/ethyl acetate (10/1)to give 24,95 g (yield 77%) specified in the connection header (stage 3).

1H NMR (Dl3, 400 MHz): δ of 2.51 (s, 3H), of 3.84 (s, 3H), 5,14 (s, 2H), 6,12 (s, 2H), 7,15 to 7.62 (m, 7H).

An example of obtaining 7: 7-(Benzyloxy)-6-methoxy-1,4-dihydro-4-chinoline

1-[2-Amino-4-(benzyloxy)-5-methoxyphenyl]-1-Etalon (24,95 g) dissolved in tetrahydrofuran (450 ml) and to the solution add sodium methoxide (24,87 g). The mixture is stirred at room temperature for one hour. Then add ethyl formate (37,07 ml), and the mixture is stirred at room temperature for 2 hours Then add water (150 ml), and the mixture is stirred over night. the pH of the reaction solution is adjusted to 4 by adding concentrated sulfuric acid at 0°C. water is Added and the mixture extracted with chloroform. The chloroform layer is dried over sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (10/1), receiving 17,16 g (yield 66%) specified in the agolove connection.

1H NMR (DMSO-d6, 400 MHz): δ of 3.84 (s, 3H), 5,19 (s, 2H), 5,97 (d, J=7,1 Hz, 1H), to 7.09 (s, 1H), 7,28-7,51 (m, 6N), 7,78 (d, J=7,3 Hz, 1H), 11,50-11,75 (W, 1H).

An example of obtaining 8: 7-(Benzyloxy)-4-chloro-6-methoxyquinoline

The phosphorus oxychloride (14,19 ml) are added to 7-(benzyloxy)-6-methoxy-1,4-dihydro-4-chinoline (17,16 g)and the mixture heated under reflux for one hour. The solvent is removed by distillation under reduced pressure. The residue is dissolved in chloroform, and the solution is alkalinized by adding an aqueous solution of sodium hydroxide, then extracted with chloroform. The chloroform layer is dried over sodium sulfate. The solvent is removed by distillation under reduced pressure, and the residue purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (10/1), receiving 3,82 g (yield 21%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 4,06 (s, 3H), 5,32 (s, 2H), 7,30-of 7.55 (m, 8H), 8,56 (d, J=4.9 Hz, 1H).

An example of obtaining 9: 4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,5-dimethylaniline

Sodium hydride (60 wt.%, 1,17 g) are added to a dimethylsulfoxide (25 ml), the mixture was stirred at 60°C for 30 min and then cooled to room temperature. Then add 4-amino-2,5-dimethylphenol (4,00 g), and the mixture is stirred at room temperature for 10 minutes then add 7-(benzyloxy)-4-chloro-6-metoxy the Olin (4,36 g). The mixture is stirred for 22 h, after which the reaction solution was added water, and then extracted with chloroform. The chloroform layer is then washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and to the residue add methanol to obtain a suspension. The precipitated crystals are collected by filtration with suction, getting 3.04 from g (yield 52%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ was 2.05 (s, 3H), of 2.16 (s, 3H), to 3.58 (s, 2H), 4,06 (s, 3H), 5,32 (s, 2H), 6,28 (d, J=5,1 Hz, 1H), is 6.61 (s, 1H), for 6.81 (s, 1H), 7,28-7,42 (m, 3H), 7,44 (s, 1H), 7,49-rate of 7.54 (m, 2H), 7,63 (s, 1H), 8,39 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 401 (M++1).

Example 10: N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,5-dimetilfenil)-N’-(2,4-differenl)urea

4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,5-dimethylaniline (300 mg) dissolved in chloroform (5 ml). To the solution were then added 2,4-differentiational (200 μl)and the mixture stirred at 70°With during the night. The reaction solution is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (75/25)to give 368 mg (yield 88%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,17 (s, 3H), and 2.26 (s, 3H), 4,06 (s, 3H), 5,33 (s, 2H), 6,29 (d, J=5,1 Hz, 1H), 6.42 per (s, 1H), 6,766,93 (m, 3H), 6,70 (s, 3H), 7,30-rate of 7.54 (m, 7H), 7,60 (s, 1H), 8,04-to 8.12 (m, 1H), 8,44 (d, J=5, 4 Hz, 1H).

An example of obtaining 11: N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,5-dimetilfenil)-N’-(2-methoxyphenyl)-urea

4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,5-dimethylaniline (300 mg) dissolved in chloroform (5 ml). Then to the solution was added 2-methoxyphenylalanine (0,24 ml)and the mixture stirred at 70°With during the night. The reaction solution is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (75/25)to give 365 mg (yield 89%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,17 (s, 3H), of 2.28 (s, 3H), 3,83 (s, 3H), 4,07 (s, 3H), 5,33 (s, 2H), 6,26 (s, 3H), of 6.29 (d, J=5.4 Hz, 1H), 6,86-7,06 (m, 4H), 7,12 (s, 1H), 7,30-7,41 (m, 3H), 7,46 (s, 1H), 7,50-7,56 (m, 3H), to 7.61 (s, 1H), 8,11-8,16 (m, 1H), 8,43 (d, J=5.4 Hz, 1H).

Example 12: 4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2-Chloroaniline

Sodium hydride (60 wt.%, 320 mg) are added to a dimethylsulfoxide (3.6 ml), the mixture was stirred at 60°C for 30 min and then cooled to room temperature. Next, add the hydrochloride 4-amino-3-chlorophenol (720 mg), and the mixture is stirred at room temperature for 10 minutes Then add 7-(benzyloxy)-4-chloro-6-methoxyquinoline (600 mg), and the mixture was stirred at 105°C for 22 h To the reaction solution was added water, and then extracted with chloroform. The chloroform layer is then washed the Ute saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and to the residue add methanol to obtain a suspension. The precipitated crystals are collected by filtration with suction, getting 533 mg (yield 66%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 4.05 (s, 3H), 4,08 (s, 2H), 5,32 (s, 2H), 6.42 per (d, J=5,1 Hz, 1H), at 6.84 (d, J=8.5 Hz, 1H), 6,93 (DD, J=2,4 Hz and 8.1 Hz, 1H), 7,14 (d, J=2.4 Hz, 1H), 7,29-7,42 (m, 3H), 7,44 (s, 1H), 7,49-7,53 (m, 2H), 7,55 (s, 1H), 8,45 (d, J=5.3 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 497 (M++1).

An example of obtaining 13: N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2-chlorophenyl)-N’-(2,4-differenl)-urea

4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2-Chloroaniline (260 mg) was dissolved in chloroform (10 ml). Then to the solution was added 2,4-differentiational (198 mg), and the mixture is stirred at room temperature for 2 hours the Reaction solution is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (10/1)to give 337 mg (yield 94%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ Android 4.04 (s, 3H), 5,32 (s, 2H), of 6.49 (d, J=5,1 Hz, 1H), 6,86-of 6.96 (m, 3H), 7,10-7,17 (m, 2H), 7,22-7,28 (m, 1H), 7,28-7,41 (m, 3H), 7,45-7,53 (m, 4H), of 7.96-of 8.04 (m, 1H), 8,27 (d, J=9.0 Hz, 1H), 8,49 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 562, 564 (M++1).

An example of obtaining 14: N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-(2,4-differenl)-mo is evina

N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2-chlorophenyl)-N’-(2,4-differenl)urea (215 mg) was dissolved in dimethylformamide (11 ml). To the solution was added palladium on coal (215 mg), and the mixture is stirred in hydrogen atmosphere at room temperature overnight. To the reaction solution was added ethyl acetate (30 ml)and the mixture is then filtered through Celite. The solvent is removed by distillation under reduced pressure, receiving 174 mg (yield 96%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 3.94 (s, 3H), 6,47 (d, J=5,1 Hz, 1H), 7,01-7,11 (m, 1H), 7,18 and 7.36 (m, 3H), 7,44-7,52 (m, 2H), 7,95 (s, 1H), 7,98-8,13 (m, 1H), 8,23 (d, J=9.5 Hz, 1H), 6,50 (d, J=5,1 Hz, 1H), 8,81 (s, 1H), 9,31 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 472 (M++1).

An example of obtaining 15: 4-([7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,3-dimethylaniline

Sodium hydride (60 wt.%, 0.32 g) are added to a dimethylsulfoxide (6 ml), and the mixture is stirred at room temperature for 30 minutes Then add 4-amino-2,3-dimethylphenol (1.10 g), and the mixture is stirred at room temperature for 10 minutes Then add 7-(benzyloxy)-4-chloro-6-methoxyquinoline (1.20 g)and the mixture stirred at 110°C for 6 hours To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, then extracted with chloroform. The chloroform layer is dried over anhydrous magnesium sulfate. Dissolve the spruce is removed by distillation under reduced pressure, and the residue purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (6/1), getting to 0.78 g (yield 49%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 1.87 (s, 3H), a 1.96 (s, 3H), of 3.97 (s, 3H), 4,78 (s, 2H), 5,23 (s, 2H), 6,12 (d, J=5.3 Hz, 1H), is 6.54 (d, J=8,4 Hz, 1H), 6,69 (d, J=8,4 Hz, 1H), 7,27-7,51 (m, 7H), 8,31 (d, J=5.3 Hz, 1H).

Example 16: N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,3-dimetilfenil)-N’-(2,4-differenl)urea

4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,3-dimethylaniline (260 mg) was dissolved in N,N-dimethylformamide (5 ml). Then to the solution was added 2,4-differentiational (121 mg), and the reaction is left to proceed at room temperature overnight. To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is washed with methanol and collected by filtration, getting 219 mg (yield 61%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 1,99 (s, 3H), 2,17 (s, 3H), 3,90 (s, 3H), of 5.24 (s, 2H), 6,18 (d, J=5,1 Hz, 1H), 6,95-6,98 (m, 2H), 7,25-7,63 (m, N), 8,05-8,08 (m, 1H), 8.34 per-at 8.36 (m, 2H), 8,79 (s, 1H).

Example of getting a 17: 7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline

7-(Benzyloxy)-4-chloro-6-methoxyquinoline (300 mg) and 3-fluoro-4-NITROPHENOL (785 mg) dissolved in chlorobenzene (3 ml) and the solution stirred at 130°C for 5 hours To the reaction solution was added chloroform, the aqueous solution of sodium hydroxide, and the mixture is stirred for one hour. The reaction solution is extracted with chloroform, and the chloroform layer is dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (1/1)to give 197 mg (yield 47%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ a 3.83 (s, 3H), of 5.25 (s, 2H), 6,91 (d, J=5,1 Hz, 1H), 7.29 trend is 7.50 (m, N), 8,18-8,23 (m, 1H), 8,56 (d, J=5,1 Hz, 1H).

An example of obtaining 18: 4-(4-Amino-3-pertenece)-6-methoxy-7-hinolinol

7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline (190 mg) was dissolved in N,N-dimethylformamide (5 ml) and triethylamine (1 ml). To the solution was added palladium hydroxide (40 mg), and the mixture is stirred in hydrogen atmosphere at room temperature overnight. The solvent is removed by distillation under reduced pressure. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of chloroform/methanol (20/1)to give 75 mg (yield 56%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ a 3.87 (s, 3H), 5,11 (s, 2H), 6,29 (d, J=5,1 Hz, 1H), 6,77-to 6.80 (m, 2H), 6,93-6,99 (m, 1H), 7,19 (s, 1H), 7,40 (s, 1H), 8,31 (d, J=5,1 Hz, 1H), there is a 10.03 (s, 1H).

An example of obtaining 19: N-(2,4-Differenl)-N’-{2-fluoro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-urea

4-(4-Amino-3-perfe is hydroxy)-6-methoxy-7-hinolinol (70 mg) was dissolved in chloroform (1.5 ml) and N,N-dimethylformamide (1 ml). Then to the solution was added 2,4-differentiational (43 mg), and the reaction is left to proceed at room temperature for 3 hours To the reaction solution was added methanol. The solvent is removed by distillation under reduced pressure. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of chloroform/methanol (20/1), receiving with a quantitative yield specified in the header of the connection.

1H NMR (DMSO-d6, 400 MHz): δ of 3.94 (s, 3H), 6,47 (d, J=5,1 Hz, 1H),? 7.04 baby mortality-7,10 (m, 2H), 7,28-7,34 (m, 2H), 7,47 (s, 1H), 8,05-of 8.15 (m, 2H), 8,30 (s, 1H), 8,43 (d, J=5,1 Hz, 1H), 8,97-9,03 (m, 2H), 10,10 (s, 1H).

An example of obtaining 20: 4-Chloro-6-methoxy-7-hinolinol

7-(Benzyloxy)-4-chloro-6-methoxyaniline (100 mg), thioanisole (300 μl) and methanesulfonyl acid (25 μl) dissolved in triftormetilfullerenov acid (1 ml). The solution was stirred at room temperature for 30 minutes the Solvent is removed by distillation under reduced pressure. The residue is neutralized by adding an aqueous solution of sodium hydroxide and add hexane to obtain a suspension. The crystals are collected by filtration with suction, receiving 53 mg (yield 75%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,98 (s, 3H), 7,33 (s, 1H), was 7.36 (s, 1H), 7,47 (d, J=4.9 Hz, 1H), 8,54 (d, J=4.9 Hz, 1H), 10,37 (W, 1H).

An example of obtaining 21: 4-Chloro-6-methoxy-7-(2-methoxy-ethoxy)quinoline

4-the ENT-6-methoxy-7-hinolinol (50 mg), potassium carbonate (40 mg), iodide, Tetra-n-butylamine (9 mg), and 2-bromatology ester (40 mg) dissolved in N,N-dimethylformamide (10 ml). The solution was stirred at 70°With during the night. The solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, then extracted with chloroform. The chloroform layer is dried over sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of hexane/acetone/dichloromethane (6/2/1)to give 47 mg (yield 74%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 3.49 (s, 3H), 3,88-3,90 (m, 2H), Android 4.04 (s, 3H), 4,32 is 4.35 (m, 2H), 7,35 (d, J=4.9 Hz, 1H), 7,40 (s, 1H), 7,43 (s, 1H), to 8.57 (d, J=4.9 Hz, 1H).

An example of obtaining 22: 2-Chloro-4-{[(6-methoxy-7-(2-methoxyethoxy)-4-chinolin]oxy}aniline

Sodium hydride (60 wt.%, 153 mg) are added to a dimethyl sulfoxide (2 ml). The mixture was stirred at 60°C for 30 min and then cooled to room temperature. Add hydrochloride 4-amino-3-chlorophenol (343 mg), and the mixture is stirred at room temperature for 10 minutes Then, to the reaction solution was added a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline (254 mg) in dimethyl sulfoxide (2 ml)and the mixture stirred at 110°With during the night. To the reaction solution we use the t water then extracted with chloroform. The chloroform layer is then washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (7/3), receiving specified in the header of the connection.

1H NMR (Dl3, 400 MHz): δ to 3.49 (s, 3H), 3,89-3,91 (m, 2H), was 4.02 (s, 3H), 4.09 to (s, 2H), 4,33 is 4.35 (m, 2H), to 6.43 (d, J=5.4 Hz, 1H), 6,85 (d, J=8.5 Hz, 1H), 6,93-of 6.96 (m, 1H), 7,15 (d, J=2.7 Hz, 1H), 7,41 (s, 1H), 7,52 (s, 1H), of 8.47 (d, J=5,1 Hz, 1H).

An example of retrieving 23: 2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]aniline

Sodium hydride (60 wt.%, 5,80 g) are added to a dimethylsulfoxide (40 ml). The mixture was stirred at 60°C for 30 min and then cooled to room temperature. Next, add the hydrochloride 4-amino-3-chlorophenol (of 13.05 g). The mixture is stirred at room temperature for 10 minutes Then add 4-chloro-6,7-dimethoxyquinazolin (8,14 g), which is chlorination derivative, synthesized by conventional method as described, for example, in J. Am. Chem. Soc., 68, 1299 (1946) or J. Am. Chem. Soc., 68, 1305 (1946). The mixture was stirred at 110°C for 30 min. Then the reaction solution was added water, and then extracted with chloroform. The chloroform layer is then washed with saturated aqueous what astora of sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and to the residue add methanol to obtain a suspension. The precipitated crystals are collected by filtration with suction, getting 9,13 g (yield 76%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 4,05-4,08 (m, 8H), 6,85 (d, J=8.5 Hz, 1H), 7,00 (DD, J=2.7 Hz, 8,8 Hz, 1H), 7,21 (d, J=2.7 Hz, 1H), 7,32 (s, 1H), 7,52 (s, 1H), 8,64 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 332 (M++1).

Example completion of 24: N-Benzyl-N-(2,4-differenl)Amin

Magnesium sulfate (5,59 g) and a minor amount of acetic acid are added to a solution of 2,4-diferencia (2.37 ml) and benzaldehyde (2,36 ml) in methanol (46 ml). The mixture is stirred at room temperature for 45 minutes Add sodium borohydride (2.64 g) under cooling on ice, and the mixture is stirred at room temperature for one hour. The solvent is removed by distillation under reduced pressure. To the residue is added water and ethyl acetate. The mixture is stirred and filtered through Celite. The organic layer is extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of hexane/acetone (30/1), receiving 3.04 from g (yield 60%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ ,34 (, 2H), 6,56-PC 6.82 (m, 3H), 7,25-7,38 (m, 5H).

An example of obtaining 25: Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate

Commercially available methylphenidat (50 g) and potassium carbonate (76 g) was dissolved in N,N-dimethylformamide (200 ml). To the solution is added dropwise benzyl bromide (33 ml) for 10 minutes the Mixture is stirred at room temperature overnight. Add water (200 ml), then extracted with ethyl acetate. Then to the organic layer, add a saturated saline solution, and the mixture is extracted with ethyl acetate. To the organic layer for drying add sodium sulfate. Next, the organic layer was filtered, and the solvent then removed by distillation under reduced pressure. The residue is dried using a vacuum pump, receiving 68 g of solid white. Then when cooled on ice was added 100 ml of acetic acid and 200 ml of nitric acid. The mixture is stirred for 8 h, after which water is added. The obtained solid is then collected by filtration, thoroughly washed with water and dried using a vacuum pump, receiving 74 g (yield 93%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ are 3.90 (s, 3H), 3,98 (s, 3H), to 5.21 (s, 2H), was 7.08 (s, 1H), 7,31 was 7.45 (m, 5H), 7,51 (s, 1H).

An example of obtaining 26: 7-(Benzyloxy)-6-methoxy-3,4-dihydro-4-hintline

Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (15.0 g) is dissolved is in acetic acid (200 ml) at room temperature. Then to the solution was added iron (powder) (13,2 g). The temperature of the mixture was raised to 90°S, and then the mixture is stirred for one hour. The obtained gray solid is filtered through Celite, then washed with acetic acid. To the mother liquor, add concentrated hydrochloric acid. Then the solvent is removed by distillation under reduced pressure. This leads to the precipitation of solids. The solid is collected by filtration, washed with ethyl acetate and simple ether and dried using a vacuum pump. Then to solid substance to obtain a suspension add chloroform and methanol, and then add 10% aqueous sodium hydroxide solution to dissolve the solids and extracted with chloroform. After washing with water, the organic layer dried over sodium sulfate. Next, the organic layer was filtered, and the solvent then removed by distillation under reduced pressure. The residue is dried using a vacuum pump, receiving 9.5 g (yield 70%) of the crude product of methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate. Methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (650 mg) was dissolved in N,N-dimethylformamide (15 ml) and methanol (3 ml). To the solution add formamid ones (0.46 ml) and sodium methoxide (373 mg). The mixture is heated to 100°C and stirred overnight. The reaction solution is cooled to room is temperature, to the cooled reaction solution was then added 10 ml of water. The reaction solution is neutralized 1 M aqueous solution of hydrochloric acid to precipitate solids. The solid is collected by filtration, washed with water and simple ether and then dried using a vacuum pump, getting 566 mg (yield 87%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,88 (s, 3H), of 5.25 (s, 2H), 7.23 percent (s, 1H), 7,33-7,49 (m, 6N), of 7.97 (s, 1H), 12,06 (W, 1H).

Example of getting a 27: 7-(Benzyloxy)-4-chloro-6-methoxy-hinzelin

The phosphorus oxychloride (515 ml) are added to 7-(benzyloxy)-6-methoxy-3,4-dihydro-4-hintline (400 mg) and diisopropylethylamine (0.3 ml)and the mixture heated under reflux for 20 minutes, the Reaction solution is cooled to room temperature. To the reaction solution were then added 10% aqueous sodium hydroxide solution, then extracted with chloroform. The organic layer is dried over sodium sulfate. The organic layer was filtered, and the solvent then removed by distillation under reduced pressure. The residue is dried using a vacuum pump, receiving 420 mg (yield 99%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 4,08 (s, 3H), of 5.34 (s, 2H), 7,35-7,51 (m, 7H), 8,86 (s, 1H).

An example of retrieving 28: Methyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate

Commercially available methyl 3-g is droxy-4-methoxybenzoate (10 g) and potassium carbonate (23 g) was dissolved in N,N-dimethylformamide (50 ml). To the solution is added dropwise benzylbromide (6.5 ml) for 10 minutes the Mixture is stirred at room temperature overnight. Add water (200 ml), extracted with ethyl acetate. Then to the organic layer, add a saturated saline solution, and then extracted with ethyl acetate. To the organic layer for drying add sodium sulfate. Next, the organic layer was filtered, and the solvent then removed by distillation under reduced pressure. The residue is dried using a vacuum pump, receiving of 8.4 g of solid white. Then 7.0 g of a solid substance is placed in a flask, and cooled on ice was added 100 ml of acetic acid and 200 ml of nitric acid. The mixture is stirred for 8 h, and then water is added. The obtained solid is collected by filtration, thoroughly washed with water and dried using a vacuum pump, receiving 7.9 g (yield 96%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ the 3.89 (s, 3H), of 3.96 (s, 3H), to 5.21 (s, 2H), 7,15 (s, 1H), 7,34 was 7.45 (m, 6N).

An example of obtaining 29: 6-(Benzyloxy)-7-methoxy-3,4-dihydro-4-hintline

Methyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate (15,8 g) dissolved in acetic acid (200 ml) at room temperature. Then to the solution was added iron (powder) (13,9 g). The mixture is heated to 90°C and stirred for one hour. The obtained gray is the solid is filtered through Celite and washed with acetic acid. Concentrated hydrochloric acid is added to the mother liquor, and the solvent then removed by distillation under reduced pressure to precipitate solids. The solid is collected by filtration, washed with ethyl acetate and ether and dried using a vacuum pump. Then, to obtain a suspension of solid matter added chloroform and methanol, and then to the suspension to dissolve the solids, add 10% aqueous sodium hydroxide solution, then extracted with chloroform. The extract is washed with water and the organic layer is then dried over sodium sulfate. Next, the organic layer was filtered, and the solvent then removed by distillation under reduced pressure. The residue is dried using a vacuum pump, receiving 10.4 g (yield 73%) of the crude product of methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate. Methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate (5.0 g) is dissolved in N,N-dimethylformamide (150 ml) and methanol (30 ml). To the solution add formamide (3.5 ml) and sodium methoxide (2.8 g). The mixture is heated to 100°and then stirred overnight. The reaction solution was then cooled to room temperature and add 10 ml of water. The reaction solution is neutralized 1 M aqueous solution of hydrochloric acid to precipitate solids. The solid is collected by filtration, washed with water and e is Il and then dried using a vacuum pump, getting 3.7 g (yield 76%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 3.92 (s, 3H), to 5.21 (s, 2H), 7,16 (s, 1H), 7,33-7,49 (m, 5H), 7,55 (s, 1H), to 7.99 (s, 1H), 12,06 (W, 1H).

Example 30: 6-(Benzyloxy)-4-chloro-7-methoxyquinazoline

The phosphorus oxychloride (3.1 ml) are added to 6-(benzyloxy)-7-methoxy-3,4-dihydro-4-hintline (3.5 g) and diisopropylethylamine (11.5 ml). The mixture is heated under reflux for 20 minutes, the Reaction solution is cooled to room temperature and then cooled to the reaction solution was added 10% aqueous sodium hydroxide solution, then extracted with chloroform. The organic layer is dried over sodium sulfate. The organic layer was filtered, and the solvent then removed by distillation under reduced pressure. The residue is dried using a vacuum pump, receiving 2.9 g (yield 72%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 4,07 (s, 3H), 5,32 (s, 2H), 7,35-7,53 (m, 7H), 8,86 (s, 1H).

An example of retrieving 31: 4-{[7-(Benzyloxy)-6-methoxy-4-hintline]oxy}-2-Chloroaniline

7-(Benzyloxy)-4-chloro-6-methoxyquinazoline (30.0 g) and tetramethyllead ammonium (13,9 g) dissolved in acetone (400 ml) and the solution stirred at room temperature. Add a solution of the hydrochloride of 4-amino-3-chlorophenol (36,0 g) in 20% aqueous sodium hydroxide solution (64 ml). The mixture was then heated to reverse the fridge for 3 hours The reaction solution is cooled to room temperature, and the cooled reaction solution was added chloroform and water, and then extracted with chloroform. The extract was washed with saturated aqueous sodium bicarbonate and saturated saline and then dried over anhydrous sodium sulfate. Next, the sodium sulfate is removed, and the solvent then removed by distillation. The residue is washed with methanol, and the washed solid is subjected to evaporation to dryness in a vacuum using a vacuum pump, receiving 36,6 g (yield 90%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 3.96 (s, 3H), of 5.34 (s, 2H), 6,86 (d, J=8,8 Hz, 1H), 7,00 (DD, J=2.7 Hz, 8,8 Hz, 1H), 7,22 (d, J=2.7 Hz, 1H), 7,35-rate of 7.54 (m, 7H), 8,53 (s, 1H).

An example of obtaining 32: N-(4-{[7-(Benzyloxy)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N’-proprotein

4-{[7-(Benzyloxy)-6-methoxy-4-hintline]oxy}-2-Chloroaniline (12.2 g) was dissolved in anhydrous chloroform. Then to the solution is added triethylamine (8,4 ml), and the mixture is stirred at room temperature. Separately triphosgene (4.5 g) is dissolved in anhydrous chloroform (12 ml)and the solution added dropwise to the solution with stirring. The mixture is stirred at room temperature for 20 min, then added n-Propylamine (4,9 ml), then stirred at room temperature for another one hour to DL the deposition of solids in white. This solid is collected by filtration and then washed with chloroform, receiving 9.4 g (yield 63%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.91 (t, J=7,3 Hz, 3H), 1,44 of 1.50 (m, 2H), 3,06-to 3.09 (m, 2H), 3,98 (s, 3H), to 5.35 (s, 2H), 6,97-7,01 (m, 1H), 7.23 percent (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,37-EUR 7.57 (m, N), to 8.20 (d, J=9,3 Hz, 1H), 8,55 (s, 1H).

An example of obtaining 33: N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N’-proprotein

N-(4-{[7-(Benzyloxy)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N’-populatemenu (42.2 g) is dissolved in triperoxonane acid (200 ml). Methansulfonate acid (11,1 ml) then the solution is added, and the mixture was stirred at 100°C for 4 h, the Reaction solution is cooled to room temperature, and triperoxonane acid is removed by distillation under reduced pressure. Chloroform and methanol added to the mixture in the form of residue, and then extracted with 10% aqueous sodium hydroxide solution three times. The aqueous layer was neutralized with concentrated hydrochloric acid to precipitate solids. The solid is washed with water, methanol and ether in this order and then dried in a vacuum using a vacuum pump, receiving 20.7 g (yield 60%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.91 (t, J=7,3 Hz, 3H), 1,42-1,49 (m, 2H), 3,06-3,17 (m, 2H), of 3.84 (s, 3H), of 6.65 (s, 1H), 7,03 (m, 1H), 7,14 (DD, J=2.7 Hz, 9.0 Hz, 1H), then 7.20 (s, 1H), 7,35 (d, J=2.7 Hz, 1H), with 8.05 (s, 1H), 8,14 (DD, J=2.7 Hz, 8,8 Hz, 1H), 8,19 (s, 1H).

An example of retrieving 34: 6,7-Dimethoxy-4-gynazole

Formamide (150 ml) is added to methyl 2-amino-3,4-dimethoxybenzoate (20,0 g, or 94.8 mmol). The mixture is heated at 160°for 8.5 hours, the Reaction solution is cooled and then filtered. The collected precipitate was washed with water (100 ml × 2 times), and the washed precipitate is dried in vacuum, obtaining 17,85 g (yield of 91.5%) of target compound.

1H NMR (DMSO-d6, 400 MHz): δ to 4.01 (s, 3H), was 4.02 (s, 3H), 7,14 (s, 1H), 7,34 (s, 1H), to 7.61 (s, 1H), of 7.97 (s, 1H).

An example of obtaining 35: 4-Chloro-6,1-dimethoxyquinazolin

Sulfolan (250 ml) and phosphorus oxychloride (250 ml=412,5 g, 2,69 mol) are added to 6,7-dimethoxy-4-hinatasou (50,1 g, 0.24 mol)and the mixture stirred at 120°C for one hour. The reaction mixture is cooled to room temperature, and the excess phosphorus oxychloride is then removed by distillation under reduced pressure. The residue is poured into ice water (1000 ml) and add chloroform (1000 ml). the pH of the aqueous layer was adjusted to 6.5 by adding 20% sodium hydroxide solution, and then separating the organic layer from the aqueous layer. The separated organic layer washed with water (1000 ml × six times), dried over sodium sulfate and then concentrated under reduced pressure. To the residue add tetrahydrofuran (470 ml)and the mixture heated under reflux. auktsionnyi the solution is cooled to a temperature of from -5° C to -10°C, filtered and dried, obtaining a 38.5 g (71.4%) of the target product.

1H NMR (DMSO-d6, 400 MHz): δ 4.09 to (s, 3H), 4.09 to (s, 3H), 7,14 (s, 1H), 7,34 (s, 1H), to 7.61 (s, 1H), of 7.97 (s, 1H).

An example of retrieving 36: 4-Chloro-6,7-dimethoxyquinazolin

Toluene (100 ml) and phosphorus oxychloride (7,4 g, to 48.6 mmol), is added to 6,7-dimethoxy-4-hinatasou (10.0 g, to 48.5 mmol)and the mixture stirred at 120°C for 6.5 hours, the Reaction solution is cooled to room temperature, then filtered, washed with toluene (100 ml, 50 ml) and dried, obtaining of 11.5 g (yield 91%) of the target product.

An example of retrieving 37: 4-(4’-Amino-3’-chloro)-phenoxy-6,7-dimethoxyquinazolin

Sodium hydroxide (8.5 g, 0.21 mol) and water (90 ml) is added to the hydrochloride 4-amino-3-chlorophenol (14.6 g, 81 mmol) and dissolve in it. To the solution was added 4-chloro-6,7-dimethoxyquinazolin (12 g, 53 mmol) and methyl (225 ml)and the mixture heated under reflux for 2 hours, the Reaction solution is cooled to approximately 50°and then to the cooled reaction solution was added chloroform (500 ml) and water (500 ml). The mixture is stirred for 10 min, after which the organic layer is separated from the aqueous layer. To the aqueous layer add chloroform (250 ml), the mixture is stirred for 10 min, then the layers separated. The organic layer is concentrated under reduced pressure. To the residue is added methanol (50 ml)and the mixture is PE is amerivault within 30 minutes The reaction solution is then filtered and dried, obtaining 15.6 g (yield 85%) of the target product.

1H NMR (DMSO-d6, 400 MHz): δ of 3.95 (s, 3H), of 3.97 (s, 3H), 5,33 (s, 2H), 6,85 (d, J=8,8 Hz, 1H), 6,98 (DD, J=2,8 Hz, J=8,8 Hz, 1H), 7,20 (d, J=2,8 Hz, 1H), was 7.36 (s, 1H), 7,51 (s, 1H), 8,53 (s, 1H).

An example of retrieving 38: 4-(4’-Amino-3’-chloro)-phenoxy-6,7-dimethoxyquinazolin

20% Aqueous sodium hydroxide solution (3.5 ml) and water (2 ml) are added to the hydrochloride 4-amino-3-chlorophenol (1.3 g, 7.2 mmol) and dissolve in it. To the solution was added 4-chloro-6,7-dimethoxyquinazolin (0.8 g, 3.6 mmol), chloroform (6 ml) and tetrabutylammonium bromide (of 0.58 g, 1.8 mmol)and the mixture heated under reflux for 2 hours, the Reaction solution is cooled. Then to the cooled reaction solution was added chloroform (10 ml) and water (10 ml)and the mixture stirred for 10 min, and then separating the organic layer from the aqueous layer. To separate the aqueous layer, add chloroform (10 ml)and the mixture stirred for 10 min, then the layers separated. The organic layer is concentrated under reduced pressure. To the residue is added methanol (2 ml)and the mixture stirred for 30 minutes, the Reaction solution is then filtered and dried, obtaining 1.0 g (yield 83%) of the target product.

Example 1: N-(2,4-Diferensial)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolve Aut in toluene (5.0 ml) and triethylamine (1.0 ml) under heating. Then to the solution was added a solution of triphosgene (103 mg) in dichloromethane (1.0 ml)and the mixture heated under reflux for 3 minutes Then add 2,4-differentiatin (54 mg)and the mixture heated under reflux for another 5 hours To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, then extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 123 mg (yield 80%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ was 4.02 (s, 3H), a 4.03 (s, 3H), 4,47 (d, J=5,9 Hz, 2H), 5,78-5,90 (m, 1H), 6,46 (d, J=5.4 Hz, 1H), 6,74-6,99 (m, 4H), 7.03 is-7,14 (m, 1H), 7,35-7,44 (m, 2H), 7,50 (s, 1H), 8,16 (t, J=9,0 Hz, 1H), of 8.47 (d, J=5,1 Hz, 1H).

Determination of molecular weight (FD-MS, m/z): 483 (M+).

Example 2: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-(2-foradil)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in toluene (10 ml) and triethylamine (0.5 ml) under heating. Then to the solution was added a solution of triphosgene (47 mg) in dichloromethane (1.0 ml)and the mixture heated under reflux for 5 minutes Then add the hydrochloride of 2-foretelling (42 mg)and the mixture heated under reflux for a further 8 hours To implement the traditional solution was added a saturated aqueous solution of sodium bicarbonate, then extracted with ethyl acetate. An ethyl acetate layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 93 mg (yield 72%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,40 (m, 1H), 3,47 (m, 1H), 3,93 (s, 3H), of 3.95 (s, 3H), 4,42 (t, J=4.9 Hz, 1H), 4,54 (t, J=4.9 Hz, 1H), 6,51 (d, J=5.4 Hz, 1H), to 6.88 (m, 1H), 7,05 (m, 1H), 7,28 (DD, J=2.7 Hz, J=11.7 Hz, 1H), 7,40 (s, 1H), 7,49 (s, 1H), 8,21 (m, 1H), of 8.47 (W, 1H), 8,48 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 404 (M++1).

Example 3: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-(2-pyridylmethyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in toluene (5 ml) and triethylamine (1 ml). The solution is then added a solution of triphosgene (104 mg) in dichloromethane, and the mixture is heated under reflux for 5 minutes Then add 2-(aminomethyl)pyridine (40 μl)and the mixture heated under reflux for 2 hours To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and chloroform (2 ml). The mixture is applied on diatomaceous earth, and then extracted with chloroform. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira mix the chloroform/methanol (8/1), getting 126 mg (yield 88%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 4,07 (s, 3H), 4.09 to (s, 3H), br4.61 (d, J=5.4 Hz, 2H), 6,40-6,50 (W, 1H), is 6.61 (d, J=5,9 Hz, 1H), 6,92-7,01 (m, 2H), 7,21-7,25 (m, 1H), was 7.36 (d, J=7.8 Hz, 1H), 7,56 (s, 1H), 7.68 per for 7.78 (m, 2H), of 7.75 (s, 1H), 8,27-to 8.34 (m, 1H), 8,49 (d, J=6,1 Hz, 1H), 8,55 (d, J=4,1 Hz, 1H).

Determination of molecular weight (FD-MS, m/z): 448 (M+).

Example 4: N-Allyl-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in toluene (5 ml) and triethylamine (1 ml) and the solution is then added a solution of triphosgene (104 mg) in dichloromethane. The mixture is heated under reflux for 5 minutes Then to the reaction solution add allylamine (22 mg)and the mixture heated under reflux for an additional 4 hours To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and chloroform (2 ml)and the mixture is applied onto diatomaceous earth, and then extracted with chloroform. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 125 mg (yield 98%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 3,91-of 3.96 (m, 2H), 4,06 (s, 3H), 4.09 to (s, 3H), 5,14-5,20 (m, 1H), 5,26-5,33 (m, 1H), 5,58-5,66 (W, 1H), 5,86 is 5.98 (m, 1H), 6,56 (d, J=5,9 Hz, 1H), 6,88-7,01 (m, 2H), 7.23 percent (1 is), at 7.55 (s, 1H), 7,66 (s, 1H), compared to 8.26-of 8.33 (m, 1H), of 8.47 (d, 10 J=5,9 Hz, 1H).

Determination of molecular weight (FD-MS, m/z): 397 (M+).

Example 5: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-proprotein

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in toluene (10 ml) and triethylamine (2 ml) and the solution is then added a solution of triphosgene (104 mg) in dichloromethane. The mixture is heated under reflux for 5 minutes Then add Propylamine (29 mg)and the mixture heated under reflux for 40 minutes To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. An ethyl acetate layer is then dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of chloroform/methanol (10/1)to give 89 mg (71%yield) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 0.97 (t, J=7,6 Hz, 3H), 1,55-of 1.64 (m, 2H), 3,24-3,29 (m, 2H), of 4.05 (s, 3H), 4,06 (s, 3H), 5,11 (t, J=5.4 Hz, 1H), 6,51 (d, J=5.4 Hz, 1H), 6,74-6,76 (m, 1H), 6,91-of 6.99 (m, 2H), of 7.48 (s, 1H), 7,52 (s, 1H), 8,18-8,23 (m, 1H), 8,49 (d, J=5.6 Hz, 1H).

Determination of molecular weight (FD-MS, m/z): 399 (M+).

Example 6: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-(4-terbutyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) p is straut in toluene (6 ml) and triethylamine (1.0 ml) under heating, and then to the solution was added a solution of triphosgene (104 mg) in dichloromethane (1.0 ml). The mixture is heated under reflux for 5 minutes Then to the reaction solution was added the hydrochloride of 4-terbutaline (55 mg)and the mixture heated under reflux for a further 2 hours To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, then extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 80 mg (yield 55%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 1,66-to 1.87 (m, 4H), 3.33 and is 3.40 (m, 2H), Android 4.04 (s, 3H), of 4.05 (s, 3H), of 4.44 (t, J=5.6 Hz, 1H), 4,56 (t, J=5.7 Hz, 1H), 4,90 (t, J=5,7 20 Hz, 1H), 6.48 in-of 6.52 (m, 2H), 6,93-7,02 (m, 2H), 7,42 (s, 1H), 7,51 (s, 1H), 8,15 (t, J=8,9 Hz, 1H), and 8.50 (d, J=5,1 Hz, 1H).

Determination of molecular weight (FD-MS, m/z): 431 (M+).

Example 7: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-(2-PROPYNYL)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (150 mg) dissolved in chloroform (10 ml) and triethylamine (2 ml), and to the solution add a solution of triphosgene (156 mg) in dichloromethane. The mixture is heated under reflux for 10 minutes Then add propargylamine (53 mg)and the mixture heated under reflux for a further 30 minutes To the reaction solution was added saturated aqueous races is the thief of sodium bicarbonate, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 164 mg (yield 87%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 2,49 is 2.51 (m, 1H), 3,90-3,95 (m, 8H), of 6.52 (d, J=5,1 Hz, 1H), 6.89 in-6,92 (m, 1H),? 7.04 baby mortality-7,06 (m, 1H), 7,26-7,29 (m, 1H), 7,39 (s, 1H), 7,49 (s, 1H), 8,16-to 8.20 (m, 1H), 8,46-8,49 (m, 2H).

Example 8: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-atilmotin

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in toluene (8 ml) and triethylamine (1.0 ml) under heating, and then to the solution was added a solution of triphosgene (47 mg) in toluene (1.0 ml). The mixture is heated under reflux for 5 minutes Then to the reaction solution was added ethylamine hydrochloride (60 mg)and the mixture heated under reflux for another 5 hours To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. An ethyl acetate layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 70 mg (yield 53%) specified in the connection header.

1 H NMR (Dl3, 400 MHz): δ to 1.21 (t, J=7,3 Hz, 3H), 3,34 (m, 2H), 4,06 (s, 3H), 4,08 (s, 3H), 5,64 (W, 1H), 6,55 (d, J=5.6 Hz, 1H), 6.89 in (DD, J=2.7 Hz, J=11,2 30 Hz, 1H), 6,97 (m, 1H), 7,26 (W, 1H), 7,54 (s, 1H), a 7.62 (s, 1H), 8,28 (t, J=9.0 Hz, 1H), of 8.47 (d, J=5.6 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 386 (M++1).

Example 9: N-butyl-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in toluene (8 ml) and triethylamine (1.0 ml) under heating, and then to the solution was added a solution of triphosgene (47 mg) in toluene (1.0 ml). The mixture is heated under reflux for 5 minutes Then to the reaction solution was added butylamine (80 mg)and the mixture heated under reflux for another 5 hours To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. An ethyl acetate layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 117 mg (yield 81%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.94 (t, J=7,3 Hz, 3H), of 1.40 (m, 2H), 1.55V (m, 2H), 3,29 (DD, J=7,1 Hz, J=12.9 Hz, 2H), 4,06 (s, 3H), 4.09 to (s, 3H), 5,72 (W, 1H), 6,56 (d, J=5,9 Hz, 1H), to 6.88 (DD, J=2.7 Hz, J=11.2 Hz, 1H), 6,97 (d, J=9.0 Hz, 1H), 7,33 (s, 1H), 7,55 (s, 1H), 7,65 (s, 1H), 8,30 (t, J=9.0 Hz, 1H), 8,46 (d, J=5,GC, 1H).

Determination of molecular mass (ESI-MS, m/z): 414 (M++1).

Example 10: N-(sec-Butyl)-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 (1 ml), and then to the solution was added a solution of triphosgene (104 mg) in dichloromethane. The mixture is heated under reflux for 5 minutes Then to the reaction solution was added sec-butylamine (48 μl). The mixture is heated under reflux for 10 minutes the Solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (8/2)to give 117 mg (yield 89%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 0.95 (t, J=7,6 Hz, 3H), of 1.18 (d, J=6.6 Hz, 3H), 1,47-of 1.55 (m, 2H), 3,79-to 3.89 (m, 1H), Android 4.04 (s, 6N), 5,28 (d, J=8,1 Hz, 1H), 6.48 in (d, J=5.4 Hz, 1H), 6.89 in-6,98 (m, 2H), was 7.08 (d, J=2.7 Hz, 1H), 7,42 (s, 1H), 7,51 (s, 1H), 8,20-8,24 5 (m, J=9.0 Hz, 1H), 8,48 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 414 (M++1).

Example 11: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-isobutylamine

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in chloroform (5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (104 mg) in dichloromethane. The mixture is heated under reflux for 5 minutes Further to reactionauditory add isobutylamine (50 μl), and the mixture is heated under reflux for 10 minutes, the Reaction solution is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (4/1). So specified in the title compound are obtained from quantitative yield.

1H NMR (CDCl3, 400 MHz): δ to 0.94 (d, J=6,6 Hz, 6N), 1,77-of 1.84 (m, 1H), 3,10-3,13 (m, 2H), a 4.03 (s, 3H), a 4.03 (s, 3H), 5,58 (t, J=5.4 Hz, 1H), 6,47 (d, J=5.4 Hz, H), 6,88-6,97 (m, 2H), 7,18 (s, 1H), 7,41 (s, 1H), to 7.50 (s, 1H), 8,18-8,23 (m, 1H), 8,48 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 414 (M++1).

Example 12: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-(1,2-dimethylpropyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-ftoranila (100 mg) dissolved in chloroform (5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (47 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 1,2-dimethylpropylene (55 μl), and the mixture is stirred at room temperature for 10 minutes the Solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 89 mg (yield 65%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 0.93 (d, J=2.2 Hz, 3H), of 0.95 (d, J=2.4 Hz, 3H), 1.14 in (d, J=6.8 Hz, 3H), 1,72 5-1,80 (m, 1H), 3,76-a-3.84 (m, 1H), Android 4.04 (s, 3H), of 4.05 (s, 3H), 4,91 (d, J=8.5 Hz, 1H, 6,48 (d, J=5.4 Hz, 1H), 6,74 (d, J=2,9 Hz, 1H), 6,91-6,98 (m, 2H), 7,42 (s, 1H), 7,51 (s, 1H), 8,18-8,23 (m, 1H), 8,49 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z); 428 (M++1).

Example 13: N-{2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]-phenyl}-N’-proprotein

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (7.5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (99 mg) in chloroform. The mixture is heated under reflux for 5 minutes Then to the reaction solution was added n-Propylamine (21 mg)and the mixture heated under reflux for a further 2 hours To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, the mixture is applied on diatomaceous earth, and then extracted with chloroform. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (8/1). So specified in the title compound are obtained from quantitative yield.

1H NMR (CDCl3, 400 MHz): δ 0,99 (t, J=7,3 Hz, 3H), 1,58-of 1.65 (m, 2H), 3,24-of 3.31 (m, 2H), Android 4.04 (s, 3H), 30 of 4.05 (s, 3H), 4,94 (t, J=5,9 Hz, 1H), 6.48 in (d, J=5,1 Hz, 1H), 6,77 (s, 1H), 7,11 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,21 (d, J=2.7 Hz, 1H), 7,43 (s, 1H), 7,52 (s, 1H), 8,27 (d, J=9.0 Hz, 1H), and 8.50 (d, J=5,1 Hz, 1H).

Determination of molecular weight (FD-MS, m/z): 415, 417 (M+).

Example 14: N-{2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]-phenyl}-N’(4-fluoro-2-were)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (122 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 4-fluoro-2-methylaniline (126 μl), and the mixture is stirred at room temperature for 2 hours To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 142 mg (yield 79%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ is 2.37 (s, 3H), Android 4.04 (s, 3H), Android 4.04 (s, 3H), of 6.31 (s, 1H), 6,47 (d, J=5,1 Hz, 1H), 6,97-7,06 (m, 3H), 7,11-7,14 (m, 1H), 7,19 (d, J=2.7 Hz, 1H), 7,41-7,44 (m, 2H), 7,50 (s, 1H), 8,35 (d, J=9,0 Hz, 1H), and 8.50 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 482, 484 (M++1).

Example 15: N-(5-Bromo-6-methyl-2-pyridyl)-N’-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (122 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 6-amino-3-bromo-2-methylpyridin (208 mg), and the mixture is stirred at room themes is the temperature value within 2 hours To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 155 mg (yield 77%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,69 (s, 3H), 4,06 (C, 6N), 6,53 (d, J=5.4 Hz, 1H), 6,56 (d, J=8.5 Hz, 1H), 7,14-7,17 (m, 1H), 7,30 (d, J=2.7 Hz, 1H), 7,44 (s, 1H), 7,53 (s, 1H), of 7.75 (d, J=8.5 Hz, 1H), to 7.93 (s, 1H), 8,49 (d, J=9.0 Hz, 1H), charged 8.52 (d, J=5.4 Hz, 1H), 11,92 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 543, 545, 547 (M++1).

Example 16: N-{2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]-phenyl}-N’-(5-chloro-2-pyridyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (122 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2-amino-5-chloropyridin (143 mg), and the mixture is stirred at room temperature for 2 hours To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 148 mg (yield 82%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 4,06 (s, 3H), 4,06 (s, 3H), 6,53 (d, J=5,1 Hz, 1H), ,95 (d, J=8,8 Hz, 1H), 7,14-7,17 (m, 1H), 7,31 (d, J=2.7 Hz, 1H), 7,44 (s, 1H), 7,53 (s, 1H), of 7.64-to 7.67 (m, 1H), 8,28 (d, J=2.7 Hz, 1H), 8,50 are 8.53 (m, 2H), of 8.92 (s, 1H), 12,11 (Sirs, 1H).

Determination of molecular mass (ESI-MS, m/z): 485, 487, 489 (M++1).

Example 17: N-(5-Bromo-2-pyridyl)-N’-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (122 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2-amino-5-bromopyridin (192 mg)and the mixture was stirred at room temperature for 2 hours To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 108 mg (yield 55%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 4,06 (s, 3H), 4,06 (s, 3H), 6,53 (d, J=5,1 Hz, 1H), 6,80 (d, J=8,8 Hz, 1H), 7,14-to 7.18 (m, 1H), 7,30 (d, J=2.7 Hz, 1H), 7,45 (s, 1H), 7,53 (s, 1H), to 7.77-7,80 (m, 1H), 8,15 (s, 1H), 10 8,39 (d, J=2.4 Hz, 1H), and 8.50 (d, J=9.0 Hz, 1H), charged 8.52 (d, J=5.4 Hz, 1H), 12,09 (Sirs, 1H).

Determination of molecular mass (ESI-MS, m/z): 529, 531, 533 (M++1).

Example 18: N-{2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]-phenyl}-N’-(2-methoxyphenyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) is dissolved which in chloroform (10 ml), and to the solution was added 2-methoxyphenylalanine (54 mg). The mixture was stirred at 60°With during the night. To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (6/4)to give 111 mg (yield 77%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 3,85 (s, 3H), Android 4.04 (s, 3H), of 4.05 (s, 3H), of 6.50 (d, J=5,1 Hz, 1H), 6.89 in-6,93 (m, 1H), 6,98-7,03 (m, 1H), 7,05-7,10 (m, 1H), 7,14 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7.23 percent (d, J=2.7 Hz, 1H), 7,35 (s, 1H), was 7.36 (s, 1H), 7,44 (s, 1H), 7,52 (s, 1H), 8,05-8,07 (m, 1H), 8.34 per (d, J=9.0 Hz, 1H), charged 8.52 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 480, 482 (M++1).

Example 19: N-{2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]-phenyl}-N’-(2-were)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (122 mg) was dissolved in chloroform (10 ml), and to the solution was added o-colorization (59 mg). The mixture is stirred at room temperature overnight. To the reaction solution was added methanol and the solvent is removed by distillation under reduced pressure. The residue is dissolved in a small amount of chloroform and to the solution add a large amount of ether to precipitate crystals. The crystals are collected by filtration, receiving 59 mg (yield 34%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,3 (s, 3H), Android 4.04 (s, 3H), of 4.05 (s, 3H), from 6.22 (s, 1H), 6,47 (d, J=5,1 Hz, 1H), 7,01 (s, 1H), 7,11-7,14 (m, 1H), 7,18 (d, J=2.7 Hz, 1H), 7,25-7,35 (m, 3H), 7,42 (s, 1H), 7,46 (d, J=6,8 Hz, 1H), 7,50 (S, 1H), of 8.37 (d, J=8,8 Hz, 1H), and 8.50 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 464, 466 (M++1).

Example 20: N-{2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]-phenyl}-N’-(5-methyl-2-pyridyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (122 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2-amino-5-picoline (120 mg), and the mixture is stirred at room temperature for 2 hours To the reaction solution was added methanol and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 119 mg (yield 69%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,31 (s, 3H), 4,06 (C, 6N), 6,53 (d, J=5.4 Hz, 1H), 6,76 (d, J=8,3 Hz, 1H), 7,13-7,16 (m, 1H), 7,29 (d, J=2.7 Hz, 1H), 7,43 (s, 1H), 7,49-7,52 (m, 1H), 7,54 (s, 1H), 8,00 (s, 1H), 8,14 35 (s, 1H), charged 8.52 (d, J=5,1 Hz, 1H), 8,55 (d, J=9.0 Hz, 1H), 12,57 (Sirs, 1H).

Determination of molecular mass (ESI-MS, m/z): 465, 467 (M++1).

Example 21: N-{2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]-phenyl}-N’-(6-methyl-2-pyridyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-Hino who yl)oxy]aniline (122 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 6-amino-2-picoline (120 mg), and the mixture is stirred at room temperature for 2 hours To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 73 mg (yield 42%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 2.57 (s, 3H), 4,06 (C, 6N), is 6.54 (d, J=5.4 Hz, 1H), 6,66 (d, J=8,1 Hz, 1H), 6,83 (d, J=7,6 Hz, 1H), 7,15-to 7.18 (m, 1H), 7,30 (d, J=2.7 Hz, 1H), 7,44 (s, 1H), 7,54-to 7.59 (m, 2H), at 8.36 (s, 1H), charged 8.52 (d, J=5,1 Hz, 1H), to 8.57 (d, J=9.0 Hz, 1H), 12,45 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 465, 467 (M++1).

Example 22: Hydrochloride of N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N’-(4-methoxyphenyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (100 mg) dissolved in chloroform (4 ml), and then to the solution was added 4-methoxyphenylalanine (60 μl). Then the reaction is left to proceed at room temperature overnight. The solvent is removed by distillation under reduced pressure. The residue is dissolved in a small amount of chloroform, and add a large amount of ether. The precipitate is collected by filtration with suction is, receiving 90 mg (yield 67%) of N-2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl-N’-(4-methoxyphenyl)urea. This product is suspended in 4 ml of methanol, and to the suspension is added a solution of hydrochloric acid in methanol. The mixture is stirred at room temperature for 4 h and then the solvent is removed by distillation, obtaining specified in the header of the connection.

1H NMR (CDCl3, 400 MHz): δ to 3.73 (s, 3H), a 4.03 (s, 3H), of 4.05 (s, 3H), of 6.90 (d, J=9,3 Hz, 2H), 6,97 (d, J=6,6 Hz, 1H), 7,37-7,41 (m, 3H), a 7.62 (s, 1H), to 7.67 (d, J=2.7 Hz, 1H), 8,39 (d, J=9.0 Hz, 1H), 8,49 (s, 1H), 8,82 (d, J=6,6 Hz, 1H), 9,49 (s, 1H).

Example 23: N-{2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]-phenyl}-N’-(1-naphthyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]aniline (122 mg) was dissolved in chloroform (10 ml), and to the solution was added 1-naphthylisocyanate (75 mg). The mixture is stirred at room temperature overnight. To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is dissolved in a small amount of chloroform and to the solution add a large amount of ether to precipitate crystals. The crystals are collected by filtration, getting 105 mg (yield 57%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ a 4.03 (s, 3H), Android 4.04 (s, 3H), 6,44 (d, J=5.4 Hz, 1H), 6,72 (s, 1H), 7,10-7,13 (m, 3H), 7,41 (s, 1H), of 7.48 (s, 1H), 7,55-of 7.69 (m, 4H), 7,88-of 7.96 (m, 2H), 8,15 (d, J=7,6 Hz, 1H), scored 8.38-8,40 (m, 1H), 8,48 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 500, 502 (M++1).

Example 24: N-(2,4-differenl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (710 mg) dissolved in chloroform (7 ml), and then to the solution was added 2,4-differentiational (310 μl). The mixture is heated under reflux for one hour, and the reaction solution was added a large amount of ether. The precipitate is collected by filtration with suction, getting 735 mg (yield 70%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ and 2.14 (s, 3H), and 2.27 (s, 3H), Android 4.04 (s, 3H), 4,06 (s, 3H), 6,27 (d, J=5.4 Hz, 1H), 6,78-6,89 (m, 2H), 6,95 (s, 1H), 7,03 (d, J=8.5 Hz, 1H), 7,10 (s, 1H), 7,40 was 7.45 (m, 2H), to 7.61 (s, 1H), 8,03-to 8.12 (m, 1H), 8,46 (d, J=5.4 Hz, 1H).

Determination of molecular weight (FAB-MS, m/z): 480 (M++1).

Example 25: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(4-fluoro-2-were) urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (120 mg) dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 4-fluoro-2-methylaniline (126 μl), and the mixture is stirred at room temperature for 2 hours To the reaction solution was added methanol, and the solvent UDA is EUT by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (91/9)to give 160 mg (yield 91%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ a 2.12 (s, 3H), 2,22 (s, 3H), of 2.25 (s, 3H), of 4.05 (s, 3H), 4,06 (s, 3H), 6,24 (d, J=5,1 Hz, 1H), 6,33 (s, 1H), 6.42 per (s, 1H), 6,94-7,03 (m, 3H), 7,43 (s, 1H), 7,46-of 7.55 (m, 2H), 7,60 (s, 1H), 8,43 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 476 (M++1).

Example 26: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(3-fluoro-2-methoxyphenyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (120 mg) dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 3-fluoro-o-anisidine (132 μl), and the mixture is stirred at room temperature for 2 hours To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (91/9)to give 23 mg (yield 13%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 2.15 (s, 3H), 2,32 (s, 3H), of 3.84 (d, J=1.7 Hz, 3H), of 4.05 (s, 3H), 4,08 (s, 3H), 6,28 (d, J=5.4 Hz, 1H), 6,72-6,77 (m, 1H), of 6.96-to 7.09 (m, 3H), 7,43 (d, J=8.5 Hz, 1H), 7,46 (s, 1H), 7,60 (s, 1H), 7.62mm (s, 1H), 8,02-with 8.05 (m, 1H), 8,46 (d, J=5.4 Hz, 1 is).

Determination of molecular mass (ESI-MS, m/z): 492 (M++1).

Example 27: N-(5-Bromo-6-methyl-2-pyridyl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (120 mg) dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 6-amino-3-bromo-2-methylpyridin (208 mg), and the mixture is stirred at room temperature for 2 hours To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (91/9)to give 103 mg (yield 52%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 2.16 (s, 3H), 2,42 (s, 3H 30), to 2.65 (s, 3H), 4,06 (s, 3H), 4,08 (s, 3H), 6,32 (d, J=5,1 Hz, 1H), only 6.64 (d, J=8,8 Hz, 1H),? 7.04 baby mortality (d, J=8,8 Hz, 1H), 7,44 (s, 1H), to 7.64 (s, 1H), 7,74 (d, J=8,8 Hz, 1H), to $ 7.91 (d, J=8,8 Hz, 1H), 8,29 (s, 1H), 8,45 (d, J=5.4 Hz, 1H), 11,30 (Sirs, 1H).

Determination of molecular mass (ESI-MS, m/z): 537, 539 (M++1).

Example 28: N-(5-Chloro-2-pyridyl)-N’-(4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (3.00 g) was dissolved in chloroform (150 ml) and triethylamine (6 ml), and then to the solution was added a solution of trip is Shena (2,74 g) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2-amino-5-chloropyridin (2.38 g)and the mixture is then stirred at room temperature for another 2 hours To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and the residue purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (20/1)to give 3.4 g (yield 77%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 2.16 (s, 3H), of 2.38 (s, 3H), 4,06 (s, 3H), 4,08 (s, 3H), of 6.31 (d, J=5.4 Hz, 1H), 6.89 in (d, J=8,8 Hz, 1H),? 7.04 baby mortality (d, J=8,8 Hz, 1H), 20 7,44 (s, 1H), 7,62-to 7.68 (m, 2H), of 7.90 (d, J=8,8 Hz, 1H), 8,23 (d, J=2.4 Hz, 1H), 8,45 (d, J=5.4 Hz, 1H), and 8.50 (s, 1H), 11,23 (Sirs, 1H).

Determination of molecular mass (ESI-MS, m/z): 479, 481 (M++1).

Example 29: N-(5-Bromo-2-pyridyl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (120 mg) dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2-amino-5-bromopyridin (192 mg)and the mixture was stirred at room temperature is PE within 2 hours To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (91/9). The solvent is removed by distillation, and the crystals precipitated from a small amount of methanol and a large number of ether. The crystals are collected by filtration, receiving 80 mg (yield 41%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 2.16 (s, 3H), of 2.38 (s, 3H), 4,06 (s, 3H), 4,08 (s, 3H), of 6.31 (d, J=5,1 Hz, 1H), of 6.96 (d, J=8.5 Hz, 1H), 7,03 (d, J=8,8 Hz, 1H), 7,45 (s, 1H), to 7.64 (s, 1H), 7,75-to 7.77 (m, 1H), 7,89 (d, J=8,8 Hz, 1H), 8,31 (d, J=2.4 Hz, 1H), 8,45 (d, J=10 a 5.4 Hz, 1H), 8,81 (s, 1H), 11,17 (Sirs, 1H).

Determination of molecular mass (ESI-MS, m/z): 523, 525 (M++1).

Example 30: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(2-methoxyphenyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (120 mg) dissolved in chloroform (10 ml), and to the solution was added 2-methoxyphenylalanine (60 μl). The mixture is stirred at room temperature overnight. To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is dissolved in a small amount of chloroform, and add a large amount of ether to precipitate crystals, which were then collected by filtration, getting 131 mg (yield 75%) of the specified reception in the e connection.

1H NMR (CDCl3, 400 MHz): δ of 2.16 (s, 3H), 2,32 (s, 3H), 3,81 (s, 3H), 4,06 (s, 3H), 4,08 (s, 3H), and 6.25 (s, 1H), of 6.26 (d, J=5.4 Hz, 1H), 6,85-6,87 (m, 1H), 6,97-7,07 (m, 4H), 7,41 (d, J=8.5 Hz, 1H), 7,44 (s, 1H), a 7.62 (s, 1H), 8,15-8,17 (m, 1H), 8,45 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 474 (M++1).

Example 31: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(2-were)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (120 mg) dissolved in chloroform (10 ml), and to the solution was added o-colorization (55 μl). The mixture is stirred at room temperature overnight. To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is dissolved in a small amount of chloroform and to the solution add a large amount of ether to precipitate crystals, which were then collected by filtration, receiving 130 mg (yield 70%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ a 2.12 (s, 3H), 2,22 (s, 3H), and 2.26 (s, 3H), of 4.05 (s, 3H), 4,07 (s, 3H), 6,23-10 6,28 (m, 3H), 7,02 (d, J=8.5 Hz, 1H), 7,14-7,17 (m, 1H), 7.24 to 7,29 (m, 2H), 7,43 (s, 1H), 7,49 (d, J=8.5 Hz, 1H), 7,60 (s, 1H), 7,63 (d, J=7,3 Hz, 1H), 8,43 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 458 (M++1).

Example 32: N-(4-Chloro-2-were)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (120 mg) dissolved in chloroform is (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 4-chloro-2-methylaniline (130 μl), and the mixture is stirred at room temperature for 2 hours To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (91/9)to give 136 mg (75%yield) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ and 2.14 (s, 3H), of 2.18 (s, 3H), and 2.27 (s, 3H), of 4.05 (s, 3H), 4,07 (s, 3H), 6,24 (d, J=5.4 Hz, 1H), 6,33 (s, 1H), 6,40 (s, 1H), 7,03 (d, J=8.5 Hz, 1H), 7,19-7,21 (m, 2H), 7,42-7,44 (m, 2H), of 7.60 (s, 1H), 7,65 (d, J=9.0 Hz, 1H), 8,44 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 492, 494 (M++1).

Example 33: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(2-pyridyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (120 mg) dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2-aminopyridine (104 mg)and the mixture heated under reflux overnight. To the reaction solution was added methanol, and the solvent is removed by distillation of the ri reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (91/9)to give 72 mg (yield 44%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 2.16 (s, 3H), 2,41 (s, 3H), 4,06 (s, 3H), 4,08 (s, 3H), 6,32 (d, J=5.4 Hz, 1H), 6,92-6,98 (m, 2H),? 7.04 baby mortality (d, J=8,8 Hz, 1H), 7,44 (s, 1H), 7,65 (s, 1H), to 7.67-of 7.69 (m, 1H), of 7.97 (d, J=8,8 Hz, 1H), 8,25-of 8.27 (m, 1H), 8,45 (d, J=5,1 Hz, 1H), 8,72 (s, 1H), 11,77 (W, 1H).

Determination of molecular mass (ESI-MS, m/z): 445 (M++1).

Example 34: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(5-methyl-2-pyridyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (120 mg) dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2-amino-5-picoline (120 mg), and the mixture is stirred at room temperature for 2 hours To the reaction solution was added methanol and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (91/9)to give 122 mg (yield 72%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 2.15 (s, 3H), of 2.28 (s, 3H), 2,39 (s, 3H), Android 4.04 (s, 3H), 4,07 (s, 3H), 6,32 (d, J=5.4 Hz, 1H), make 6.90 (d, J=8,3 Hz, 1H), 7,02 (d, J=8,8 Hz, 1H), 7,43 (s, 1H), 7,45-of 7.48 (m, 1H), to 7.64 (s, 1H), to 7.99 (d, J=8,8 is C, 1H), of 8.06 (d, J=1.5 Hz, 1H), 5 8,44 (d, J=5.4 Hz, 1H), 9,23 (s, 1H), 11,77 (W, 1H).

Determination of molecular weight (FD-MS, m/z): 458 (M+).

Example 35: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(6-methyl-2-pyridyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (120 mg) dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (110 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 6-amino-2-picoline (120 mg)and the mixture heated under reflux overnight. To the reaction solution was added methanol, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (40/60)to give 64 mg (yield 38%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 2.16 (s, 3H), of 2.44 (s, 3H), of 2.54 (s, 3H), 4,06 (s, 3H), 4,08 (s, 3H), 6,32 (d, J=5.4 Hz, 1H), is 6.61 (d, J=8,3 Hz, 1H), PC 6.82 (d, J=25 7,6 Hz, 1H),? 7.04 baby mortality (d, J=8,8 Hz, 1H), 7,44 (s, 1H), 7,53-EUR 7.57 (m, 1H), 7,65 (s, 1H), 7,79 (s, 1H), to 7.99 (d, J=8,8 Hz, 1H), 8,44 (d, J=5,1 Hz, 1H), 11,76 (W, 1H).

Determination of molecular weight (FD-MS, m/z): 458 (M+).

Example 36: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(4-methoxyphenyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,3-dimethylaniline (100 mg) dissolved in chloroform (4 ml), then the solution add Aut 4-methoxyphenylalanine (60 μl). The mixture is then left to interact at room temperature overnight, and the solvent is removed by distillation under reduced pressure. The residue is dissolved in a small amount of chloroform and to the solution add a large amount of ether. The precipitate is then collected by filtration with suction, getting 115 mg (yield 78%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 2,02 (s, 3H), of 2.30 (s, 3H), 3,76 (s, 3H), 4,06 (s, 3H), of 4.12 (s, 3H), 6,46 (d, J=6.3 Hz, 1H), 6,78 (d, J=9.0 Hz, 2H), 6,91 (d, J=8,8 Hz, 1H), 7,39 (d, J=9.0 Hz, 2H), to 7.67 (s, 1H), 7,69 (d, J=8,8 Hz, 1H), 7,92 (s, 1H), 8,20-8,23 (m, 1H).

Determination of molecular mass (ESI-MS, m/z): 474 (M++1).

Example 37: N-(2,4-differenl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimethylaniline (200 mg) dissolved in chloroform (15 ml), and then to the solution was added 2,4-differentiational (88 μl). The mixture is heated under reflux for one hour. The reaction solution is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (4/1)to give 287 mg (yield 97%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 2,17 (s, 3H), and 2.26 (s, 3H), of 4.05 (s, 3H), 4,06 (s, 3H), of 6.31 (d, J=5.4 Hz, 1H), to 6.57 (s, 1H), for 6.81-to 6.95 (m, 3H), 7,00 (s, 1H), 7,43 (s, 1H), 7,55 (s, 1H), to 7.59 (s, 1H), 8,05-8,13 (m, 1H), of 8.47 (d, J=5.4 Hz, 1H).

Determination of molecular weight (FD-M, m/z): 479 (M+).

Example 38: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-proprotein

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimethylaniline (150 mg) dissolved in chloroform (13 ml) and triethylamine (1.5 ml), and then to the solution was added a solution of triphosgene (151 mg) in chloroform. The mixture is heated under reflux for 5 minutes Then to the reaction solution was added n-Propylamine (33 mg)and the mixture heated under reflux for a further 2 hours To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is applied on diatomaceous earth, and then extracted with chloroform. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (4/1)to give 178 mg (yield 95%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 0.94 (t, J=7,3 Hz, 3H), 1,51-of 1.65 (m, 2H), of 2.15 (s, 3H), and 2.26 (s, 3H), 3,21-10 of 3.28 (m, 2H), of 4.05 (s, 3H), 4,06 (s, 3H), 4.63 to-4,69 (m, 1H), 5,97 (s, 1H), of 6.31 (d, J=5,1 Hz, 1H), 6,98 (s, 1H), 7,43 (s, 2H), 7,58 (s, 1H), 8,46 (d, J=5.4 Hz, 1H).

Determination of molecular weight (FD-MS, m/z): 409 (M+).

Example 39: N-(4-Chloro-2-were)-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 (10 ml) and triethylamine (1 ml), and then to the solution was added Rast the EOS triphosgene (92 20 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 4-chloro-2-methylaniline (44 μl), and the mixture is stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, then extracted with chloroform. The chloroform layer is dried over sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is dissolved in a small amount of chloroform and to the solution add a large amount of ether to precipitate crystals, which were then collected by filtration, receiving 118 mg (yield 78%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 2.16 (s, 3H), of 2.21 (s, 35 3H), of 2.23 (s, 3H), of 4.05 (s, 3H), 4,06 (s, 3H), 6,28 (d, J=5.4 Hz, 1H), 6.30-in (s, 1H), 6,32 (s, 1H), 6,98 (s, 1H), 7,22-of 7.23 (m, 2H), 7,43 (s, 1H), 7,58 (s, 1H), to 7.59-7,63 (m, 2H), 8,45 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 492, 494 (M++1).

Example 40: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-(4-fluoro-2-were)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimethylaniline (100 mg) dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (92 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 4-fluoro-2-methyl aniline (42 μl), and the offer was stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is dissolved in a small amount of chloroform and to the solution add a large amount of ether to precipitate crystals, which were then collected by filtration, getting 108 mg (yield 74%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,15 (C, 6N), is 2.30 (s, 3H), of 4.05 (s, 3H), 4,06 (s, 3H), 6,24 (s, 2H), 6,28 (d, J=5,1 Hz, 1H), 6,94 (s, 1H), of 6.96-7,00 (m, 2H), 7,42 (s, 1H), 7,49-7,52 (m, 1H), 7,58 (s, 1H), to 7.64 (s, 1H), 8,44 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 476 (M++1).

Example 41: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-(3-fluoro-2-methoxyphenyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimethylaniline (100 mg) dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (92 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 3-fluoro-o-anisidine (44 μl), and the mixture is stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over Sul is blockhead sodium. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 126 mg (yield 83%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 2.16 (s, 3H), and 2.27 (s, 3H), 3,83 (d, J=1.7 Hz, 3H), Android 4.04 (s, 3H), 4,07 (C, 10 3H), of 6.31 (d, J=5,1 Hz, 1H), 6,74-6,79 (m, 1H), 6,97-7,03 (m, 3H), 7,44 (s, 1H), EUR 7.57 (s, 1H), 7,60 (s, 1H), 7,66 (s, 1H), 8,02-of 8.04 (m, 1H), 8,48 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 492 (M++1).

Example 42: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-(2-were)urea

4-[(6, 7-Dimethoxy-4-chinolin)oxy]-2,5-dimethylaniline (100 mg) dissolved in chloroform (10 ml), and to the solution was added o-colorization (46 μl). The mixture is stirred at room temperature overnight. To the reaction solution was added methanol. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 111 mg (yield 79%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 2,12 (C, 6N), and 2.26 (s, 3H), a 4.03 (s, 3H), of 4.05 (s, 3H), 6,27 (d, J=5,1 Hz, 1H), 6,77 (s, 1H), for 6.81 (s, 1H), 6,91 (s, 1H), 7,11-30 to 7.15 (m, 1H), 7,22 (s, 1H), 7,24 (s, 1H), 7,42 (s, 1H), to 7.59 (s, 1H), 7,63 (d, J=7.8 Hz, 1H), 7,68 (s, 1H), 8,43 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 458 (M++1).

Example 43: N-{4-[(6,7-Dimethoxy-4-nail)oxy]-2,5-dimetilfenil}-N’-(2-methoxyphenyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimethylaniline (100 mg) dissolved in chloroform (10 ml), and to the solution was added 2-methoxyphenylalanine (49 μl). The mixture is heated under reflux during the night. To the reaction solution was added methanol. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1), getting mentioned in the title compound in quantitative yield.

1H NMR (CDCl3, 400 MHz): δ and 2.14 (s, 3H), 2,24 (s, 3H), of 3.75 (s, 3H), a 4.03 (s, 3H), 4,07 (s, 3H), of 6.31 (d, 10 J=5,1 Hz, 1H), at 6.84-6.87 in (m, 1H), 6,95-7,03 (m, 3H), 7,06 (s, 1H), 7,44 (s, 1H), 7,56 (s, 1H), to 7.61 (s, 1H), 7,63 (s, 1H), 8.17-a to 8.20 (m, 1H), 8,46 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 474 (M++1).

Example 44: N-(5-Bromo-6-methyl-2-pyridyl)-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 (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (92 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 6-amino-3-bromo-2-methylpyridin (69 mg), and the mixture is stirred at room temperature overnight. To the reaction solution was added saturated aqueous solution of sodium bicarbonate and the mixture extracted with chlorofo the IOM. The chloroform layer is dried over sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is dissolved in a small amount of chloroform and to the solution add more ether to precipitate crystals, which were then collected by filtration, receiving 80 mg (yield 48%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 2.18 (s, 3H), 2,42 (s, 3H), 2,65 (s, 3H), 4,06 (s, 3H), 4,08 (s, 3H), 6,34 (d, J=5.4 Hz, 1H), to 6.57 (d, J=8.5 Hz, 1H), 6,98 (s, 1H), 7,43 (s, 1H), 7.62mm (s, 1H), of 7.70 (s, 1H), 7,74 (d, J=8.5 Hz, 1H), with 8.05 (s, 1H), 8,46 (d, J=5.4 Hz, 1H), 11,17 (W, 1H).

Determination of molecular mass (ESI-MS, m/z): 537, 539 (M++1).

Example 45: N-(2,6-Dimethoxy-3-pyridyl)-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 (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (92 mg) in dichloromethane. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 3-amino-2,6-dimethoxypyridine (70 mg), and the mixture is stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over sodium sulfate. The solvent is removed by distillation under reduced pressure. About who headed the remainder of the dissolve in a small amount of chloroform, to the solution add a large amount of ether to precipitate crystals, which were then collected by filtration, receiving 124 mg (yield 79%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 2,17 (s, 3H), and 2.27 (s, 3H), with 3.89 (s, 3H), of 3.95 (s, 3H), 4,06 (s, 3H), 4,07 (C, 25 3H), of 6.31 (d, J=5,1 Hz, 1H), 6,34 (d, J=8.5 Hz, 1H), 6,36 (s, 1H), 6,74 (s, 1H), 6,99 (s, 1H), 7,44 (, 1H), EUR 7.57 (s, 1H), 7,60 (s, 1H), to 8.20 (d, J=8,3 Hz, 1H), 8,46 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 505 (M++1).

Example 46: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-(4-methoxyphenyl)urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2,5-dimethylaniline (100 mg) dissolved in chloroform (4 ml), and then to the solution was added 4-methoxyphenylalanine (60 μl). The mixture is left to interact at room temperature over night. The solvent is removed by distillation under reduced pressure. The residue is dissolved in a small amount of chloroform and to the solution add a large amount of ether. The resulting precipitate is collected by filtration with suction, receiving 110 mg (yield 74%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 2,07 (s, 3H), and 2.26 (s, 3H), 3,76 (s, 3H), a 4.03 (s, 3H), 4,08 (s, 3H), to 6.39 (d, J=6,1 Hz, 1H), 6,80 (d, J=9.0 Hz, 2H), 6.87 in (s, 1H), was 7.36 (d, J=9.0 Hz, 2H), 7,55 (W, 1H), 7.62mm (s, 1H), to 7.67 (s, 1H), 7,80 (s, 1H), 8,19 (W, 1H), 8,27 (d, J=10 6,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 474 (M+ +1).

Example 47: N-{4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-nitrophenyl}-N’-proprotein

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-nitroaniline (150 mg) dissolved in chloroform (10 ml) and triethylamine (1.5 ml), and then to the solution was added a solution of triphosgene (144 mg) in chloroform. The mixture is heated under reflux for 5 minutes Then add n-Propylamine (31 mg). The mixture is heated under reflux for a further 2 hours To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is placed on diatomaceous earth, followed by extraction with chloroform. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatographie on silica gel, elwira a mixture of chloroform/acetone (4/1)to give 160 mg (yield 86%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ a 1.01 (t, J=7.5 Hz, 3H), 1,59 was 1.69 (m, 2H), 3.27 to to 3.34 (m, 2H), of 4.05 (s, 3H), 4,06 (s, 3H), 4,95-5,01 (W, 1H), 6,47 (d, J=5.4 Hz, 1H), 7,43-7,51 (m, 3H), of 8.04 (d, J=2.7 Hz, 1H), 8,53 (d, J=5.4 Hz, 1H), 8,81 (d, J=9,3 Hz, 1H), 9,74-9,79 (W, 1H).

Determination of molecular weight (FD-MS, m/z): 426 (M+).

Example 48: N-(2,4-Differenl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-nitrophenyl}urea

4-[(6,7-Dimethoxy-4-chinolin)oxy]-2-nitroaniline (100 mg) dissolved in chloroform (10 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (96 mg) in chloroform. The mixture heating the Ute under reflux for 5 minutes Next, to the reaction solution was added 2,4-diptiranjan (45 mg)and the mixture continued to heat under reflux overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is applied on diatomaceous earth, and then extracted with chloroform. The solvent is removed by distillation under reduced pressure. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of chloroform/acetone (3/1)to give 81 mg (yield 56%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 4.05 (s, 3H), 4,06 (s, 3H), of 6.50 (d, J=5,1 Hz, 1H), 6,91-6,98 (m, 3H), 7,45 (s, 1H), 7,49 (s, 1H), 7,50-rate of 7.54 (m, 1H), 7,88-of 7.97 (m, 1H), with 8.05 (d, J=2,9 Hz, 1H), 8,54 (d, J=5,1 Hz, 1H), 8,77 (d, J=9,3 Hz, 1H), 9,98 (s, 1H).

Determination of molecular weight (FD-MS, m/z): 496 (M+).

Example 49: N-{3,5-Dichloro-4-[(6,7-dimethoxy-4-chinolin)-hydroxy]phenyl}-N’-(2,4-differenl)urea

3,5-Dichloro-4-[(6,7-dimethoxy-4-chinolin)oxy]-aniline (53 mg) was dissolved in chloroform (5 ml), and to the solution was added 2,4-differentiational (34 μl). The mixture is heated under reflux during the night. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 56 mg (yield 74%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 4.05 (s, 3H) 4.09 to (C, 35 3H), of 6.26 (d, J=5.4 Hz, 1H), 6,86-6,93 (m, 2H), 7,05 (s, 1H), 7,44 (s, 1H), 7,46 (s, 1H), 7,60 (s, 2H), to 7.64 (s, 1H), 8,01-with 8.05 (m, 1H), 8,48 (d, J=5.4 Hz, 1H).

Determination of molecular weight (FAB-MS, m/z): 520, 522, 524 (M++1).

Example 50: N-(2,4-Differenl)-N’-(2-fluoro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-chinolin]oxy}phenyl)-urea

N-(2,4-Differenl)-N’-{2-fluoro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}urea (20 mg), potassium carbonate (7 mg), iodide, Tetra-n-butylamine (2 mg), and hydrochloride of N-(2-chloroethyl)research (10 mg) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 70°With during the night. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of chloroform/methanol (30/1)to give 14 mg (yield 57%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 2.57 (t, J=4.4 Hz, 4H), 2,88 (m, 2H), 3,69 (t, J=4.4 Hz, 4H), of 3.94 (s, 3H), 4.26 deaths (t, J=5,9 Hz, 2H), to 6.43 (d, J=5,1 Hz, 1H), 6,77-to 6.95 (m, 4H), 7,35 (s, 1H), 7,43 (s, 1H), of 7.96-8,02 (m, 1H), 8,13-8,17 (m, 1H), 8,44 (d, J=5,1 Hz, 1H).

Example 51: N-(2-Chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)-hydroxy]phenyl}-N’-(2,4-differenl)m is cavino (174 mg) was dissolved in N,N-dimethylformamide (9 ml) and the solution is then added potassium carbonate (64 mg), iodide, Tetra-n-butylamine (14 mg) and the hydrochloride of N-(2-chloroethyl)of the research (86 mg). The mixture was stirred at 70°C for 17 h and then the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, then extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (20/1)to give 75 mg (yield 35%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 2,60-to 2.67 (m, 4H), 2.95 points (t, J=6.0 Hz, 2H), 3,71-with 3.79 (m, 4H), to 4.01 (s, 3H), 4,33 (t, J=6.0 Hz, 2H), 6,50 (d, J=5,1 Hz, 1H), 6,85-6,97 (m, 2H), 7,09-7,17 (m, 2H), 7,22-7,27 (m, 2H), 7,42 (, 1H), 7,50 (s, 1H), 7,97 shed 8.01 (m, 1H), 8,28 (d, J=9.0 Hz, 1H), 8,51 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 585, 587 (M++1).

Example 52: N-(2,4-Differenl)-N’-(4-{[6-methoxy-7-(2-morpholinoethoxy)-4-chinolin]oxy}-2,5-dimethyl-phenyl)urea

N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,5-dimetilfenil)-N’-(2,4-differenl)urea (366 mg) was dissolved in N,N-dimethylformamide (6 ml), and to the solution was added palladium hydroxide (366 mg). The mixture is stirred in hydrogen atmosphere at room temperature overnight. The solvent is removed by distillation under reduced pressure. The residue is dissolved in chloroform and methanol. The reaction solution is filtered is via Celite. Next, the solvent is removed by distillation under reduced pressure. The residue (213 mg), potassium carbonate (109 mg), and iodide, Tetra-n-butylamine (12 mg) and the hydrochloride of N-(2-chloroethyl)of the research (74 mg) was dissolved in N,N-dimethylformamide (5 ml)and the solution stirred at 70°With during the night. The solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The chloroform layer is dried over sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of chloroform/methanol (10/1)to give 106 mg (yield 55%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 2,17 (s, 3H), and 2.27 (s, 3H), of 2.64 (t, J=4.6 Hz, 4H), 2,96 (t, J=6.0 Hz, 2H), 3,76 (t, J=4.6 Hz, 4H), a 4.03 (s, 3H), 4,34 (t, J=6,0 5 Hz, 2H), of 6.31 (d, J=5.4 Hz, 1H), 6,47 (s, 1H), for 6.81-6,92 (m, 3H), 7,00 (s, 1H), 7,43 (s, 1H), 7,54 (s, 1H), 7,58 (s, 1H), 8,05-to 8.12 (m, 1H), of 8.47 (d, J=5.4 Hz, 1H).

Example 53: N-(4-{[6-Methoxy-7-(2-morpholinoethoxy)-4-chinolin]oxy}-2,5-dimetilfenil)-N’-(2-methoxyphenyl)-urea

N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,5-dimetilfenil)-N’-(2-methoxyphenyl)urea (363 mg) was dissolved in N,N-dimethylformamide (6 ml) and to the solution was added palladium hydroxide (363 mg). The mixture is stirred in hydrogen atmosphere at room temperature overnight. The solvent is removed by distillation PR is the reduced pressure. The residue is dissolved in chloroform and methanol and the solution filtered through Celite. Next, the solvent is removed by distillation under reduced pressure. The residue (191 mg), potassium carbonate (219 mg), and iodide, Tetra-n-butylamine (12 mg) and the hydrochloride of N-(2-chloroethyl)of the research (148 mg) was dissolved in N, N-dimethylformamide (5 ml). The solution was stirred at 70°With during the night. The solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The chloroform layer is dried over sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of chloroform/methanol (10/1)to give 101 mg (yield 55%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 2,17 (s, 3H), of 2.28 (s, 3H), of 2.64 (t, J=4.5 Hz, 4H), 2,96 (t, J=5,9 Hz, 2H), 3,76 (t, J=4.6 Hz, 4H), 3,83 (s, 3H), Android 4.04 (s, 3H), 4,34 (t, J=6.0 Hz, 2H), 6,30 (d, J=5.4 Hz, 2H), 6,86-6,90 (m, 1H), of 6.96-7,06 (m, 3H), 7,16 (s, 1H), 7,43 (s, 1H), EUR 7.57 (s, 1H), to 7.59 (s, 1H), 8,11-8,16 (m, 1H), 8,46 (d, J=5.4 Hz, 1H).

Example 54: N-(2-Chloro-4-{[6-methoxy-7-(2-methoxyethoxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea

Sodium hydride (60 wt.%, 153 mg) are added to a dimethyl sulfoxide (2 ml), the mixture was stirred at 60°C for 30 min and then cooled to room temperature. To the reaction solution was added the hydrochloride 4-amino-3-chlorophenol (34 mg), and the mixture is stirred at room temperature for 10 minutes Next to the reaction solution was added a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)-quinoline (254 mg) in dimethyl sulfoxide (2 ml). The mixture was stirred at 110°With during the night. To the reaction solution was added water, and then extracted with chloroform. The chloroform layer is then washed with saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (7/3)to give 332 mg of a mixture containing as a main product 2-chloro-4-{[(6-methoxy-7-(2-methoxyethoxy)-4-chinolin]-oxy}aniline. A portion of the mixture by mass of 83 mg dissolved in chloroform (5 ml), and to the solution was added 2,4-differentiational (32 μl). The mixture is heated under reflux during the night. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1), receiving 50 mg specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,75-of 3.77 (m, 2H), of 3.94 (s, 3H), 4,27-the 4.29 (m, 2H), 6,55 (d, J=5,1 Hz, 1H),? 7.04 baby mortality-7/09 (m, 1H), 7,25 was 7.36 (m, 2H), 7,42 (s, 1H), 7,50 (s, 1H), 7,51 (s, 1H), 8,09-of 8.15 (m, 1H), 8,24 (d, J=9,0 Hz, 1H), 8,49 (d, J=5.4 Hz, 1H), 8,82 (s, 1H), 9,31 (s, 1H).

Example 55: N-(2-Chloro-4-{[6-is ethoxy-7-(2-methoxyethoxy)-4-chinolin]oxy}phenyl)-N’-(2-methoxyphenyl)urea

Sodium hydride (60 wt.%, 153 mg) are added to a dimethyl sulfoxide (2 ml)and the mixture stirred at 60°C for 30 min and then cooled to room temperature. To the reaction solution was added the hydrochloride 4-amino-3-chlorophenol (343 mg), and the mixture is stirred at room temperature for 10 minutes Next to the reaction solution was added a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline (254 mg) in dimethyl sulfoxide (2 ml)and the mixture stirred at 110°With during the night. To the reaction solution was added water, and then extracted with chloroform. The chloroform layer is then washed with a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (7/3)to give 332 mg of a mixture containing as a main product 2-chloro-4-{[(6-methoxy-7-(2-methoxy-ethoxy)-4-chinolin]oxy}aniline. A portion of the mixture by mass of 83 mg dissolved in chloroform (5 ml), and to the solution was added 2-methoxyphenylalanine (35 μl). The mixture is heated under reflux during the night. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 31 mg of the specified reception in the e connection.

1H NMR (DMSO-d6, 400 MHz): δ 3,75-of 3.77 (m, 2H), 3,90 (s, 3H), of 3.94 (s, 3H), 4,27-the 4.29 (m, 2H), 6,55 (d, J=5,1 Hz, 1H), 6.89 in-7,05 (m, 3H), 7.24 to 7,27 (m, 1H), 7,42 (s, 1H), of 7.48 (d, J=2.7 Hz, 1H), 7,50 (s, 1H), 8,08-8,11 (m, 1H), 8,18 is 8.22 (m, 1H), 8,49 (d, J=5.4 Hz, 1H), 8,99-9,03 (m, 2H).

Example 56: N-(2,4-Differenl)-N’-(4-{[6-methoxy-7-(2-methoxyethoxy)-4-chinolin]oxy}-2,3-dimetilfenil)urea

N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,3-dimetilfenil)-N’-(2,4-differenl)urea (213 mg) was dissolved in N,N-dimethylformamide (5 ml) and triethylamine (1 ml), and to the solution was added palladium hydroxide (40 mg). The mixture is stirred in hydrogen atmosphere at room temperature overnight. The reaction solution is filtered through Celite and then washed with a mixture of chloroform/methanol. The solvent is removed by distillation under reduced pressure. A portion of the residue (184 mg) weighing 90 mg dissolved in N,N-dimethylformamide (1.5 ml), and to the solution was added potassium carbonate (32 mg), iodide, Tetra-n-butylamine (7 mg) and 2-bromatology ester (32 mg). The mixture was stirred at 70°With during the night. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of chloroform/AC the tone (2/1), receiving 110 mg specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 1.97 (s, 3H), 2,17 (s, 3H), and 3.31 (s, 3H), 3,70 (t, J=4.4 Hz, 2H), 3,90 (s, 3H), is 4.21 (t, J=4.4 Hz, 2H), 6,18 (d, J=5,1 Hz, 1H), 6,95-6,98 (m, 2H), 7,22-7,31 (m, 1H), 7,34 (s, 1H), 7,51 (s, 1H), 7.62mm (d, J=8,8 Hz, 1H), 8,03-8,10 (m, 1H), at 8.36 (d, J=5,1 Hz, 1H), scored 8.38 (s, 1H), 8,79 (s, 1H).

Example 57: N-(4-{[6-Methoxy-7-(2-methoxyethoxy)-4-chinolin]oxy}-2,3-dimetilfenil)-N’-(2-methoxyphenyl)-urea

N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,3-dimetilfenil)-N’-(2-methoxyphenyl)urea (161 mg) was dissolved in N, N-dimethylformamide (4 ml) and triethylamine (1 ml), and to the solution was added palladium hydroxide (32 mg). The mixture is stirred in hydrogen atmosphere at room temperature overnight. The reaction solution is filtered through Celite and washed with a mixture of chloroform/methanol. The solvent is removed by distillation under reduced pressure. A portion of the residue (223 mg) weight of 110 mg was dissolved in N,N-dimethylformamide (1.5 ml), and to the solution was added potassium carbonate (23 mg), iodide, Tetra-n-butylamine (5 mg) and 2-bromatology ester (23 mg). The mixture was stirred at 70°With during the night. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by the method of subtly is lainey chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 89 mg specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 2,00 (s, 3H), 2,17 (s, 3H), 3,70 (t, J=4,2 Hz, 2H), 3,83 (s, 3H), 3,90 (s, 3H), 4,22 (t, J=4,2 Hz, 2H), to 6.19 (d, J=5,1 Hz, 1H), for 6.81-to 6.88 (m, 2H), 6,94-6,97 (m, 2H), 7,34 (s, 1H), 7,51 (s, 1H), 7,58 (d, J=8,8 Hz, 1H), 8,07 (d, J=8,8 Hz, 1H), at 8.36 (d, J=5,1 Hz, 1H), 8,48 (s, 1H), 8,58 (s, 1H).

Example 58 N-(2,4-Differenl)-N’-(4-{[6-methoxy-7-(2-methoxyethoxy-4-chinolin]oxy}-2,5-dimetilfenil)urea

N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,5-dimetilfenil)-N’-(2,4-differenl)urea (366 mg) was dissolved in N,N-dimethylformamide (6 ml), and to the solution was added palladium hydroxide (366 mg). The mixture is stirred in hydrogen atmosphere at room temperature overnight. The solvent is removed by distillation under reduced pressure. The residue is dissolved in chloroform, and methanol and the solution filtered through Celite. Next, the solvent is removed by distillation under reduced pressure. The residue (213 mg), potassium carbonate (109 mg), and iodide, Tetra-n-butylamine (12 mg) and 2-bromatology ether (40 ml) dissolved in N,N-dimethylformamide (5 ml)and the solution stirred at 70°With during the night. The solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The chloroform layer is dried over sodium sulfate. The solvent is removed by distillation under reduced Yes the tion. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of chloroform/methanol (10/1)to give 124 mg (yield 73%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,17 (s, 3H), and 2.26 (s, 3H), 3,49 (s, 3H), 3,90 (t, J=4,8 Hz, 2H), a 4.03 (s, 3H), 4,34 (t, J=4,8 Hz, 2H), 6,30 (d, J=5,1 Hz, 1H), to 6.57 (s, 1H), for 6.81-to 6.95 (m, 3H), 7,00 (s, 1H), 7,43 (s, 1H), 7,55 (s, 1H), EUR 7.57 (s, 1H), 8,05-to 8.14 (m, 1H), 8,46 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 524 (M++1).

Example 59: N-(4-{[6-Methoxy-7-(2-methoxyethoxy)-4-chinolin]oxy}-2,5-dimetilfenil)-N’-(2-methoxyphenyl)-urea

N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,5-dimetilfenil)-N’-(2-methoxyphenyl)urea (363 mg) was dissolved in N,N-dimethylformamide (6 ml) and to the solution was added palladium hydroxide (363 mg). The mixture is stirred in hydrogen atmosphere at room temperature overnight. The solvent is removed by distillation under reduced pressure, and the residue is dissolved in chloroform and methanol. The solution is filtered through Celite. Then the solvent is removed by distillation under reduced pressure. The residue (191 mg), potassium carbonate (110 mg), iodide, Tetra-n-butylamine (12 mg) and 2-bromatology ester (80 mg) was dissolved in N,N-dimethylformamide (5 ml)and the solution stirred at 70°With during the night. The solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with what cloroformo. The chloroform layer is dried over sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of chloroform/methanol (10/1)to give 128 mg (yield 76%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,17 (s, 3H), of 2.28 (s, 3H), 3,49 (s, 3H), 3,83 (s, 3H), 3,90 (t, J=4,8 Hz, 15 2H), Android 4.04 (s, 3H), 4,35 (t, J=4.9 Hz, 2H), 6,30 (d, J=5.4 Hz, 1H), 6,33 (s, 1H), 6,86-of 6.90 (m, 1H), of 6.96-7,06 (m, 3H), 7,17 (s, 1H), 7,43 (s, 1H), 7,56 (s, 1H), 7,58 (s, 1H), 8,12-8,17 (m, 1H), 8,45 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 518 (M++1).

Example 60: N-(4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]-oxy}-2,3-dimetilfenil)-N’-(2-methoxyphenyl)-urea

4-{[7-(Benzyloxy)-6-methoxy-4-chinolin]oxy}-2,3-dimethylaniline (260 mg) was dissolved in N,N-dimethylformamide (5 ml) and then to the solution was added 2-methoxyphenylalanine (116 mg). The mixture is left to react at room temperature over night. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by thin layer chromatography on silica gel, elwira a mixture of chloroform/acetone (2/1)to give 169 mg (yield 47%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 1,99 (s, 3H), 2,02 (s, 3H), 3,83 (s, 3H), 3,90 (s, 3H), of 5.25 (s, 2H), 6,18 (d, J=5.3 Hz, 1H), for 6.81-6.87 in (m, 2H), 6,95 (d, J=6,1 Hz, 1H), 7,29-to 7.59 (m, 7H), 8,07 (d, J=6,1 Hz, 1H), 8,35 (d, J=5.3 Hz, 1H), 8,48 (s, 1H), 8,58 (s, 1H).

Example 61: N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N’-(2,4-differenl)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (214 mg) was dissolved in chloroform (5 ml) and then to the solution was added 2,4-differentiational (180 μl). The mixture is left to react at 70°C for 4 h, and the reaction solution was added a large amount of ether. The precipitate is collected by filtration with suction, getting 146 mg (yield 46%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,98 (s, 3H), 3,99 (s, 3H), 7.03 is-7,10 (m, 1H), 7,28-7,37 (m, 2H), 7,40 (s, 1H), 7,56 (s, 2H), 8,08-8,21 (m, 2H), to 8.57 (s, 1H), 8,80 (s, 1H), of 9.30 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 487, 489 (M++1).

Example 62: N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N’-proprotein

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (5,13 g) dissolved in chloroform (100 ml) and triethylamine (50 ml), and then to the solution was added a solution of triphosgene (4.59 g) in chloroform (3 ml). The mixture is stirred for 30 minutes Then to the reaction solution was added n-Propylamine (2,74 g), and the mixture is stirred for a further 2 hours To the reaction solution was added saturated aqueous dissolve the bicarbonate of sodium, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (50/1), getting to 4.14 g (yield 64%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.91 (t, J=7,3 Hz, 3H), 1.41 to 1,53 (m, 2H), 3,05-of 3.12 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), of 6.99 (t, J=5.4 Hz, 1H), 7,22 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,38 (s, 1H), 7,46 (d, J=2,9 Hz, 1H), 7,54 (s, 1H), 8,04 (s, 1H), to 8.20 (d, J=9,3 Hz, 5 1H), 8,55 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 417 (M++1).

Example 63 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]phenyl}-N’-atilmotin

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (50 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added ethylamine hydrochloride (69 mg)and the mixture continued to stir at room temperature overnight. Methanol is added to the reaction solution, and the solution purified by HPLC, elwira a mixture of chloroform/methanol to give 10 mg (yield 16%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 1.07 (t, J=7,3 Hz, 3H), 3,11-3,14 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), 6,10 (t, J=5.4 Hz, 1H), 7,14 (d, J=9.0 Hz, 2H), 7,37 (who, 1H), 7,46 (d, J=9.0 Hz, 2H), 7,55 (s, 1H), 8,49 (W, 1H), 8,53 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 369 (M++1).

Example 64: N-{4-[(6,7-Dimethoxy-4-hintline)oxy]phenyl}-N’-proprotein

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (50 mg) in chloroform. The mixture is stirred at room temperature for 30

minutes Next to the reaction solution was added Propylamine (21 μl)and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the solution purified by HPLC, elwira a mixture of chloroform/methanol, receiving 30 mg (yield 47%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 0.89 (t, J=7,6 Hz, 3H), 1.41 to 1.50 in (m, 2H), 3.04 from-is 3.08 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), x 6.15 (t, J=5,9 Hz, 1H), 7,15 (d, J=8,8 Hz, 2H), 7,37 (s, 1H), 7,46 (d, J=9.0 Hz, 2H), 7,55 (s, 1H), 8,48 (W, 1H), 8,53 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 383 (M++1).

Example 65: N-butyl-N’-{4-[(6,7-dimethoxy-4-hintline)-oxy]phenyl}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (50 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added butyl is min (22 μl), and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 29 mg (yield 43%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.91 (t, J=7,3 Hz, 3H), of 1.28 to 1.47 (m, 4H), 3,07-of 3.12 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), 6,12 (t, J=5.6 Hz, 1H), 7,15 (d, J=8,8 Hz, 2H), 7,37 (s, 1H), 7,46 (d, J=9.0 Hz, 2H), 7,55 (s, 1H), of 8.47 (W, 1H), 8,53 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 397 (M++1).

Example 66 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-phenyl}-N’-pencilmation

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (50 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution add amylamine (26 μl), and the mixture is stirred at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 21 mg (30%yield) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 0.89 (t, J=7,1 Hz, 3H), of 1.27 to 1.47 (m, 4H), of 1.41 to 1.48 (m, 2H), 3,06-5 3,11 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), 6,13 (t, J=5.6 Hz, 1H), 7,15 (d, J=9.0 Hz, 2H), 7,37 (s, 1H), 7,46 (d, J=8,8 Hz, 2H), 7,55 (s, 1H), of 8.47 (W, 1H), 8,53 (s, 1H).

Determination of molecular weight of ESI-MS, m/z); 411 (M++1).

Example 67 N-(sec-Butyl)-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) is dissolved

in chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (50 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then add second-butylamine (23 μl), and the mixture is stirred at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 33 mg (yield 49%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 0.88 (t, J=7,3 Hz, 3H), of 1.08 (d, J=6.6 Hz, 3H), of 1.40 to 1.47 (m, 2H), to 3.58-to 3.64 (m, 1H), of 3.97 (s, 3H), 3,99 (s, 3H), 5,98 (t, J=8,1 Hz, 1H), 7,15 (d, J=9.0 Hz, 2H), 7,37 (s, 1H), 7,46 (d, J=9.0 Hz, 2H), 7,55 (s, 1H), scored 8.38 (s, 1H), 8,53 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 397 (M++1).

Example 68: N-Allyl-N’-{4-[(6,7-Dimethoxy-4-hintline)-oxy]phenyl}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (50 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution add allylamine hydrochloride (31 mg) and the mixture is stirred at room temperature overnight. To the reaction R is the target add methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 21 mg (yield 33%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 3.73 is 3.76 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), 5,07-to 5.21 (m, 2H), of 5.84-of 5.92 (m, 1H), 6,28 (t, J=5.6 Hz, 1H), 7,16 (d, J=9.0 Hz, 2H), 7,38 (s, 1H), 7,47 (d, J=9.0 Hz, 2H), 7,55 (s, 1H), 8,53 (s, 1H), 8,59 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 381 (M++1).

Example 69 N-{4-[(6,7-Dimethoxy-4-hintline)-oxy]-phenyl}-N’-(2-PROPYNYL)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (50 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added the hydrochloride propargylamine (31 mg), and the mixture is stirred at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 26 mg (yield 41%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,11-of 3.12 (m, 1H), 3,89-3,90 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), of 6.49 (t, J=5,9 Hz, 1H), 7,17 (d, J=9.0 Hz, 2H), 7,38 (s, 1H), of 7.48 (d, J=8,8 Hz, 2H), 7,55 (s, 1H), 8,53 (s, 1H), 8,68 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 379 (M++1).

Example 70: N-(2,4-Diferensial)-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}urea

4-[(6,7-Dimethoxy-4-hinata inil)oxy]aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (50 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2,4-differentiatin (22 μl), and the mixture is stirred at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 32 mg (yield 41%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 3.97 (s, 3H), 3,98 (s, 3H), 4,32-to 4.33 (m, 2H), 6,66 (t, J=5,9 Hz, 1H), 7,06-7,10 (m, 1H), 7,16 (d, J=8,8 Hz, 2H), 7,19-7,24 (m, 1H), 7,37 (s, 1H), 7,40-7,44 (m, 1H), of 7.48 (d, J=9.0 Hz, 2H), at 7.55 (s, 1H), charged 8.52 (s, 1H), 8,69 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 467 (M++1).

Example 71: N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-phenyl}-N’-(2-pyridylmethyl)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.2 ml) and then to the solution was added a solution of triphosgene (50 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2,4-differentiatin (31 μl), and the mixture is stirred at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 31 mg (yield 43%) specified in the connection header.

1H NMR (DMS-d 6, 400 MHz): δ of 3.42 (s, 2H), 3,98 (s, 3H), 3,99 (s, 3H), 7,16-7,19 (m, 2H), 7,22-7,27 (m, 3H), 7,38 (s, 1H), EUR 7.57 (s, 1H), to 7.67 (d, J=8,8 Hz, 2H), 7,88-a 7.92 (m, 1H), 8,46-8,48 (m, 1H), 8,54 (s, 1H), 8,87 (s, 1H), 12,19 (s, 1H).

Determination of molecular weight (FD-MS, m/z): 431 (M+).

Example 72 N-(2,4-Differenl)-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added 2,4-differentiational (24 μl). The mixture is heated under reflux during the night. The precipitated crystals are collected by filtration and washed, receiving 55 mg (yield 72%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,98 (s, 3H), 3,99 (s, 3H),? 7.04 baby mortality-was 7.08 (m, 2H), 7,24 (d, J=8,8 Hz, 2H), 7,29-7,35 (m, 1H), 7,38 (s, 1H), 7,54 (d, J=9.0 Hz, 2H), 7,56 (s, 1H), 8,06-to 8.14 (m, 1H), 8,51-8,54 (m, 1H), 8,54 (, 1H), 9,11-9,12 (m, 1H).

Determination of molecular mass (ESI-MS, m/z): 453 (M++1).

Example 73: N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-phenyl}-N’-(4-forfinal)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added p-forgenerations (23 μl). The mixture is heated under reflux during the night. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 26 mg (yield 36%) specified in the connection header.

1H NMR (DMSO-d 6, 400 MHz): δ 3,98 (s, 3H), 3,99 (20 MN), 7,11-to 7.15 (m, 2H), 7,22 (d, J=8,8 Hz, 2H), 7,38 (s, IE), 7,46 is 7.50 (m, 2H), 7,54 (d, J=9.0 Hz, 2H), 7,56 (s, 1H), 8,54 (s, 1H), 8,72 (s, 1H), up 8.75 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 435 (M++1).

Example 74 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-phenyl}-N’-(2-were)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added o-colorization (25 μl). The mixture is heated under reflux during the night. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 30 mg (yield 41%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ and 2.26 (s, 3H), 3,98 (s, 3H), 3,99 (s, 3H), 6,93-6,98 (m, 1H), 7,13-7,19 (m, 2H), 7,22 (d, J=8,8 Hz, 2H), 7,38 (s, 1H), 7,54-7,56 (m, 3H), 7,83-7,86 (m, 1H), to 7.93 (s, 1H), 8,54 (s, 1H), 9,10-9,11 (m, 1H).

Determination of molecular mass (ESI-MS, m/z): 431 (M++1).

Example 75 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-phenyl}-N’-(2-methoxyphenyl)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added 2-methoxyphenylalanine (27 μl). The mixture is heated under reflux during the night. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 34 mg (yield 45%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ the 3.89 (s, 3H), 3,98 (s, 3H), 3,99 (s, 3H), 6.89 in-7,05 (m, 3H), 7,22 (d, J=8,8 Hz, 2H), 7,38 (s, 1H), 7,54 (d, J=8,8 Hz, 2H), 7,56 (s, 1H), 8,13-of 8.15 (m, 1H), 8,23-8,24 (m, 1H), 8,54 (s, 1H), 9,40-9,41 (m, 1H).

Determination of molecular mass (ESI-MS, m/z): 447 (M++1).

Example 76 N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N’-atilmotin

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (200 mg) dissolved in chloroform (5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (179 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added ethylamine hydrochloride (246 mg) and the mixture is stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, getting 159 mg (yield 65%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ a 1.08 (t, J=7,1 Hz, 3H), 3,11 -, and 3.16 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), of 6.96 (t, J=5.6 Hz, 1H), 7.23 percent (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,39 (s, 1H), 7,47 (d, J=2.7 Hz, 1H), 7,55 (s, 1H), 8,02 (, 1H), to 8.20 (d, J=9,3 Hz, 1H), 8,56 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 403 (M++1).

Example 77: N-butyl-N is-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (45 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added butylamine (22 μl), and the mixture is stirred at room temperature for another 30 minutes To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 30 mg (yield 46%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.91 (t, J=7,3 Hz, 3H), 1,31 of 1.46 (m, 4H), 3,09-3,14 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), of 6.96 (t, J=5.6 Hz, 1H), 7.23 percent (DD, J =2.7 Hz, 9.0 Hz, 1H), 7,39 (s, 1H), 7,47 (d, J=2.7 Hz, 1H), 7,55 (s, 1H), 8,03 (s, 1H), to 8.20 (d, J=9.0 Hz, 1H), 8,56 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 431 (M++1).

Example 78 N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N’-pencilmation

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (45 mg) in chloroform. The mixture is stirred at room temperature for 30 min. Then the reaction solution add amylamine (26 μl), and the mixture is stirred at room temperature for another 30 minutes To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 33 mg (yield 49%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.90 (t, J=7,1 Hz, 3H), of 1.24 to 1.34 (m, 4H), USD 1.43 to 1.48 (m, 2H), is 3.08-3,14 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), 6,97 (t, J=5,1 Hz, 1H), 7.23 percent (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,39 (s, 1H), 7,47 (d, J=2,8 Hz, 1H), 7,55 (s, 1H), 8,03 (s, 1H), to 8.20 (d, J=9.0 Hz, 1H), 8,56 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 445 (M++1).

Example 79 N-(sec-Butyl)-N’-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (45 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added sec-butylamine (23 μl), and the mixture is stirred at room temperature for another 30 minutes To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over betwo the major sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 34 mg (yield 52%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 0.89 (t, J=7,6 Hz, 3H), of 1.09 (d, J=6.6 Hz, 3H), 1,43 of 1.46 (m, 2H), to 3.58-3,66 (m, 1H), of 3.97 (s, 3H), 3,99 (s, 3H), to 6.88 (d, J=7,6 Hz, 1H), 7,22 (DD, J=2,4 Hz and 9.3 Hz, 1H), 7,39 (s, 1H), 7,47 (d, J=2.7 Hz, 1H), 7,55 (s, 1H), 7,98 (s, 1H), 8,23 (d, J=9.0 Hz, 1H), 8,55-8,56 (m, 1H).

Determination of molecular mass (ESI-MS, m/z): 431 (M++1).

Example 80: N-Allyl-N’-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (45 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added the hydrochloride allylamine (21 mg), and the mixture is stirred at room temperature for another 30 minutes To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 45 mg (yield 72%) specified in the connection header.

1H NMR (DMSO-d , 400 MHz): δ 3,76-with 3.79 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), 5,10-5,24 (m, 2H), 5,85-5,94 (m, 1H), 7,11 (t, J=5.4 Hz, 1H), 7,24 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,39 (s, 1H), 7,49 (d, J=2.7 Hz, 1H), 7,55 (s, 1H), 8,14 (s, 1H), 8,19 (d, J=9.0 Hz, 1H), 8,56 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 415 (M++1).

Example 81: N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N’-(2-PROPYNYL)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (45 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added the hydrochloride propargylamine (21 mg), and the mixture is stirred at room temperature for a further 30 minutes the Precipitated crystals are collected by filtration and washed, receiving 38 mg (yield 61%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,16-3,17 (m, 1H), 3,93-3,95 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), 7,25 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,30 (t, J=5.6 Hz, 1H), 7,39 (s, 1H), 7,50 (d, J=2.7 Hz, 1H), 7,55 (s, 1H), 8,16 (d, J=9,3 Hz, 1H), 8,18 (s, 1H), 8,56 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 413 (M++1).

Example 82 N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N’-(2,4-diferensial)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (45 mg) chloroforme. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2,4-differentiatin (22 μl), and the mixture is stirred at room temperature for a further 30 minutes the Precipitated crystals are collected by filtration and washed, receiving 48 mg (yield 64%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 3.97 (s, 3H), 3,99 (s, 3H), 4,33 is 4.36 (m, 2H), 7,08 for 7.12 (m, 1H), 7,22-7,28 (m, 2H), 7,39 (s, 1H), 7,42-7,46 (m, 1H), 7,49 (d, J=2.7 Hz, 1H), 7,54 (s, 1H), 8,18-to 8.20 (m, 2H), 8,56 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 501 (M++1).

Example 83 N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N’-(2-pyridylmethyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (45 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2-(methylamino)pyridine (19 ml)and the mixture stirred at 60°C for one hour. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 26 mg (Ihad 37%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 3,51 (s, 2H), 4,07 (s, 3H), 4,07 (s, 3H), 7.03 is-7,10 (m, 2H), 7,19 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,35 (s, 1H), was 7.36 (d, J=2.7 Hz, 1H), 7,54 (s, 1H), 7,76-7,81 (m, 1H), scored 8.38-8,43 (m, 1H), 8,56 (d, J=9.0 Hz, 1H), 8,64 (s, 1H), 13,53 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 466 (M++1).

Example 85 N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N’-(4-forfinal)urea

2-Chloro-4-1(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (5 ml), and then to the solution was added p-forgenerations (21 μl). The mixture was stirred at 60°C for one hour. The precipitated crystals are collected by filtration and washed, receiving 57 mg (yield 81%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,98 (s, 3H), 3,99 (s, 3H), 7,13-7,17 (m, 2H), 7,30 (DD, J=2,4 Hz and 8.8 Hz, 1H), 7,40 (s, 1H), of 7.48-7,51 (m, 2H), 7,55-7,56 (m, 2H), 8,21 (d, J=9.0 Hz, 1H), 8,31 (s, 1H), to 8.57 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 469 (M++1).

Example 86 N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N’- (2-methoxyphenyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (5 ml), and then to the solution was added 2-methoxyphenylalanine (24 μl). The mixture was stirred at 60°C for one hour. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 39 mg (yield 54%) specified in sagola the ke of the connection.

1H NMR (DMSO-d6, 400 MHz): δ are 3.90 (s, 3H), 3,98 (s, 3H), 3,99 (s, 3H), 6.89 in-7,05 (m, 3H), 7,29 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,40 (s, 1H), 7,54 (d, J=2.7 Hz, 1H), 7,56 (s, 1H), 8,09-8,16 (m, 2H), 8,58 (s, 1H), 8,96-9,02 (m, 2H).

Determination of molecular mass (ESI-MS, m/z): 418 (M++1).

Example 87: N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N’-(5-chloro-2-pyridyl)urea

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (5 ml) and triethylamine (1 ml), and then to the solution was added a solution of triphosgene (45 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2-amino-5-chloropyridin (23 mg)and the mixture stirred at 60°C for one hour. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 39 mg (yield 53%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,98 (s, 3H), of 4.00 (s, 3H), 7,33 (DD, J=2.7 Hz, 9.3 Hz, 1H), 7,40 (s, 1H), 7,43-of 7.48 (m, 1H), 7,56 (s, 1H), 7,60 (d, J=2.7 Hz, 1H), to $ 7.91 (DD, J=2.7 Hz, 9.0 Hz, 1H), 8,35 (d, J=8,8 Hz, 1H), to 8.40 (d, J=2.4 Hz, 1H), 8,58 (s, 1H), 10,17 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 486 (M++1).

Primer: N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-2-forfinal}-N’-proprotein

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-fluoro-aniline (50 mg) dissolved in chloroform (3 ml), and triethylamine (0.3 ml), and then to the solution was added a solution of triphosgene (47 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added Propylamine (20 ml)and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 9 mg (yield 14%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.90 (t, J=7, 6 Hz, 3H), 1,43-1,49 (m, 2H), 3,05-3,10 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), of 6.61 (t, J=5.6 Hz, 1H), 7,05-7,07 (m, 1H), 7,27-7,31 (m, 1H), 7,38 (s, 1H), 7,54 (s, 1H), 8,14-8,19 (m, 1H), 8,28-8,29 (m, 1H), 8,55 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 401 (M++1).

Example 89 N-butyl-N’-{4-[(6,7-dimethoxy-4-hintline)-oxy]-2-forfinal}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-fluoro-aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and then to the solution was added a solution of triphosgene (47 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then add butylamine (24 μl)and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/meth is Nol, receiving 25 mg (yield 38%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.91 (t, J=7,3 Hz, 3H), of 1.30 to 1.47 (m, 4H), 3,09-3,13 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), return of 6.58 (t, J=5.6 Hz, 1H),? 7.04 baby mortality-7,07 (m, 1H), 7,28-7,31 (m, 1H), 7,38 (s, 1H), 7,54 (s, 1H), 8,14-8,19 (m, 1H), compared to 8.26-of 8.28 (m, 1H), 8,55 (s, 1H).

Determination of molecular mass (ESI-MS, m/z)415 (M++1).

Example 90 N-(sec-Butyl)-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-forfinal}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-fluoro-aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and then to the solution was added a solution of triphosgene (47 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added sec-butylamine (25 μl)and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 12 mg (yield 18%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 0.89 (t, J=7,6 Hz, 3H), of 1.08 (d, J=6.6 Hz, 3H), of 1.39 to 1.48 (m, 2H), to 3.58-to 3.64 (m, 1H), of 3.97 (s, 3H), 3,99 (s, 3H), 6,51 (d, J=7,6 Hz, 1H),? 7.04 baby mortality-was 7.08 (m, 1H), 7,30 (DD, J=2,4 Hz, 11.7 Hz, 1H), 7,39 (s, 1H), 7,54 (s, 1H), 8,16 is 8.22 (m, 2H), 8,56 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 415 (M++1).

Example 91: N-Allyl-N’-(4-[(6,7-dimethoxy-4-hintline)-oxy]-2-forfinal)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]2-fluoro-aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and then to the solution was added a solution of triphosgene (47 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added the hydrochloride allylamine (30 mg)and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 18 mg (yield 28%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,75-with 3.79 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), 5,08-5,22 (m, 2H), of 5.84-5,94 (m, 1H), 6,72 (t, J=5,9 Hz, 1H), 7,06-was 7.08 (m, 1H), 7,30-7,33 (m, 1H), 7,39 (s, 1H), 7,54 (s, 1H), 8,13-8,18 (m, 1H), 8,40 (s, 1H), 8,56 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 399 (M++1).

Example 92 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-2-forfinal}-N’-(2-PROPYNYL)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-fluoro-aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and then to the solution was added a solution of triphosgene (47 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added the hydrochloride propargylamine (29 mg)and the mixture continued to stir at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over besod the first sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue was washed with chloroform, receiving 21 mg (yield 33%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,15 (t, J=2.4 Hz, 1H), 3,91-of 3.94 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), 7,07-7,11 (m, 1H), 7,33 (DD, J=2,4 Hz, 11.7 Hz, 1H), 7,39 (s, 1H), 7,54 (s, 1H), 8,09-of 8.15 (m, 1H), of 8.47-8,48 (m, 1H), 8,56 (s, 1H).

Determination of molecular mass (ESI-MS, m/z); 397 (M++1).

Example 93 N-(2,4-Diferensial)-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-forfinal}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-fluoro-aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and then to the solution was added a solution of triphosgene (47 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added 2,4-differentiatin (28 μl)and the mixture continued to stir at room temperature overnight. The precipitated crystals are collected by filtration and washed, receiving 20 mg (yield 26%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 3.97 (s, 3H), 3,99 (s, 3H), 4,34 (d, J=5.8 Hz, 2H), 7,07-7,11 (m, 3H), 7,21-7,27 (m, 1H), 7,30-7,33 (m, 1H), 7,39 (s, 1H), 7,41-7,47 (m, 1H), 7,54 (s, 1H), 8,12-8,16 (m, 1H), 8,46-of 8.47 (m, 1H), 8,55 (s, 1H).

Determination of molecular weight (FD-MS, m/z): 484 (M+).

Example 94 N-(2,4-Differenl)-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-forfinal}urea

4-[(6,7-Dimmock and-4-hintline)oxy]-2-fluoro-aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added 2,4-differentiational (29 μl). The mixture was stirred at 60°With during the night. The precipitated crystals are collected by filtration and washed, receiving 50 mg (yield 67%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 3,98 (s, 3H), 3,99 (C, 10 3H),? 7.04 baby mortality-was 7.08 (m, 1H), 7,13-to 7.15 (m, 1H), 7,29-7,40 (m, MN), at 7.55 (s, 1H), 8,10-8,23 (m, 2H), to 8.57 (s, 1H), 8,97-9,04 (m, 2H).

Determination of molecular mass (ESI-MS, m/z): 471 (M++1).

Example 95 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-2-forfinal}-N’-(2-were)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-fluoro-aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added o-colorization (30 μl). The mixture was stirred at 60°With during the night. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 17 mg (yield 24%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz); δ and 2.27 (s, 3H), 3,98 (s, 3H), 3,99 (s, 3H), 6,95-6,98 (m, 1H), 7,12-7,20 (m, 3H), of 7.36-7,39 (m, 2H), 7,55 (s, 1H), 7,86 (d, J=7.8 Hz, 1H), 8,21 compared to 8.26 (m, 1H), 8,35 (s, 1H), to 8.57 (s, 1H), 9,00-9,02 (m, 1H).

Determination of molecular mass (ESI-MS, m/z): 449 (M++1).

Example 96 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-2-forfinal}-N’-(2-methoxyphenyl)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-fluoro-aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added 2-methoxyphenyl solanet (32 μl). The mixture was stirred at 60°With during the night. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 22 mg (30%yield) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ the 3.89 (s, 3H), 3,98 (s, 3H), 3,99 (s, 3H), 6,88? 7.04 baby mortality (m, 3H), 7,11-7,14 (m, 1H), 7,35-7,39 (m, 1H), 7,40 (s, 1H), 7,56 (s, 1H), 8,12-of 8.15 (m, 1H), 8,19-of 8.25 (m, 1H), to 8.57 (s, 1H), 8,75-8,78 (m, 1H), 9,26-9,29 (m, 1H).

Determination of molecular mass (ESI-MS, m/z): 465 (M++1).

Example 97 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-3-were}-N’-proprotein

4-[(6,7-Dimethoxy-4-hintline)oxy]-3-methyl-aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (48 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added Propylamine (20 ml)and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 30 mg (yield 47%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 0.89 (t, J=7.5 Hz, 3H), 1.41 to 1.50 in (m, 2H), 2,03 (s, 3H), 3,03-is 3.08 (m, 2H), 3,98 (s, 3H), 3,99 (s, 3H), 6,13 (t, J=5.4 Hz, 1H 25),? 7.04 baby mortality (d, J=8.5 Hz, 1H), 7,28 (DD, J=2,4 Hz, 8.5 Hz, 1H), of 7.36 (d, J=2.4 Hz, 1H), 7,38 (s, 1H), 7,58 (s, 1H), 8,39 (s, 1H), and 8.50 (s, 1H).

Definition molecularmass (ESI-MS, m/z): 397 (M++1).

Example 98 N-butyl-N’-{4-[(6,7-dimethoxy-4-hintline)-oxy]-3-were}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-3-methyl-aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (48 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added butylamine (24 μl)and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 31 mg (yield 47%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.91 (t, J=7,3 Hz, 3H), 1,29 of 1.46 (m, 4H), 2,03 (s, 3H), 3,07-of 3.12 (m, 2H), 3,98 (s, 3H), 3,99 (s, 3H), 6,11 (t, J=5.6 Hz, 1H), 7,05 (d, J=8,8 Hz, 1H), 7,27 (DD, J=2.3 Hz, 8.5 Hz, 1H), of 7.36 (d, J=2.4 Hz, 1H), 7,38 (s, 1H), 7,58 (s, 1H), 8,39 (s, 1H), 8,51 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 411 (M++1).

Example 99 N-(2,4-Differenl)-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-3-were}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-3-methyl-aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added 2,4-differentiational (23 μl). The mixture is heated under reflux during the night. The precipitated crystals are collected by filtration and washed, receiving 59 mg (yield 79%) specified in the header with the unity.

1H NMR (DMSO-d6, 400 MHz): δ 2,07 (s, 3H), 3,99 (s, 3H), 3,99 (s, 3H), 7.03 is-was 7.08 (m, 1H), 7,14 (d, J=8.5 Hz, 1H), 7,29-7,37 (m, 2H), 7,39 (s, 1H), 7,43 (d, J=2.4 Hz, 1H), 7,60 (s, 1H), 8.07-a to 8.14 (m, 1H), charged 8.52 (s, 1H), 9,03-9,05 (m, 1H).

Determination of molecular mass (ESI-MS, m/z): 467 (M++1).

Example 100 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-3-were)-N’-(4-forfinal)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-3-methyl-aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added p-forgenerations (22 μl). The mixture is heated under reflux during the night. The precipitated crystals are collected by filtration and washed, receiving 42 mg (yield 58%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 2,07 (s, 3H), 3,98 (s, 3H), 3,99 (s, 3H), 7,10-7,14 (m, 3H), 7,35 (DD, J=2,4 Hz, 8.5 Hz, 1H), 7,39 (s, 1H), 7,43 (d, J=2.4 Hz, 1H), 7,46-7,49 (m, 2H), to 7.59 (s, 1H), 8,51 (s, 1H), 8,66 (s, 1H), to 8.70 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 449 (M++1).

Example 101: N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-3-were}-N’-(2-methoxyphenyl)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-3-methyl-aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added 2-methoxyphenylalanine (26 μl). The mixture is heated under reflux during the night. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 41 mg (yield 55%) pointed to by the th in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 2,07 (s, 3H), with 3.89 (s, 3H), 3,99 (s, 3H), 3,99 (s, 3H), 6,88-6,97 (m, 2H), 7,01-7,03 (m, 1H), 7,12 (d, J=8.5 Hz, 1H), 7,35 (DD, J=2,4 Hz, 8.5 Hz, 1H), 7,39 (s, 1H), 7,44 (d, J=2.4 Hz, 1H), 7,60 (s, 1H), 8,13-of 8.15 (m, 1H), 8,23 (s, 1H), charged 8.52 (s, 1H), was 9.33 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 461 (M++1).

Example 102 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-2-were}-N’-proprotein

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-methyl-aniline (50 mg) dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (48 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added Propylamine (20 ml)and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 30 mg (yield 47%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.90 (t, J=7,3 Hz, 3H), 1,42-is 1.51 (m, 2H), of 2.21 (s, 3H), 3.04 from-to 3.09 (m, 2H), of 3.97 (s, 3H), 3,99 (s, 3H), 6,53 (t, J=5.6 Hz, 1H), 7,02 (DD, J=2.7 Hz, 8,8 Hz, 1H), was 7.08 (d, J=2.7 Hz, 1H), 7,37 (s, 1H), 7,54 (s, 1H), 7,65 (s, 1H), a 7.85 (d, J=8,8 Hz, 1H), 8,53 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 397 (M++1).

Example 103: N-butyl-N’-{4-[(6,7-dimethoxy-4-hintline)-oxy]-2-were}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-methyl-aniline (50 mg) dissolved the chloroform (3 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (48 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added butylamine (24 μl)and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 37 mg (yield 56%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 0.92 (t, J=7,1 Hz, 3H), of 1.31 to 1.48 (m, 4H), of 2.21 (s, 3H), is 3.08-3,13 (m, 20 2N), of 3.97 (s, 3H), 3,99 (s, 3H), 6,50 (t, J=5.4 Hz, 1H), 7,02 (DD, J=2.7 Hz, 8,8 Hz, 1H), was 7.08 (d, J=2.7 Hz, 1H), 7,37 (s, 1H), 7,54 (s, 1H), to 7.64 (s, 1H), 7,86 (d, J=8,8 Hz, 1H), 8,53 (s, 1H).

Determination of molecular weight (ES1-MS, m/z): 411 (M++1).

Example 104: N-(2,4-Differenl)-N’-(4-[(6,7-dimethoxy-4-hintline)oxy]-2-were}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-methyl-aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added 2,4-differentiational (23 μl). The mixture is heated under reflux during the night. The precipitated crystals are collected by filtration and washed with getting listed in the title compound in quantitative yield.

1H NMR (DMSO-d6, 400 MHz): δ to 2.29 (s, 3H), 3,98 (s, 3H), 3,99 (s, 3H), 7.03 is-7,11 (m, 2H), 7,16 (d, J=2.7 Hz, 1H), 7,29-7,35 (m, 1H), 7,38 (s, 1H), 7,55 (s, 1H), 7,87-of 7.90 (m, 1H), 8,13-8,19 (m, 1H), at 8.36-8,39 (m, 1H), 8,55 (s, 1H), 8,92-8,95 (m, 1H).

the Determination of molecular mass (ESI-MS, m/z): 467 (M++1).

Example 105 N-(4-[(6,7-Dimethoxy-4-hintline)oxy]-2-were}-N’-(4-forfinal)urea

4-1(6,7-Dimethoxy-4-hintline)oxy]-2-methyl-aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added p-forgenerations (22 μl). The mixture is heated under reflux during the night. The precipitated crystals are collected by filtration and washed with getting listed in the title compound in quantitative yield.

1H NMR (DMSO-d6, 400 MHz): δ of 2.28 (s, 3H), 3,98 (s, 3H), 3,99 (s, 3H), 7,08-to 7.15 (m, 4H), 7,38 (s, 1H), 7,47-to 7.50 (m, 2H), 7,55 (s, 1H), 7,84-7,88 (m, 1H), 7,98 (s, 1H), 8,55 (s, 1H), 9,03-9,05 (m, 1H).

Determination of molecular mass (ESI-MS, m/z): 449 (M++1).

Example 106 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-2-were}-N’-(2-methoxyphenyl)urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-methyl-aniline (50 mg) dissolved in chloroform (3 ml), and then to the solution was added 2-methoxyphenylalanine (26 μl). The mixture is heated under reflux during the night. The precipitated crystals are collected by filtration and washed, receiving 70 mg (yield 95%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 2.29 (s, 3H), 3,90 (s, 3H), 3,98 (s, 3H), 3,99 (s, 3H), 6.87 in-6,97 (m, 2H), 7,02? 7.04 baby mortality (m, 1H), was 7.08 (DD, J=2,9 Hz and 8.8 Hz, 1H), 7,14 (d, J=2.7 Hz, 1H), 7,38 (s, 1H), 7,55 (s, 1H), to 7.84 (d, J=8,8 Hz, 1H), 8,13-of 8.15 (m, 1H), 8,55 (s, 1H), 8,58 (s, 1H), 8,61-to 8.62 (m, 1H).

Determination of molecular mass is (ESI-MS, m/z): 461 (M++1).

Example 107 N-{4-[(6,7-Dimethoxy-4-hintline)oxy]-2-nitrophenyl}-N’-proprotein

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-nitro-aniline (50 mg) dissolved in chloroform (10 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (43 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added Propylamine (18 μl)and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 24 mg (yield 38%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.91 (t, J=7,6 Hz, 3H), 1,45-is 1.51 (m, 2H), 3,06-to 3.09 (m, 2H), 3,98 (s, 3H), of 4.00 (s, 3H), 7,40 (s, 1H), 7,52 (W, 1H), 7,58 (s, 1H), to 7.67-of 7.70 (m, 1H), 8,04-of 8.06 (m, 1H), scored 8.38-to 8.41 (m, 1H), to 8.57 (s, 1H), 9,35 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 428 (M++1).

Example 108: N-butyl-N’-{4-[(6,7-dimethoxy-4-hintline)-oxy]-2-nitrophenyl}urea

4-[(6,7-Dimethoxy-4-hintline)oxy]-2-nitro-aniline (50 mg) dissolved in chloroform (10 ml) and triethylamine (0.2 ml), and then to the solution was added a solution of triphosgene (43 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added butylamine (22 μl)and the mixture continued to stir at room Tempe is the atur during the night. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 15 mg (yield 23%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ of 0.91 (t, J=7,3 Hz, 3H), 1.30 and for 1.49 (m, 4H), 3,10-3,15 (m, 2H), 3,98 (s, 3H), of 4.00 (s, 3H), 7,40 (s, 1H), 7,51 (W, 1H), EUR 7.57 (s, 1H), 7,68 (DD, J=2,9 Hz, 9.3 Hz, 1H), with 8.05 (d, J=2,9 Hz, 1H), to 8.40 (d, J=9,2 Hz, 1H), to 8.57 (s, 1H), 9,35 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 442 (M++1).

Example 109 N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N-methoxymethyl-N’-proprotein

N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (100 mg) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added sodium hydride (60 wt.%, 88 mg). The mixture is stirred at room temperature for 15 minutes Then to the reaction solution was added chloromethylation ether (67 μl), and the mixture is stirred at room temperature for a further 30 minutes the Solvent is removed by distillation under reduced pressure and to the residue water is added. The mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 18 mg (yield 18%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δto 0.89 (t, J=7,6 Hz, 3H), 1,46-of 1.55 (m, 2H), 3,20 (W, 2N), of 3.48 (s, 3H), 4,07 (s, 3H), 4,08 (s, 3H), 4,54 (W, 2H), 7,29 (DD, J=2.7 Hz, 8.5 Hz, 1H), 7,37 (s, 1H), 7,47 (d, J=8,8 Hz, 1H), 7,50 (s, 1H), 7,50 (d, J=2,7 Hz, 1H), 8,66 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 461 (M++1).

Example 110: N-Acetyl-N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-proprotein

N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (100 mg) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added sodium hydride (60 wt.%, 88 mg). The mixture is stirred at room temperature for 15 minutes Then to the reaction solution add acetylchloride (63 μl), and the mixture is stirred at room temperature for a further 2 hours the Solvent is removed by distillation under reduced pressure and to the residue water is added. The mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/acetone, getting 27 mg (yield 26%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ and 0.98 (t, J=7,3 Hz, 3H), 1,59 by 1.68 (m, 2H), 2,04 (s, 3H), 3.27 to to 3.36 (m, 2H), 4,07 (s, 3H), 4,08 (s, MN), 7,31-7,33 (m, 1H), 7,35 (s, 1H), 7,41 (d, J=9.0 Hz, 1H), 7,50-7,51 (m, 2H), 8,63 (, 1H), remaining 9.08 (W, 1H).

Determination of molecular mass (ESI-MS, m/z): 459 (M++1).

Example 111: N’-{2-Chloro-4-[(6,7-dimethoxy-4-chinsali who yl)-oxy]phenyl}-N-methyl-N-proprotein

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (56 mg) was dissolved in chloroform (4 ml) and triethylamine (0.3 ml), and then to the solution was added a solution of triphosgene (50 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution was added N-methylpropylamine (26 μl), and the mixture is stirred at room temperature for another one hour. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol. The solvent is removed by distillation, and the obtained crystals are washed with hexane, receiving 42 mg (yield 58%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 0,99 (t, J=7,3 Hz, 3H), 1,64-of 1.74 (m, 2H), is 3.08 (s, 3H), 3,34 (t, J=7,6 Hz, 2H), 4,07 (s, 3H), 4,08 (s, 3H), 7,00 (s, 1H), 7,17 (DD, J=2.7 Hz, 9.3 Hz, 1H), 7,31 (d, J=2.7 Hz, 1H), 7,38 (, 1H), 7,53 (s, 1H), to 8.41 (d, J=9.0 Hz, 1H), 8,64 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 431 (M++1).

Example 112: N’-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N-ethyl-N-proprotein

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (80 mg) dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and then to the solution was added a solution of triphosgene (72 mg) in chloroform. The mixture is stirred at room temperature for 15 minutes Then to the reaction solution was added N-ethylpropylamine (44 μl), and the mixture is stirred at room is the temperature for another 30 minutes To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol. The solvent is removed by distillation. The resulting crystals are washed with hexane, receiving 40 mg (yield 37%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ and 1.00 (t, J=7,3 Hz, 3H), of 1.28 (t, J=7,1 Hz, 3H), 1,69-of 1.74 (m, 2H), 3,32 10 (t, J=7,6 Hz, 2H), 3.43 points (kb, J=7,1 Hz, 2H), 4,07 (s, 3H), 4,07 (s, 3H), 7,02 (s, 1H), 7,17 (DD, J=2,9 Hz and 9.2 Hz, 1H), 7,31 (d, J=2.7 Hz, 1H), was 7.36 (s, 1H), 7,53 (s, 1H), 8,42 (d, J=9.0 Hz, 1H), 8,63 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 445 (M++1).

Example 113: N’-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N,N-dipropylamine

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (100 mg) dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and then to the solution was added a solution of triphosgene (90 mg) in chloroform. The mixture is stirred at room temperature for 15 minutes Then to the reaction solution add dipropylamine (62 μl), and the mixture is stirred at room temperature for another 30 minutes To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol. The solvent is removed by distillation and the obtained crystals are washed with hexane, receiving 48 mg (yield 35%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 0,99 (t, J=7,3 Hz, 6N), from 1.66 to 1.76 (m, 4H), 3,32 (t, J=78 Hz, 4H), 4,07 (s, 3H), 4,07 (s, 3H), 7,03 (s, 1H), 7,16 (DD, J=2.7 Hz, 9.3 Hz, 1H), 7,31 (d, J=2.7 Hz, 1H), 7,34 (s, 1H), 7,52 (s, 1H), 8,43 (d, J=9.0 Hz, 1H), 8,63 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 459 (M++1).

Example 114: N-butyl-N’-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N-metalmachine

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (80 mg) dissolved in chloroform (3 ml), triethylamine (0.3 ml), and then to the solution was added a solution of triphosgene (72 mg) in chloroform. The mixture is stirred at room temperature for 15 minutes Then to the reaction solution was added N-methylbutylamine (43 μl), and the mixture is stirred at room temperature for another 30 minutes To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol. The solvent is removed by distillation, and the obtained crystals are washed with hexane, receiving 26 mg (yield 24%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 0,99 (t, J=7,3 Hz, 15 3H), 1,38 was 1.43 (m, 2H), 1,62-of 1.66 (m, 2H), of 3.07 (s, 3H), 3,40 (t, J=7,3 Hz, 2H), 4,07 (s, 3H), 4,07 (s, 3H), 7,00 (s, 1H), 7,17 (DD, J=2.7 Hz, 9.3 Hz, 1H), 7,31 (d, J=2.7 Hz, 1H), was 7.36 (s, 1H), 7,53 (s, 1H), to 8.41 (d, J=9,3 Hz, 1H), 8,63 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 445 (M++1).

Example 115: N’-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N-(4-chlorophenyl)-N-metalmachine

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (80 mg) is dissolved in chlorine is forme (3 ml) and triethylamine (0.3 ml), and then to the solution was added a solution of triphosgene (72 mg) in chloroform. The mixture is stirred at room temperature for 15 minutes Then to the reaction solution was added 4-chloro-N-methylaniline (35 μl)and the mixture heated under reflux for a further 30 minutes To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, and the solvent is removed by distillation. The resulting crystals are washed with ether, receiving 83 mg (yield 69%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ to 3.36 (s, 3H), 4,06 (s, 3H), 4,07 (s, 3H), 6.89 in (s, 1H), 7,17 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7.23 percent (d, J=2.7 Hz, 1H), 7,33-7,35 (m, 3H), of 7.48-to 7.50 (m, 3H), to 8.41 (d, J=9.0 Hz, 1H), 8,61 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 499 (M++1).

Example 116: N’-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N,N-determation

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (2 ml) and triethylamine (0.5 ml), and then to the solution was added a solution of triphosgene 10 (48 mg) in chloroform. The mixture is stirred at room temperature for 30 minutes Then to the reaction solution add diethylamine (0.5 ml)and the mixture continued to stir at room temperature overnight. Methanol is added to the reaction solution, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 37 mg (o is d 93%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 1.30 (t, J=7,1 Hz, 6N), 3,44 (kV, J=7,1 Hz, 4H), of 4.12 (s, 3H), 4,20 (s, 3H), 7,16 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,27 (s, 1H), 7,31 (d, J=2.7 Hz, 1H), to 7.59 (s, 1H), 8,15 (s, 1H), 8,48 (d, J=9,0 Hz, 1H), 8,81 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 431 (M++1).

Example 117 N-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N’-metalmachine

2-Chloro-4-[(6,7-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (2 ml), triethylamine (0.5 ml), and then to the solution was added a solution of triphosgene (48 mg) in chloroform. The mixture is stirred at room temperature for 30 min. Then the reaction solution is cooled to -78°and to the cooled reaction solution was added methylamine hydrochloride (130 mg). The temperature of the mixture spontaneously increases, and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 41 mg (yield 70%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 2.68 (d, J=4.4 Hz, 3H), of 3.97 (s, 3H), 3,99 (s, 3H), 6,86-6,88 (ha, 1H), 7,21 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,37 (s, 1H), 7,43 (d, J=2.7 Hz, 1H), 7,53 (s, 1H), 8,07 (s, 1H), 8,17 (d, J=9, 0 Hz, 1H), 8,54 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 389 (M++1).

Example 118: N’-{2-Chloro-4-[(6,7-dimethoxy-4-hintline)-hydroxy]phenyl}-N,N-dimethylation

2-Chloro-4-[(6,-dimethoxy-4-hintline)oxy]-aniline (50 mg) dissolved in chloroform (2 ml) and triethylamine (0.5 ml), and then to the solution was added a solution of triphosgene (48 mg) in chloroform. The mixture is stirred at room temperature for 30 min. Then the reaction solution is cooled to -78°and to the cooled reaction solution was added dimethylamine hydrochloride (250 mg). The temperature of the mixture spontaneously increases, and the mixture continued to stir at room temperature overnight. To the reaction solution was added methanol, and the mixture is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 33 mg (yield 53%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 3,11 (C, 6N), of 4.12 (s, 3H), 4,20 (s, 3H), 7,05 (s, 1H), 7,17 (DD, J=2,4 Hz and 9.3 Hz, 1H), 7,31 (d, J=2.4 Hz, 1H), to 7.59 (s, 1H), 8,15 (s, 1H), 8,46 (d, J=9,3 Hz, 1H), 8,82 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 403 (M++1).

Example 119 N-(2-Chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-proprotein

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N’-populatemenu (75 mg), potassium carbonate (51 mg) and 1,3-dibromopropane (76 μl) dissolved in N,N-dimethylformamide (4 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation of the ri reduced pressure. The residue is washed with ether, receiving 74 mg (yield 78%) of N-(4-{[7-(3-bromopropane)-6-methoxy-4-hintline]-oxy}-2-chlorophenyl)-N’-propylacetic as an intermediate connection.

The intermediate compound (74 mg), potassium carbonate (51 mg) and morpholine (130 μl) dissolved in N,N-dimethylformamide (4 ml)and the solution stirred at room temperature overnight. The solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 49 mg (yield 63%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 0.89 (t, J=7,44 Hz, 3H), 1.41 to 1.50 in (m, 2H), 1,97 (t, J=6,83 Hz, 1H), 2,33-2,49 (m, 4H), 3.04 from-to 3.09 (m, 2H), 3,32-to 3.38 (m, 4H), 3,52-3,68 (m, 3H), a 4.03 (s, 3H), 4,23-the 4.29 (m, 1H), 4,32 (t, J=of 5.89 Hz, 1H), 6,98 (t, J=5,49 Hz, 1H), 7,21 (DD, J=2,68, 9,03 Hz, 1H), was 7.36 (s, 1H), 7,46 (d, J=2,68 Hz, 1H), 7,53 (d, J=7,81 Hz, 1H), 8,03 (s, 1H), 8,18 (d, J=9,27 Hz, 1H), 8,54 (d, J=4,39 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 529 (M+).

Example 120 N-(2-Chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-proprotein

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (72 mg), CT is eat potassium (30 mg) and 1,2-dibromethane (62 μl) dissolved in N,N-dimethylformamide (4 ml), and the solution is stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 40 mg (yield 45%) of N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-hintline]-oxy}-2-chlorophenyl)-N’-propylacetic as an intermediate connection.

The intermediate compound (45 mg), potassium carbonate (30 mg) and morpholine (80 μl) is dissolved in N,N-dimethylformamide (2 ml)and the solution stirred at room temperature overnight. The solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 42 mg (yield 56%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 0.89 (t, J=to 7.32 Hz, 3H), 1,43-1,49 (m, 2H), 2,32-of 2.38 (m, 2H), 2,66 (W, 1H), and 2.79 (t, J=5,86 Hz, 1H), 3.04 from-to 3.09 (m, 2H), 3,29-to 3.36 (m, 4H), 3,53 (m, 1H), 3,57-3,59 (m, 2H), 3.96 points (s, 3H), or 4.31 (t, J=5,85 Hz, 1H), 6,98 (m, 1H), 7,21-of 7.23 (m, 1H), 7,41 (s, 1H), 7,46-7,47 (m, 1H), 7,55 (d, J=12,69 Hz, 1H), 8,03 (s, 1H), 8,19 (d, J=9,27 Hz, 1H), 8,55 (d, J=lower than the 5.37 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 517 (M++1).

Example 121 N-(2-Chloro-4-{[7-(3-hydroxypropoxy)-6-methoxy-4-hintline]oxy}phenyl)-N’-proprotein

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N’-populatemenu (55 mg), potassium carbonate (20 mg) and 3-bromo-1-propanol (62 μl) dissolved in N,N-dimethylformamide (4 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 25 mg (yield 40%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 0.91 (t, J=7,44 Hz, 3H), 1,24 (W, 1H), 1,43-of 1.52 (m, 2H), 1,97 (t, J=6.22 per Hz, 2H), 3,06-3,11 (m, 2H), 3,56-3,71 (m, 2H), of 3.97 (s, 3H), 4,27 (m, 2H), 6,99 (t, J=5,62 Hz, 1H), 7.23 percent (DD, J=2,68, 9,03 Hz, 1H), 7,38 (d, J=9,03 Hz, 1H), 7,47 (d, J=2,68 Hz, 1H), 7,54 (s, 1H), with 8.05 (s, 1H), to 8.20 (d, J=9,03 Hz, 1H), 8,55 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 461 (M++1).

Example 122 N-(2-Chloro-4-{[7-(2-hydroxyethoxy)-6-methoxy-4-hintline]oxy}phenyl)-N’-proprotein

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (50 mg, potassium carbonate (30 mg) and ethylenepropylene (44 μl) dissolved in N,N-dimethylformamide (4 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 12 mg (yield 22%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 0.91 (t, J=7,44 Hz, 3H), 1,42-1,49 (m, 2H), 3,06-3,11 (m, 2H), 3,80-a 3.83 (m, 2H), 3,98 (s, 3H), 4,22 (t, J=with 4.64 Hz, 2H), to 4.98 (t, J 35=lower than the 5.37 Hz, 1H), 6,99 (t, J=lower than the 5.37 Hz, 1H), 7,33 (DD, J=2,69 Hz, 9,03 Hz, 1H), 7,39 (s, 1H), of 7.48 (d, J=2,68 Hz, 1H), 7,55 (s, 1H), with 8.05 (s, 1H), 8,19 (d, J=9,27 Hz, 1H), 8,55 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 447 (M++1).

Example 123 N-(2-Chloro-4-{[6-methoxy-7-(4-pyridyloxy)-4-hintline]oxy}phenyl)-N’-proprotein

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg), and hydrochloride of 4-chloromethylpyridine (41 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 3 hours To the reaction mixture, water is added, then extracted with a mixture of a mixture of chloroform-propanol (3/1). The organic layer drying is over anhydrous sodium sulfate and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, receiving 65 mg (yield 66%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 0.96 (t, J=7,6 Hz, 3H), 1,53-of 1.64 (m, 2H), 3,25 (DD, J=7,3 Hz, 12.9 Hz, 2H), 4,07 (s, 3H), 5,32 (s, 2H), 6,66 (s, 1H), 7,14 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,27 (s, 1H), 7,29 (d, J=2.7 Hz, 1H), 7,41 (d, J=5,9 Hz, 2H), 7,54 (s, 1H), 8,24 (d, J=9.0 Hz, 1H), 8,59 (s, 1H), 8,63 (d, J=6,1 Hz, 2H).

Determination of molecular mass (ESI-MS, m/z): 494 (M++1).

Example 124 N-[2-Chloro-4-({6-methoxy-7-[(5-morpholinomethyl)-oxy]-4-hintline}oxy)phenyl]-N’-proprotein

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (70 mg), potassium carbonate (30 mg) and pentamethylbenzene (80 μl) is dissolved in N,N-dimethylformamide (5 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 43 mg (yield 46%) of N-[4-({7-(5-bromopentyl)oxy}-6-methoxy-4-hintline)oxy]-2-chlorophenyl]-N’-propylacetic as intermediate compounds. The intermediate compound (43 mg), potassium carbonate (30 mg) and morpholine (70 μl) dissolved in N,N-dimethylformamide (4 ml)and the solution stirred at room temperature overnight. Rest ritel removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 30 mg (yield 68%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 1,71 (t, J=to 7.32 Hz, 3H), 2,28 (t, J=7,20 Hz, 2H), 2.63 in (m, 2H), is 3.08-3,14 (m, 5H), 3,29-3,30 (m, 5H), 3,47 (W, 1H), to 3.73 (m, 1H), 3,86-3,90 (m, 2H), 4,36 (t, J=4,65 Hz, 3H), 4,46 (t, J=4,76 Hz, 1H), 4,77 (s, 1H), 4,99 (t, J=6,34 Hz, 2H), 7,80 (m, 1H), 8,02 (DD, J=2,68 Hz, 9,27 Hz, 1H), 8,18 (s, 1H), 8,27 (d, J=2,68 Hz, 1H), 8.34 per (s, 1H), cent to 8.85 (s, 1H), 9,00 (d, J=9,03 Hz, 1H), 9,35 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 559 (M++1).

Example 125 N-{2-Chloro-4-[(6-methoxy-7-{[5-(1H-1,2,3-triazole-1-yl)pentyl]oxy]-4-hintline)oxy]phenyl}-N’-proprotein

Triazole (0,41 ml), 1-bromo-5-chloropentane (1.0 ml), tetrabutylammonium iodide (10 mg) and 3 M aqueous sodium hydroxide solution (1 ml) dissolved in acetone (10 ml)and the solution stirred at 50°C for 18 hours To the reaction mixture, water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography, elwira chloroform, getting connected intermediate the e (390 mg).

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg), and previously obtained intermediate compound (52 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 120°C for 5 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, receiving 41 mg (yield 38%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 0.96 (t, J=7,6 Hz, 3H), 1,50-of 1.65 (m, 4H), 1,90-of 2.08 (m, 4H), 3,24 (DD, J=7,1 Hz, 12.9 Hz, 2H), 4,01 (s, 3H), 4,17 (t, J=6.6 Hz, 2H), of 4.44 (t, J=7,3 Hz, 2H), 4,88-4,94 (m, 1H), 6,32 (s, 1H), 7,14 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,25 (s, 1H), 7,29 (d, J=2.7 Hz, 1H), of 7.48 (s, 1H), 7,55 (s, 1H), of 7.70 (s, 1H), 8,23 (d, J=9.0 Hz, 1H), 8,58 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 540 (M++1).

Example 126: N’-(2-Chloro-4-{[6-methoxy-7-(4-pyridyloxy)-4-hintline]oxy}phenyl)-N,N-diethyl-urea

The original connection (N’-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N,N-determation, 83 mg), potassium carbonate (138 mg), and hydrochloride of 4-chloromethylpyridine (49 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added, and the extraction is carried out mixture is Yu chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, receiving 57 mg (yield 56%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 1.26 (t, J=7,3 Hz, 6N), 3,41 (kb, J=7,1 Hz, 4H), 4,08 (s, 3H), 5,32 (s, 2H), 6,98 (s, 1H), 7,14 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,27 (s, 1H), 7,29 (d, J=2.7 Hz, 1H), 7,41 (d, J=5,9 Hz, 2H), at 7.55 (s, 1H), of 8.37 (d, J=9.0 Hz, 1H), 8,58 (s, 1H), 8,63 (d, J=5,9 Hz, 2H).

Determination of molecular mass (ESI-MS, m/z): 508 (M++1).

Example 127 N-(2-Chloro-4-{[6-methoxy-7-(4-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-proprotein

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (70 mg), potassium carbonate (30 mg) and pentamethylene bromide (80 μl) is dissolved in N,N-dimethylformamide (5 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 43 mg (yield 46%) of N-(4-{[7-(4-bromobutoxy)-6-methoxy-4-hintline]-oxy}-2-chlorophenyl)-N’-propylacetic as an intermediate connection.

The intermediate compound (43 mg), potassium carbonate (30 mg) and morpholine (40 μl) are dissolved in N,N (4 ml), and the solution is stirred at room temperature overnight. The solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 23 mg (yield 53%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 0,99 (t, J=to 7.32 Hz, 3H), 1.56 to of 1.62 (m, 13H), 2,00-of 2.08 (m, 2H), 3,26 of 3.28 (m, 2H), Android 4.04 (s, 3H), 4,24 (m, 2H), 4,72-of 4.77 (m, 1H), 6,65 (s, 1H), 6,99 (s, 1H), 7,19-7,26 (m, 1H), 7,30 (s, 1H), 7,32-7,34 (m, 1H), 7,51 (s, 1H), 8,25 (d, J=9,03 Hz, 1H), 8,61 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 545 (M++1).

Example 128 N-[2-Chloro-4-({6-methoxy-7-[2-(4-methylpiperazin)-ethoxy]-4-hintline}oxy)phenyl]-N’-proprotein

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (60 mg), potassium carbonate (30 mg) and 1,2-dibromethane (70 μl) dissolved in N,N-dimethylformamide (4 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by elegance under reduced pressure. The residue is washed with ether, receiving 46 mg (yield 62%) of N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-hintline]-oxy}-2-chlorophenyl)-N’-propylacetic as an intermediate connection.

The intermediate compound (46 mg), potassium carbonate (20 mg) and N-methylpiperazine (50 μl) are dissolved in N,N-dimethylformamide (3 ml)and the solution stirred at room temperature overnight. The solvent is removed by distillation under reduced pressure, to the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 24 mg (yield 50%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 0,99 (t, J=to 7.32 Hz, 3H), 1,61-of 1.64 (m, 2H), 2,75 (m, 2H), 3.00 and-and 3.16 (m, 4H), 3.25 to and 3.16 (m, 4H), 3.25 to be 3.29 (m, 2H), was 4.02 (s, 3H), 4,27 is 4.35 (m, 2H), 4,78 of 4.83 (m, 2H), 5,33 (s, 3H), 6,69 (s, 1H), 7,17 (DD, J=2,68 Hz, 9,03 Hz, 1H), 7,31 (s, 1H), 7,49 (s, 1H), compared to 8.26 (d, J=9,27 Hz, 1H), 8,59 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 530 (M++1).

Example 129 N-{2-Chloro-4-[(7-{2-[(2-hydroxyethyl)(methyl)-amino]ethoxy}-6-methoxy-4-hintline)oxy]-phenyl}-N’-proprotein

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (65 mg), potassium carbonate (30 mg) and 1,2-dibromide is (30 μl) are dissolved in N,N-dimethylformamide (4 ml), and the solution is stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 36 mg (yield 45%) of N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-hintline]-oxy}-2-chlorophenyl)-N’-propylacetic as an intermediate connection.

The intermediate compound (36 mg), potassium carbonate (30 mg) and N-methylethanolamine (30 μl) are dissolved in N,N-dimethylformamide (3 ml)and the solution stirred at room temperature overnight. The solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 21 mg (yield 55%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ and 0.98 (t, J=to 7.32 Hz, 3H), of 1.59 (m, 2H), 1,94 (bs, 1H), 3,23 (m, 2H), a 4.03 (s, 3H), 4,07-to 4.15 (m, 4H), was 4.76 (m, 4H), to 5.35 (s, 3H), 7,10-7,17 (m, 1H), 7,28 (s, 3H), 7,40 (s, 1H), 7,54 (s, 1H), of 8.37 (d, J=9,03 Hz, 1H), 8,64 (s, 1H).

Determination of molecular whom assy (ESI-MS, m/z): 504 (M++1).

Example 130 N-[2-chloro-4-({6-methoxy-7-[3-(4-methylpiperazin)-propoxy]-4-hintline}oxy)phenyl]-N’-proprotein

M-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (75 mg), potassium carbonate (30 mg) and 1,3-dibromopropane (75 μl) is dissolved in N,N-dimethylformamide (4 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 50 mg (yield 52%) of N-(4-{[7-(3-bromopropane)-6-methoxy-4-hintline]-oxy}-2-chlorophenyl)-N’-propylacetic as an intermediate connection.

The intermediate compound (30 mg), potassium carbonate (20 mg) and N-methylpiperazine (40 μl) are dissolved in N,N-dimethylformamide (3 ml)and the solution stirred at room temperature overnight. The solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chlorine the product/methanol, receiving 20 mg (yield 63%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 0,99 (t, J=to 7.32 Hz, 3H), 1,58-of 1.62 (m, 2H), 2,25-2,50 (m, 3H), 2,70-to 2.85 (m, MN), 2,92 are 2.98 (m, 3H), of 3.25 (m, 2H), Android 4.04 (s, 3H), 4,25 (m, 2H), a 4.83 (m, 3H), of 5.34 (s, 3H), 6,70 (s, 1H), 35 7,21 (DD, J=2,68, 9,03 Hz, 1H), 7,26 (s, 2H), 7,31 (s, 1H), 7,49 (s, 1H), 8,18 (d, J=9,27 Hz, 1H), 8,59 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 544 (M++1).

Example 131: N’-[2-Chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)ethoxy]-4-hintline}oxy)phenyl]-N,N-determation

The original connection (N’-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N,N-dieselmachine, 83 mg), potassium carbonate (138 mg) and 2-(1H-1,2,3-triazole-1-yl)ethyl 4-methyl-1-bansilalpet (59 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving the intermediate connection. To a solution of intermediate compound and triethylamine (0,027 ml) in chloroform (1 ml) add triphosgene (90 mg) at 0°and the mixture is stirred for 30 minutes, the Reaction mixture was cooled to 0°and then to the cooled reaction mixture is added dropwise diethylamine (0,044 ml). The temperature of the mixture was raised to room te is the temperature within 2 hours To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution, then extracted with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, receiving 30 mg (yield 29%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 1.26 (t, J=7,1 Hz, 6N), to 3.41 (q, J=7,1 Hz, 4H), a 4.03 (s, 3H), 4,53 (t, J=4.9 Hz, 2H), 4,94 (t, J=5,1 Hz, 2H), 6,98 (s, 1H), 7,13 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,26 (s, 1H), 7,73 (s, 1H), 7,94 (s, 1H), scored 8.38 (d, J=9.0 Hz, 1H), at 8.60 (s, 1H).

Example 132: 3-{[4-(3-Chloro-4-{[(diethylamino)carbonyl]amino}-phenoxy)-6-methoxy-7-hintline]oxy}-propyl-N,N-diethyl-carbamate

The original connection (N’-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N,N-determation, 83 mg), potassium carbonate (138 mg) and 3-bromo-1-propanol (0,027 ml) dissolved in N,N-5-dimethylformamide (1 ml)and the solution stirred at 80°C for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving the intermediate connection. To a solution of intermediate compound and triethylamine (0,027 ml) in chloroform (1 ml) at 0°With add triphosgene (90 mg), and the mixture is stirred tip is of 30 minutes The reaction mixture was cooled to 0°and then to the cooled reaction mixture is added dropwise diethylamine (0,044 ml). The temperature of the mixture was raised to room temperature over 2 hours To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution and extracted with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, receiving 19 mg (yield 17%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ was 1.04 (t, J=7,1 Hz, 6N), to 1.22 (t, J=7,3 Hz, 6N), to 3.09 (q, J=7,1 Hz, 4H), 3,36 (kV, J=7,1 Hz, 4H), of 3.75 (t, J=6.3 Hz, 2H), of 3.97 (s, 3H), 4,29 (t, J=6,1 Hz, 2H), 6,93 (s, 1H), 7,10 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,24 (d, J=2.7 Hz, 1H), 7,27 (s, 1H), 7,45 (s, 1H), with 8.33 (d, J=9,3 Hz, 1H), 8,55 (s, 1H).

Example 133 N-[2-Chloro-4-({6-methoxy-7-[3-(4-pyridylthio)-propoxy]-4-hintline}oxy)phenyl]-M'-proprotein

The original connection (N-(4-{[7-(3-bromopropane)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and 4-mercaptopyridine (22 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution was stirred at room temperature for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation at pony is hinnon pressure. The residue is washed with ether, receiving 60 mg (yield 72%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 0.91 (t, J=7,6 Hz, 3H), 1,50-1,60 (m, 2H), 2,24 of-2.32 (m, 2H), 3,11-3,24 (m, 4H), to 3.99 (s, 3H), 4,25 (t, J=5,9 Hz, 2H), 4,70-4,80 (m, 1H), 6,62 (s, 1H), 7,11 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,11 15-7,16 (m, 2H), 7.23 percent (s, 1H), 7,25 (d, J=2.7 Hz, 1H), 7,45 (s, 1H), 8,19 (d, J=9.0 Hz, 1H), 8.30 to-a 8.34 (m, 2H), 8,55 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 554 (M++1).

Example 134 N-{2-Chloro-4-[(6-methoxy-7-{3-[(1-methyl-1H-1,2,3,4-tetrazol-5-yl)thio]propoxy}-4-hintline)-hydroxy]phenyl}-N’-proprotein

The original connection (N-(4-{[7-(3-bromopropane)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and 5-mercapto-1-tetrazol (23 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution was stirred at room temperature for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 71 mg (yield 85%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 0.91 (t, J=7,3 Hz, 3H), 1,51-of 1.56 (m, 2H), 2,39-2,48 (m, 2H), 3,17-of 3.23 (m, 2H), of 3.56 (t, J=7,1 Hz, 2H), 3,86 (s, 3H), of 3.97 (s, 3H), 4,27 (t, J=5,9 Hz, 2H), 4.75 V-4,82 (m, 1H), 6,63 (s, 1H), 7,10 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,24 (d, J=3,7 Hz, 1H), 7,44 (s, 1H), 8,19 (d, J=9.0 Hz, 1H), 8,55 (s, 1H).

Determine what their molecular mass (ESI-MS, m/z: 559 (M++1).

Example 135 N-(2-Chloro-4-{[6-methoxy-7-(3-piperidino-propoxy)-4-hintline]oxy}phenyl)-N’-proprotein

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (500 mg), potassium carbonate (857 mg) and 1,3-dibromopropane (0.5 ml) dissolved in N,N-dimethylformamide (5 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added and extracted with a mixture of chloroform/2-propanol (4/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 451 mg (71%yield) of N-(4-{[7-(3-bromopropane)-6-methoxy-4-hintline]oxy}-2-chlorophenyl}-N’-propyl-urea. N-(4-{[7-(3-Bromopropane)-6-methoxy-4-hintline]oxy}-2-chlorophenyl}-N’-populatemenu (70 mg), potassium carbonate (54 mg) and piperidine (39 μl) dissolved in N, N-dimethylformamide (2 ml)and the solution stirred at room temperature overnight. The solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, Elya is the ROI with a mixture of chloroform/methanol (20/1), receiving 35 mg (yield 50%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ and 0.98 (t, J=7,6 Hz, 3H), 1,46 (W, 2H), 1,54-of 1.66 (m, 8H), 2,15 (W, 2H), 2,44 (W, 2H), 2,55 (W, 2H), 3,20-3,30 (m, 2H), Android 4.04 (s, 3H), 4,27 (t, J=6.6 Hz, 2H), 4,77 (t, J=5,9 Hz, 1H), 6,65 (s, 1H), 7, 17 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,32 (d, J=2.7 Hz, 1H), 7,33 (s, 1H), 7,49 (s, 1H), 8,24 (d, J=9.0 Hz, 1H), 8,61 (s, 1H).

Example 136 N-[2-Chloro-4-({7-methoxy-6-[2-(4-methylpiperazin)-ethoxy]-4-hintline}oxy)phenyl]-N’-proprotein

N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (500 mg), potassium carbonate (857 mg) and 1,3-dibromopropane (0.5 ml) dissolved in N,N-dimethylformamide (5 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added and extracted with a mixture of chloroform/2-propanol (4/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 451 mg (71%yield) of N-(4-{[6-(2-bromoethoxy)-7-methoxy-4-hintline]oxy}-2-chlorophenyl}-N’-propyl-urea. N-(4-{[6-(2-Bromoethoxy)-7-methoxy-4-hintline]oxy}-2-chlorophenyl}-N’-populatemenu (50 mg), potassium carbonate (40 mg) and N-methylpiperazine (50 μl) are dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature overnight. The solvent is removed by distillation with igenom pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 20 mg (yield 44%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ and 0.98 (t, J=7,3 Hz, 3H), 1.56 to of 1.65 (m, 2H), 1.77 in (Shir, 4H), 2,31 (s, 3H), 2,53 (W, 2H), 2,71 (W, 2N), of 2.97 (t, J=6,1 Hz, 3H), 3,24-3,29 (m, 2H), Android 4.04 (s, 3H), 4,32 (t, J=6,1 Hz, 2H), a 4.83 (Shir, 1H), 6,69 (s, 1H), 7,16 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,30 (s, 1H), 7,31 (s, 1H), 7,55 (s, 1H), 8,25 (d, J=9.0 Hz, 1H), to 8.62 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 529 (M++1).

Example 137 N-[2-Chloro-4-({7-methoxy-6-[3-(4-methyl-piperazine)-propoxy]-4-hintline}oxy)phenyl]-N’-proprotein

N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-hintline)oxy]-phenyl}-N’-populatemenu (500 mg), potassium carbonate (857 mg) and 1,3-dibromopropane (0.5 ml) dissolved in N,N-dimethylformamide (5 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added and extracted with a mixture of chloroform/2-propanol (4/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ether, p is the beam 451 mg (71%yield) of N-(4-{[6-(3-bromopropane)-7-methoxy-4-hintline]oxy}-2-chlorophenyl}-N’-propylacetic. N-(4-{[6-(3-Bromopropane)-7-methoxy-4-hintline]oxy}-2-chlorophenyl}-N’-populatemenu (50 mg), potassium carbonate (40 mg) and N-methylpiperazine (50 μl) are dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature overnight. The solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 20 mg (yield 44%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ and 0.98 (t, J=7,6 Hz, 3H), 1,58-of 1.64 (m, 2H), 1,71 (Shir, 4H), 2,31 (s, 3H), 2,53 (W, 2H), 2,71 (W, 2H), 2,11-2,17 (m, 2H), 2,30 (s, 3H), 2,59-2,62 (m, 2H), 3,24-3,29 (m, 2H), Android 4.04 (s, 3H), 4.26 deaths (t, J=6.6 Hz, 2H), 4,80 (W, 1H), to 6.67 (s, 1H), 7,17 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,31 (s, 1H), 7,31 (s, 1H), 7,52 (s, 1H), 8,25 (d, J=9.0 Hz, 1H), 5 8,61 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 543 (M++1).

Example 138 N-(2-Chloro-4-{[7-methoxy-6-(2-pyridyloxy)-4-hintline]oxy}phenyl)-N’-proprotein

The original compound (N-{2-chloro-4-[(6-hydroxy-7-methoxy-4-hintline)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg), and hydrochloride of 2-(chloromethyl)pyridine (41 mg) was dissolved in N,N-dimethylformamide (1 ml), and rest the R stirred at 120° C for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ethyl acetate, receiving 54 mg (yield 55%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 0.91 (t, J=7,6 Hz, 3H), 1,51 is 1.58 (m, 2H), 3,17-up 3.22 (m, 2H), was 4.02 (s, 3H), 4,69 (W, 1H), are 5.36 (s, 2H), to 6.57 (s, 1H), was 7.08 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,21-7,29 (m, 2H), 7,53-of 7.55 (m, 2H), 7,66-7,71 (m, 1H), 8,15 (d, J=9.0 Hz, 1H), 8,55-to 8.57 (m, 2H).

Determination of molecular mass (ESI-MS, m/z): 494 (M++1).

Example 139 N-(2-Chloro-4-{[7-methoxy-6-(3-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-proprotein

The original connection (N-(4-{[6-(3-propoxy)-7-methoxy-4-hintline]oxy}-2-chlorophenyl)-N’-propylbetaine, 54 mg), potassium carbonate (138 mg) and morpholine (0,017 ml) dissolved in N, N-dimethylformamide (1 ml)and the solution stirred at 120°C for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ethyl acetate, receiving 42 mg (yield 77%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ of 0.91 (t, J=7,6 Hz, 3H), 1,47-to 1.59 (m, 4H), 1,88 is 2.00 (m, 2H), 2,35-2,48 (m, 4H), 3,20 (the d, J=7,3 Hz, 12.9 Hz, 2H), 3,62-3,74 (m, 4H), of 3.97 (s, 3H), 4,15 (t, J=6.3 Hz, 2H), 4,74-4,80 (m, 1H), 6,63 (s, 1H), to 7.09 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,24 (d, J=2.7 Hz, 1H), 7,42 (s, 1H), 8,18 (d, J=9, 0 Hz, 1H), 8,54 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 530 (M++1).

Example 140 N-{2-Chloro-4-[(6-{3-(2-hydroxyethyl)-(methyl)-amino]propoxy}-7-methoxy-4-hintline)oxy]-phenyl}-N’-proprotein

The original connection (N-(4-{[6-(3-bromopropane)-7-methoxy-4-hintline]oxy}-2-chlorophenyl)-N’-propyl-urea, 51 mg), potassium carbonate (68 mg) and 2-(methylamino)ethanol (15 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 25 mg (yield 48%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 0.95 (t, J=7,6 Hz, 3H), 1,53-of 1.62 (m, 2H), 2,08-of 2.15 (m, 2H), 2,30 (s, 3H), 2,58 (t, J=5.4 Hz, 2H), 2,68 (t, J=7,1 Hz, 2H), 3,21-3,26 (m, 2H), 3,60 (t, J=5.4 Hz, 2H), was 4.02 (s, 3H), 4,23 (t, J=6.3 Hz, 2H), is 5.06 (t, J=5.6 Hz, 1 Hz), 6,79 (s, 1H), 7,13 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,27-7,28 (m, 2H), of 7.48 (s, 1H), 8,21 (d, J=9.0 Hz, 1H), 8,58 (s, 1H).

Example 141 N-(2-Chloro-4-{[6-methoxy-7-(2-pyridyl-methoxy)-4-chinolin]oxy}phenyl)-N’-proprotein

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methox the-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) hydrochloride and 2-chloromethylpyridine (41 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, receiving 81 mg (yield 82%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.97 (t, J=7,6 Hz, 3H), 1,54-of 1.65 (m, 2H), 3,25 (DD, J=7,1 Hz, 12.9 Hz, 2H), of 4.05 (s, 3H), 4.75 V-4,82 (m, 1H), 5,42 (s, 2H), 6,46 (d, J=5.4 Hz, 1H), to 6.67 (s, 1H), was 7.08 (DD, J=2,9 Hz, 9.0 Hz, 1H), 7,19 (d, J=2.7 Hz, 1H), 7,44 (s, 1H), 7,53 (s, 1H), 7,56 (d, J=7.8 Hz, 1H), 7,69 (dt, J=2.0 Hz, 7.8 Hz, 1H), 8,25 (d, J=9.0 Hz, 1H), 8,46 (d, J=5,1 Hz, 1H), 8,61 (d, J=4,6 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 493 (M++1).

Example 142 N-(2-Chloro-4-{[6-methoxy-7-(3-pyridyl-methoxy)-4-chinolin]oxy}phenyl)-N’-proprotein

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg), and hydrochloride of 3-chloromethylpyridine (41 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by lane is racing under reduced pressure. The residue is purified by HPLC, receiving 70 mg (71%yield) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 0.97 (t, J=7,3 Hz, 3H), 1,54-of 1.65 (m, 2H), 3,25 (DD, J=7,3 Hz, 12.9 Hz, 2H), was 4.02 (s, 3H), 4,82-of 4.90 (m, 1H), and 5.30 (s, 2H), 6,47 (d, J=5.4 Hz, 1H), 6,72 (s, 1H), to 7.09 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,19 (d, J=2.7 Hz, 1H), 7,32 (DD, J=4,9 Hz, 7.8 Hz, 1H), 7,47 (s, 1H), 7,52 (s, 1H), to 7.84 (d, J=5 and 7.8 Hz, 1H), compared to 8.26 (d, J=9,3 Hz, 1H), of 8.47 (d, J=5.4 Hz, 1H), 8,58 (d, J=3.2 Hz, 1H), up 8.75 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 493 (M++1).

Example 143 N-(2-Chloro-4-{[6-methoxy-7-(4-pyridyl-methoxy)-4-chinolin]oxy}phenyl)-N’-proprotein

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg), and hydrochloride of 4-chloromethylpyridine (41 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, receiving 71 mg (71%yield) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 0.97 (t, J=7,6 Hz, 3H), 1,54-of 1.65 (m, 2H), 3,25 (DD, J=7,1 Hz, 12.9 Hz, 2H), of 4.05 (s, 3H), 4,86 to 4.92 (m, 1H), 5,32 (s, 2H), 6.48 in (d, J=4,7 Hz, 1H), 6.73 x (s, 1H), was 7.08 (DD, J=2,7 Hz, 9.0 Hz, 1H), 7,19 (d, J=2,9 Hz, 1H), 7,38 (s, 1H), 7,41 (d, J=6,1 Hz, 2H), 7,54 (s, 1H), compared to 8.26 (d, J=9.0 Hz, 1H), 8,46(d, J=5.4 Hz, 1H), 8, 61 (d, J=6,1 Hz, 2H).

Determination of molecular mass (ESI-MS, m/z): 493 (M++1).

Example 144 N-(2-Chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-chinolin]oxy}phenyl)-N’-proprotein

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 100 mg), potassium carbonate (172 mg) and 1,2-dibromethane (0,086 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution was stirred at room temperature for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, obtaining an intermediate compound (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-chinolin]oxy}-2-chlorophenyl)-N’-propylacetic). The intermediate compound, potassium carbonate (138 mg) and morpholine (0.17 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 2 hours To the reaction mixture, water is added, and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 70 mg (yield 54%) specified in the connection header.

1H NMR (Dl3400 MHz): δ of 0.91 (t, J=7,6 Hz, 3H), 1,50-to 1.59 (m, 2H), 2.57 m (t, J=4.6 Hz, 4H), 2,88 (t, J=5,9 Hz, 2H), 3,18 is 3.23 (m, 2H), 3,68 (t, J=4.6 Hz, 4H), of 3.94 (s, 3H), 4.26 deaths (t, J=5,9 Hz, 2H), to 4.98 (t, J=5.3 Hz, 2H), 6,41 (d, J=5.3 Hz, 1H), 6,74 (W, 1H), 7,03 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,14 (d, J=2.7 Hz, 1H), 7,34 (s, 1H), 7,43 (s, 1H), 8,42 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 515 (M++1).

Example 145 N-[2-Chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)ethoxy]-4-chinolin}oxy)phenyl]-N’-proprotein

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and 2-(1H-1,2,3-triazole-1-yl)ethyl 4-methyl-1-bansilalpet (59 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 120°C for 5 hours To the reaction the mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform-methanol, receiving 92 mg (yield 92%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.97 (t, J=7,6 Hz, 3H), 1,57-to 1.63 (m, 2H), 3,23 of 3.28 (m, 2H), 4,01 (s, 3H), to 4.52 (t, J=5,1 Hz, 2H), 4,81 (W, 1H), is 4.93 (t, J=5,1 Hz, 2H), 6,47 (d, J=5.4 Hz, 1H), 6,69 (s, 1H), was 7.08 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,18 (d, J=2.7 Hz, 1H), 7,37 (s, 1H), 7,51 (s, 1H), 7,72 (d, J=1.0 Hz, 1H), of 7.97 (d, J=1.0 Hz, 1H), compared to 8.26 (d, J=9.0 Hz, 1H), 8,48 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 497 (M++1).

Por the measures 146: N-[2-Chloro-4-({7-[2-(1H-1-imidazolyl)-ethoxy]-6-methoxy-4-chinolin}oxy)phenyl]-N’-proprotein

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and 2-(1H-1-imidazolyl)ethyl 4-methyl-1-benzene-sulfonate (59 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 120°C for 5 hours To the reaction mixture add water and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and the residue purified by HPLC, elwira a mixture of chloroform/methanol, receiving 81 mg (yield 82%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 0.96 (t, J=7,6 Hz, 3H), 1,50-of 1.65 (m, 2H), 1,90-of 2.08 (m, 2H), 3,24 (DD, J=7,1 Hz, 12.9 Hz, 2H), 4,01 (s, 3H), 4,17 (t, J=6.6 Hz, 2H), of 4.44 (t, J=7,3 Hz, 2H), 4,88-4,94 (m, 1H), 6,32 (s, 1H), 7,14 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,25 (s, 1H), 7,29 (d, J=2.7 Hz, 1H), of 7.48 (s, 1H), 7,55 (s, 1H), of 7.70 (s, 1H), 8,23 (d, J=9.0 Hz, 1H), 8,58 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 496 (M++1).

Example 147 N-(2-Chloro-4-{[7-(3-hydroxypropoxy)-6-methoxy-4-chinolin]oxy}phenyl)-N’-proprotein

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and 3-bromo-1-propanol (0,027 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added, and extracted with cm is sue chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 94 mg (yield 100%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.92 (t, J=7,6 Hz, 3H), 1,45-of 1.62 (m, 2H), 2,09-to 2.18 (m, 2H), 3,21 (DD, J=7,1 Hz, 12.9 Hz, 2H), a 3.87 (t, J=5.6 Hz, 2H), of 3.94 (s, 3H), or 4.31 (t, J=6,1 Hz, 2H), 4,81-to 4.87 (m, 1H), 6.42 per (d, J=a 5.1 Hz, 1H), 6,69 (s, 1H), 7,03 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,14 (d, J=2.7 Hz, 1H), was 7.36 (s, 1H), 7,43 (s, 1H), to 8.20 (d, J=9.0 Hz, 1H), 8,42 (d, J=5.4 Hz, 1H).

Example 148 N-[2-Chloro-4-({6-methoxy-7-[2-(4-methylpiperazin)-ethoxy]-4-chinolin}oxy)phenyl]-N’-proprotein

The original connection (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-chinolin]oxy}-2-chlorophenyl)-N’-propylbetaine, 50 mg), potassium carbonate (138 mg) and 1-methylpiperazine (by 0.055 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 54 mg (yield 100%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.92 (t, J=7,3 Hz, 3H), 1,49-of 1.62 (m, 2H), 2,24 (s, 3H), 2,35-2,70 (m, 2H), 2,90 (t, J=4.6 Hz, 2H), 3,21 (DD, J=7,3 Hz, 12.9 Hz, 2H), of 3.94 (s, 3H), 4.26 deaths (t, J=6,1 is C, 2H), 4.75 V-is 4.85 (m, 1H), 6,41 (d, J=5,1 Hz, 1H), to 6.67 (s, 1H),? 7.04 baby mortality 5 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,14 (d, J=2.7 Hz, 1H), 7,34 (s, 1H), 7,42 (s, 1H), 8,19 (d, J=9.0 Hz, 1H), 8,42 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 528 (M++1).

Example 149 N-(2-Chloro-4-{[7-(2-hydroxyethoxy)-6-methoxy-4-chinolin]oxy}phenyl)-N’-proprotein

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and 2-bromoethanol (0,021 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 80 mg (yield 90%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 0.96 (t, J=7,6 Hz, 3H), 1,54-of 1.65 (m, 2H), 3,25 (DD, J=7,1 Hz, 12.9 Hz, 2H), 3,99 (s, MN), 4,07 (t, J=4.4 Hz, 2H), 4,28 (t, J=4.6 Hz, 2H), 6,46 (d, J=5.4 Hz, 1H), 6,77 (d, J=8,3 Hz, 1H), was 7.08 (s, 1H), was 7.08 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,42 (s, 1H), 7,49 (s, 1H), 8,25 (d, J=9.0 Hz, 1H), 8,48 (d, J=2,9 Hz, 1H).

Example 150 N-{2-Chloro-4-[(7-{2-[(2-hydroxyethyl)-(methyl)-amino]ethoxy}-6-methoxy-4-chinolin)oxy]phenyl}-N’-proprotein

The original connection (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-chinolin]oxy}-2-chlorophenyl)-N’-propylbetaine, 50 the g), potassium carbonate (138 mg) and 2-(methylamino) ethanol (0,040 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 53 mg (yield 106%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.97 (t, J=7,6 Hz, 3H), 1,54-of 1.65 (m, 2H), 2,42 (s, 3H), 2,69 (t, J=5,1 Hz, 2H), 3,00 (t, J=5.6 Hz, 2H), 3,26 (DD, J=7,1 Hz, a 12.7 Hz, 2H), to 3.64 (t, J=5,1 Hz, 2H), 3,99 (s, 3H), 4.26 deaths (t, J=5.6 Hz, 2H), 4,66-4,69 (m, 1H), 6,46 (d, J=5,1 Hz, 1H), 6,70 (s, 1H), to 7.09 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,19 (d, J=2.7 Hz, 1H), 7,39 (s, 1H), 7,47 (s, 1H), 8,24 (d, J=9.0 Hz, 1H), of 8.47 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 503 (M++1).

Example 151 N-(2-Chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-chinolin]oxy}phenyl)-N’-proprotein

The original connection (N-(4-{[7-(3-bromopropane)-6-methoxy-4-chinolin]oxy}-2-chlorophenyl)-N’-propylbetaine, 52 mg), potassium carbonate (138 mg) and morpholine (0,044 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed p is the distillation under reduced pressure. The residue is washed with ether, receiving 23 mg (yield 44%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 0.92 (t, J=7,6 Hz, 3H), 1,49 is 1.60 (m, 2H), 2,02-2,11 (m, 2H), 2.40 a-2,47 (m, 4H), 2,52 (t, J=7,1 Hz, 2H), 3,21 (DD, J=7,1 Hz, 12.9 Hz, 2H), 3,62 at 3.69 (m, 4H), of 3.95 (s, 3H), 4,20 (t, J=6,6 Hz, 2H), 4,70-4,78 (m, 1H), 6,41 (d, J=5,1 Hz, 1H), only 6.64 (s, 1H),? 7.04 baby mortality (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,15 (d, J=2.7 Hz, 1H), 7,37 (s, 1H), 7,43 (s, 1H), to 8.20 (d, J=9.0 Hz, 1H), 8,42 (d, J=5.4 Hz, 1H).

Example 152 N-[2-Chloro-4-(6-methoxy-7-{[3-(4-methyl-piperazine derivatives)propoxy]-4-chinolin}oxy)phenyl]-N’-proprotein

The original connection (N-(4-{[7-(3-bromopropane)-6-methoxy-4-chinolin]oxy}-2-chlorophenyl)-N’-propylbetaine, 52 mg), potassium carbonate (138 mg) and 1-methylpiperazine (by 0.055 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 41 mg (yield 76%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.92 (t, J=7,6 Hz, 3H), 1,49-of 1.64 (m, 2H), 2,02 is 2.10 (m, 2H), of 2.23 (s, 3H), 2,30-of 2.56 (m, 8H), 2,52 (t, J=7,3 Hz, 2H), 3,20 (DD, J=7,1 Hz, 12.9 Hz, 2H), of 3.94 (s, 3H), 4,19 (t, J=6,8 Hz, 2H)of 4.83 to 4.92 (m, 1H), 6,40 (d, J=5,1 Hz, 1H), 6,69 (s, 1H), 7,03 (DD, J=2,9 Hz, 9.3 Hz, 1H), 7,14 (d, J=2.7 Hz, 1H), 7,35 (s, 1H), 7,42 (s, 1H), 8,19 (d, J=9.0 Hz, 1H), 8,42 (d, J=5.4 Hz, 1 is).

Determination of molecular mass (ESI-MS, m/z): 542 (M++1).

Example 153 N-[2-Chloro-4-(6-methoxy-7-{[3-(1H-1,2,3-triazole-1-yl)propoxy]-4-chinolin}oxy)phenyl]-N’-proprotein

Triazole (0,41 ml), 1-bromo-3-chloropropane (0,79 ml), tetrabutylammonium iodide (10 mg) and 3 M aqueous sodium hydroxide solution (1 ml) dissolved in acetone (10 ml)and the solution stirred at 50°C for 18 hours To the reaction mixture, water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography, elwira chloroform, obtaining an intermediate compound (327 mg).

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and intermediate compound (43 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 54 mg (yield 52%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.97 (t, J=7,6 Hz, 3H), 1,54-of 1.65 (m, 2H), 2,49-of 2.58 (m, 2H), 3,2 (DD, J=7,1 Hz to 13.2 Hz, 2H), 4,01 (s, 3H), 4,15 (t, J=5,9 Hz, 2H), 4,69 (t, J=6.6 Hz, 2H), 4,90-5,00 (m, 1H), 6,46 (d, J=5,1 Hz, 1H), 6,77 (s, 1H), was 7.08 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,19 (d, J=2.7 Hz, 1H), was 7.36 (, 1H), 7,51 (s, 1H), to 7.61 (s, 1H), to 7.67 (s, 1H), compared to 8.26 (d, J=9.0 Hz, 1H), of 8.47 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 511 (M++1).

Example 154 N-[2-Chloro-4-({7-[3-(1H-1-imidazolyl)propoxy]-6-methoxy-4-chinolin}oxy)phenyl]-N’-proprotein

The imidazole (680 mg), 1-bromo-3-chloropropane (0,79 ml), tetrabutylammonium iodide (10 mg) and 3M aqueous sodium hydroxide solution (1 ml) dissolved in acetone (10 ml)and the solution stirred at 50°C for 18 hours To the reaction mixture, water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography, elwira chloroform, obtaining an intermediate compound (1-(3-chlorpropyl)-1H-imidazole, 525 mg).

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and intermediate compound (42 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced is the making. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 23 mg (yield 23%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 0.91 (t, J=7,3 Hz, 3H), 1,48 is 1.60 (m, 2H), 2,27-of 2.36 (m, 2H), 3,20 (DD, J=6,8 Hz, 12.9 Hz, 2H), of 3.97 (s, 3H), 4,06 (t, J=5,9 Hz, 2H), 4,21 (t, J=6,8 Hz, 2H), to 6.39 (d, J=5.4 Hz, 1H), 6.90 to (with, 1H), 6,98? 7.04 baby mortality (m, 2H), 7,12 (d, J=2.7 Hz, 1H), 7,30 (s, 1H), 7,44-of 7.48 (m, 2H), by 8.22 (d, J=9.0 Hz, 1H), to 8.41 (d, J=5.4 Hz, 1H).

Example 155 N-{2-Chloro-4-[(7-{2-[di(2-hydroxyethyl)amino]-ethoxy}-6-methoxy-4-chinolin)oxy]phenyl}-N’-proprotein

The original connection (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-chinolin]oxy}-2-chlorophenyl)-N’-propylbetaine, 50 mg), potassium carbonate (138 mg) and 1-methylpiperazine (by 0.055 ml) dissolved in N,N-dimethylformamide (1 ml), and the mixture is stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 46 mg (yield 92%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.92 (t, J=7,3 Hz, 3H), 1,50-1,60 (m, 2H), 2,74 (t, J=4.9 Hz, 4H), 3.04 from (t, J=4.9 Hz, 2H), 3,15-3,24 (m, 2H), 3,60 (t, J=5, 1 Hz, 4H), of 3.94 (s, 3H), 4,17 (t, J=5.0 Hz, 2H), 6,41 (d, J=5.4 Hz, 1H), 6.75 in (s, 1H),? 7.04 baby mortality (DD, J=2,4 Hz and 8.8 Hz, 1H), 7,14 (d, J=2.7 Hz, 1H), 7,38 (s, 1H), 7,43 (s, 1H), 8,19 (d, J=9.0 Hz, 1H), 8,42 (d, J=5.4 Hz, 1H).

Example 156 N-{2-Chloro-4-(7-{3-[di(2-hydroxyethyl)amino]-propoxy}-6-methoxy-4-chinolin)oxy]phenyl}-N’-proprotein

The original connection (N-(4-{[7-(3-bromopropane)-6-methoxy-4-chinolin]oxy}-2-chlorophenyl)-N’-propylbetaine, 52 mg), potassium carbonate (138 mg) and diethanolamine (53 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 41 mg (yield 82%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.89 (t, J=7,3 Hz, 3H), 1,46-of 1.56 (m, 2H), 1,97-2,05 (m, 2H), 2.63 in (t, J=5.1 Hz, 4H), 2,69 (t, J=6,1 Hz, 2H), 3,19 (DD, J=7,1 Hz to 13.2 Hz, 2H), 3,60 (t, J=4.9 Hz, 4H), of 3.94 (s, 3H), 4,32 (t, J=5,9 Hz, 2H), 5,27 to 5.35 (m, 1H), 6,37 (d, J=5.4 Hz, 1H), 6,94 (s, 1H), 7,01 (DD, J=2,9 Hz, 9.0 Hz, 1H), 7,10 (d, J=2.7 Hz, 1H), 7,42 (s, 1H), 7,53 (s, 1H), 8,19 (d, J=9.0 Hz, 1H), 8,35 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z); 547 (M++1).

Example 157 N-{2-Chloro-4-[(7-{3-[(2-hydroxyethyl)(methyl)-amino]propoxy}-6-methoxy-4-chinolin)oxy]-phenyl}-N’-proprotein

The original connection (N-(4-{[7-(3-bromopropane)-6-methoxy-4-chinolin] oxy}-2-chlorophenyl)-N’-propylbetaine, 52 mg), potassium carbonate (138 mg) and 2-(methylamino) ethanol (0,040 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture are added water and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 51 mg (yield 98%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 0.91 (t, J=7,6 Hz, 3H), 1,45-to 1.59 (m, 2H), 2.05 is (t, J=6,8 Hz, 2H), 2,24 (s, 3H), of 2.51 (t, J=5,1 Hz, 2H), 2,59 (t, J=7,1 Hz, 2H), 3,20 (DD, J=6,8 Hz, 12.9 Hz, 2H), only 3.57 (t, J=5.4 Hz, 2H), of 3.95 (s, 3H), 4,22 (t, J=6.3 Hz, 2H), 5,00-5,08 (m, 1H), 6,40 (d, J=5,1 Hz, 1H), 6,79 (s, 1H), 7,03 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,13 (d, J=2.7 Hz, 1H), 7,426 (s, 1H), 7,433 (s, 1H), 8,19 (d, J=9.0 Hz, 1H), to 8.40 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 517 (M++1).

Example 158 N-[2-Chloro-4-({6-methoxy-7-[4-(1H-1,2,3-triazole-1-yl)butoxy]-4-chinolin}oxy)phenyl]-N’-proprotein

Triazole (0,41 ml), 1-bromo-4-chlorobutane (0,93 ml), tetrabutylammonium iodide (10 mg) and 3 M aqueous sodium hydroxide solution (1 ml) dissolved in acetone (10 ml)and the solution stirred at 50°C for 18 hours To the reaction mixture, water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography, elwira chloroform, obtaining an intermediate compound (1-(4-chlorobutyl)-1H-1,2,3-triazole, 314 mg).

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 the g) and intermediate compound (48 mg) was dissolved in N,N-dimethylformamide (1 ml), and the solution is stirred at 80°C for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 42 mg (yield 40%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.96 (t, J=7,3 Hz, 3H), 1,54-of 1.65 (m, 2H), 1,88-to 1.98 (m, 2H), 2,14-of 2.24 (m, 2H), 3,26 (DD, J=6,6 Hz to 13.2 Hz, 2H), 3,99 (s, 3H), 5 4,20 (t, J=5,9 Hz, 2H), 4,55 (t, J=7,1 Hz, 2H), 5,00-of 5.06 (m, 1H), 6,46 (d, J=5.4 Hz, 1H), 6,80 (s, 1H), was 7.08 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,19 (d, J=2.7 Hz, 1H), 7,37 (s, 1H), 7,49 (s, 1H), 7.68 per-7,72 (m, 2H), compared to 8.26 (d, J=9.0 Hz, 1H), of 8.47 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 525 (M++1).

Example 159 N-{2-Chloro-4-[(6-methoxy-7-{[5-(1H-1,2,3-triazole-1-yl)pentyl]oxy}-4-chinolin)oxy]phenyl}-N’-proprotein

Triazole (0,41 ml), 1-bromo-5-placenta (1.0 ml), tetrabutylammonium iodide (10 mg) and 3 M aqueous sodium hydroxide solution (1 ml) dissolved in acetone (10 ml)and the solution stirred at 50°C for 18 hours To the reaction mixture, water is added, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography, elwira chloroform, receiving the intermediate soy is inania (1-(5-chloropentyl-1H-1,2,3-triazole, 390 mg).

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and intermediate compound (51 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 3 hours To the reaction mixture, water is added, and the mixture is extracted with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 33 mg (yield 31%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.92 (t, J=7,6 Hz, 3H), 1,47-to 1.59 (m, 2H), 1.85 to 2,03 (m, 4H), 3,21 (DD, J=6,6 Hz to 13.2 Hz, 2H), of 3.94 (s, 3H), 4,11 (t, J=6.3 Hz, 2H), to 4.38 (t, J=7,1 Hz, 2H), 4,86-4,94 (m, 1H), 6,41 (d, J=a 5.4 Hz, 1H), of 6.71 (s, 1H), 7,03 (DD, J=2,4 Hz, 5 9,0 Hz, 1H), 7,14 (d, J=2.7 Hz, 1H), 7,31 (s, 1H), 7,43 (s, 1H), 7,51 (s, 1H), to 7.64 (s, 1H), to 8.20 (d, J=9.0 Hz, 1H), to 8.41 (d, J=5.4 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 539 (M++1).

Example 160 N-[2-Chloro-4-({7-[4-(1H-1-imidazolyl)butoxy]-6-methoxy-4-chinolin}oxy)phenyl]-N’-proprotein

The imidazole (680 mg), 1-bromo-4-chlorobutane (0,93 ml), Tetra-butylammonium iodide (10 mg) and 3M aqueous sodium hydroxide solution (1 ml) dissolved in acetone (10 ml)and the solution stirred at 50°C for 18 hours To the reaction mixture, water is added, and the mixture is extracted with chloroform. The organic layer su is at over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography, elwira chloroform, obtaining an intermediate compound (1-(4-chlorobutyl)-1H-imidazole, 756 mg).

The original compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]phenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and intermediate compound (48 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 3 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 29 mg (yield 28%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.96 (t, J=7,3 Hz, 3H), 1,54-of 1.65 (m, 2H), 1,83-of 1.95 (m, 2H), 1,98-of 2.08 (m, 2H), 3,25 (DD, J=6,8 Hz, a 12.7 Hz, 2H), 4.00 points (s, 3H), 4,10 (t, J=7,1 Hz, 2H), 4,20 (t, J=6,1 Hz, 2H), 5.08 to 5,16 (m, 1H), 6,46 (d, J=5,1 Hz, 1H), 6,83 (s, 1H), 6,97 (s, 1H), 7,06 (s, 1H), was 7.08 (DD, J=2,9 Hz, 9.3 Hz, 1H), 7,18 (d, J=2.7 Hz, 1H), 7,37 (s, 1H), 7,49 (s, 1H), 7,58 (s, 1H), compared to 8.26 (d, J=9.0 Hz, 1H), 8,46 (d, J 5=5.4 Hz, 1H).

Example 161 N-(2-Chloro-4-{[6-methoxy-7-(4-pyridyloxy)- 4-hintline]oxy}phenyl)-N’-(2,4-debtor-phenyl)urea

The original connection (N’-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N’-(2,4-differenl)urea, 80 mg), potassium carbonate (13 mg) and the hydrochloride of 4-chloromethylpyridine (41 mg) was dissolved in N,N-dimethylformamide (1 ml), and the solution is stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 50 mg (yield 52%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ a 4.03 (s, 3H), 5,46 (s, 2H), 7.03 is-7,11 (m, 1H), 7,28-7,38 (m, 1H), 7,47 (s, 1H), 7,50 (d, J=5,9 Hz, 2H), 7,56 (d, J=2.7 Hz, 1H), to 7.61 (s, 1H), 7,95 (s, 1H), 8,09-8,18 (m, 1H), 8,19 (d, J=9,0 Hz, 1H), to 8.57 (s, 1H), 8,63 (d, J=5,9 Hz, 2H), 8,81 (s, 1H), of 9.30 (s, 1H).

Example 162 N-(2-Chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-(2,4-debtor-phenyl)urea

The original connection (N’-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N’-(2,4-differenl)urea, 100 mg), potassium carbonate (857 mg) and 1,2-dibromethane (of 0.085 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, obtaining an intermediate compound (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N’-(2,4-differenl)urea).

Temporarily the second connection, potassium carbonate (138 mg) and morpholine (0.05 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 57 mg (yield 46%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ to 2.54 2.63 in (m, 4H), 2,85-to 2.94 (m, 2H), 3,66-to 3.73 (m, 4H), of 3.97 (s, 3H), 4,25-4,32 (m, 2H), 6,77-to 6.88 (m, 2H), to 7.09 (s, 1H), 7,14 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,257 (s, 1H), UAH 7,264 (s, 1H), 7,44 (, 1H), of 7.90-to 7.99 (m, 1H), they were 8.22 (d, J=9.0 Hz, 1H), 8,56 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 586 (M++1).

Example 163 N-(2-Chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline] oxy} phenyl) -NY-(2,4-debtor-phenyl) urea

The original connection (N-(4-{[7-(3-bromopropane)-6-methoxy-4-hintline] oxy}-2-chlorophenyl)-N’-(2,4-differenl)urea, 59 mg), potassium carbonate (857 mg) and morpholine (0,043 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation at ponie nom pressure. The residue is washed with ether, receiving 53 mg (yield 89%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2.06 to of 2.16 (m, 2H), 2,43-to 2.57 (m, 4H), of 2.56 (t, J=6,8 Hz, 2H), 3,68 of 3.75 (m, 4H), a 4.03 (s, 3H), 4,27 (t, J=6.6 Hz, 2H), 6,79-6,91 5 (m, 2H), 7,14 (s, 1H), 7,19 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,28 (s, 1H), 7,29 (d, J=9.0 Hz, 1H), 7,33 (s, 1H), 7,49 (s, 1H), compared to 8.26 (d, J=9.0 Hz, 1H), 8,61 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 600 (M++1).

Example 164 N-[2-Chloro-4-({6-methoxy-7-[3-(4-methyl-piperazine)-propoxy]-4-hintline)oxy)phenyl]-N’-(2,4-differenl)urea

The original connection (N-(4-{[7-(3-bromopropane)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N’-(2,4-differenl)urea, 59 mg), potassium carbonate (138 mg) and 1-methylpiperazine (by 0.055 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 58 mg (yield 95%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,01-2,12 (m, 2H), of 2.23 (s, 3H), 2,23 is 2.80 (m, 8H), of 2.51 (t, J=7,1 Hz, 2H), of 3.97 (s, 3H), 4,20 (t, J=7.2 Hz, 2H), 6.73 x-6,87 (m, 2H), 7,13 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,24 (d, J=2,7 Hz, 1H), 7,27 (s, 1H), 7,30 (s, 1H), 7,44 (s, 1H), to $ 7.91-of 8.00 (m, 2H), 8,21 (d, J=9.0 Hz, 1H), 8,56 (s, 1H).

Example 165 N-(2-Chloro-4-[(1-{3-[(2-hydro is setil)-(methyl)-amino]propoxy}-6-methoxy-4-hintline)oxy]-phenyl}-N’-(2,4-differenl)urea

The original connection (N-(4-{[7-(3-bromopropane)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N’-(2,4-differenl)urea, 59 mg), potassium carbonate (138 mg) and 2-(methylamino)ethanol (0,040 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 58 mg (yield 100%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 2.06 to of 2.16 (m, 2H), 2,30 (s, 3H), 2.57 m (t, J=5,1 Hz, 2H), 2,65 (t, J=6,8 Hz, 1H), 3,63 (t, J=5.4 Hz, 2H), was 4.02 (s, 3H), 4,28 (t, J=6,1 Hz, 2H), 6,79-6,91 (m, 2H), 7,18 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,28 (d, J=2.7 Hz, 1H), 7,37 (s, 1H), of 7.48 (s, 1H), of 7.96-of 8.06 (m, 2H), compared to 8.26 (d, J=9.0 Hz, 1H), 8,59 (s, 1H).

Determination of molecular mass (ESI-MS, m/z: 588 (M++1).

Example 166 N-[2-Chloro-4-({6-methoxy-7-[2-(4-methylpiperazine)-ethoxy]-4-chinolin}oxy)phenyl]-N’-(2,4-differenl)urea

The original connection (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-chinolin]oxy}-2-chlorophenyl)-N’-(2,4-differenl)urea, 50 mg), potassium carbonate (138 mg) and 1-methylpiperazine (by 0.055 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-ol is panel (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 48 mg (yield 93%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,31 (s, 3H), 2.40 a is 2.75 (m, 8H), 2.95 points (t, J=6,1 Hz, 2H), 3,99 (s, 3H), or 4.31 (t, J=5,9 Hz, 2H), 6.48 in (d, J=5,1 Hz, 1H), 6,85-of 6.96 (m, 3H), 7,12 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,15 (s, 1H), 35 7,22 (d, J=2.7 Hz, 1H), 7,40 (s, 1H), 7,47 (s, 1H), 7,94-8,03 (m, 1H), 8,25 (d, J=9.0 Hz, 1H), 8,49 (d, J=5,1 Hz, 1H).

Example 167 N-{2-Chloro-4-[(7-{2-[(2-hydroxyethyl)-(methyl)-amino]ethoxy}-6-methoxy-4-chinolin)oxy]phenyl}-N’-(2,4-differenl) urea

The original connection (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-chinolin] oxy}-2-chlorophenyl)-N’-(2,4-differenl)urea, 50 mg), potassium carbonate (138 mg) and 2-(methylamine)ethanol (0,040 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 48 mg (yield 97%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 2.44 (s, 3H), 2,71 (t, J=4.9 Hz, 2H), to 3.02 (t, J=5.6 Hz, 4H), 3,66 (t, J=5, 1 Hz, 2H), of 3.97 (s, 3H), 4,27 (t, J=5.6 Hz, 2H), 6,46 (d, J=5.4 Hz, 1H), 6,80-6,93 (m, 2H), 7,11 (DD, J=2,7 Hz, 9.0 Hz, 1H), 7,19 (d, J=2.7 G is, 1H), 7,45 (s, 1H), of 7.96-of 8.04 (m, 1H), 8,25 (d, J=9.0 Hz, 1H), 8,48 (d, J=5,1 Hz, 1H).

Example 168 N-(2-Chloro-4-{[6-methoxy-7-(3-morpholino-propoxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)-urea

The original connection (N-(4-{[7-(3-bromopropane)-6-methoxy-4-chinolin]oxy}-2-chlorophenyl)-N’-(2,4-differenl)urea, 50 mg), potassium carbonate (138 mg) and morpholine (0,044 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 32 mg (yield 64%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 2.06 to of 2.16 (m, 2H), 2,43 is 2.51 (m, 4H), of 2.56 (t, J=7,3 Hz, 2H), 3,68-3,74 (m, 4H), of 4.00 (s, 3H), 4,25 (t, J=6.6 Hz, 2H), 6,47 (d, J=5,1 Hz, 1H), 6,84-6,93 (m, 2H), 7,06 (s, 1H), 7,12 5 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,22 (d, J=2,9 Hz, 1H), 7,42 (s, 1H), 7,47 (s, 1H), 7.95 is-of 8.04 (m, 1H), 8,25 (d, J=9.0 Hz, 1H), 8,48 (d, J=5.4 Hz, 1H).

Example 169 N-(2-Chloro-4-{[6-methoxy-7-(3-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)-urea

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)-hydroxy]phenyl}-N’-(2,4-differenl)urea (55 mg), potassium carbonate (31 mg) and the hydrochloride of 3-picolylamine (22 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for one hour. Rast is oritel removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 30 mg (yield 48%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ a 4.03 (s, 3H), 5,31 (s, 2H), of 6.49 (d, J=5.4 Hz, 1H), 6,77-to 6.88 (m, 2H), 7,10-7,16 (m, 2H), 7,31-7,35 (m, 1H), of 7.48 (s, 1H), 7,54 (s, 1H), 7,86 (d, J=7.8 Hz, 1H), of 7.96 (s, 1H), 8,03-8,10 (m, 1H), 8,32 (d, J=9.0 Hz, 1H), 8,42 (s, 1H), 8,49 (d, J=5.4 Hz, 1H), 8,59 (d, J=3,9 Hz, 1H), 8,77 (s, 1H).

Example 170 N-[2-Chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)ethoxy]-4-chinolin}oxy)phenyl]-N’-(2,4-differenl)urea

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)-hydroxy]phenyl}-N’-(2,4-differenl)urea (55 mg), potassium carbonate (31 mg) and 2-(1H-1,2,3-triazole-1-yl) ethyl 4-methyl-1-bansilalpet (36 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°within one hours. The solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 46 mg (yield 72%) specified in the connection header.

1H NMR (Dl , 400 MHz): δ was 4.02 (s, 3H), 4,53 (d, J=4.9 Hz, 2H), 4.95 points (d, J=5,1 Hz, 2H), 6,47 (d, J=5,1 Hz, 1H), 6,83-6,92 (m, 2H), 7,11 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,16 (d, J=2.7 Hz, 1H), 7,39 (s, 1H), 7,52 (s, 1H), 7,58 (s, 1H), of 7.70 (s, 1H), 7,76 (s, 1H), 8,00 (s, 1H), 8,01-8,07 (m, 1H), 8,29 (d, J=9.0 Hz, 1H), 8,49 (d, J=5.4 Hz, 1H).

Example 171 N-(2-Methoxy-4-{[6-methoxy-7-(3-morpholine-propoxy)-4-hintline]oxy}phenyl)-N’-proprotein

N-4-[(7-Hydroxy-6-methoxy-4-hintline)oxy]-2-methoxy-phenyl}-N’-proprotein (100 mg), potassium carbonate (138 mg) and 1,3-dibromopropane (56 mg) was dissolved in N,N-dimethylformamide (5 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added and extracted with a mixture of chloroform/2-propanol (4/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 53 mg (yield 41%) of N-(4-[7-(3-bromopropane)-6-methoxy-4-hintline]oxy-2-methoxy-phenyl}-N’-propylacetic. N-(4-{[6-(3-Bromopropane)-7-methoxy-4-hintline]oxy}-2-chlorophenyl}-N’-populatemenu (50 mg), potassium carbonate (60 mg) and N-methylpiperazine (100 μl) are dissolved in N,N-dimethylformamide (2 ml)and the solution stirred at room temperature for 16 hours the Solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 22 mg (yield 42%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ to 0.97 (t, J=7,6 Hz, 3H), 1.56 to to 1.60 (m, 2H), 2,14 (W, 2H), 2,50 (Shir, 4H), 2,58 (W, 2H), 3,23-3,26 (m, 2H), 3,74 (Shir, 4H), a 3.87 (s, 3H), Android 4.04 (s, 3H), 4,27-or 4.31 (m, 2H), 4,62 with 4.64 (m, 1H), 6,65 (s, 1H), 6,79-6,85 (m, 2H), 7,33 (s, 1H), 7,53 (s, 1H), 8,10 (d, J=8.5 Hz, 1H), to 8.62 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 526 (M++1).

Example 172 N-(2,4-Differenl)-N’-(2-methoxy-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline]oxy}-phenyl)urea

N-(2,4-Differenl)-N’-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]-2-methoxyphenylacetone (375 mg), potassium carbonate (442 mg) and 1,3-dibromopropane (242 mg) was dissolved in N,N-dimethylformamide (5 ml)and the solution was stirred at room temperature for 3 hours the Solvent is removed by distillation under reduced pressure. To the residue water is added, then extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 210 mg (yield 45%) of N-{4-[7-(3-bromopropane)-6-methoxy-4-hintline]hydroxy-2-methoxyphenyl}-N’-(2,4-differenl)urea.

N-(4-{[6-(bromopropane)-7-methoxy-4-hintline]oxy}-2-chlorophenyl}-N’-populatemenu (130 mg), the triethylamine (0.5 ml) and morpholine (0.5 ml) dissolved in N,N-dimethylformamide (4 ml)and the solution stirred at room temperature for 18 hours the Solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 81 mg (yield 62%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 1,97 is 2.00 (m, 2H), 2,39 (Shir, 4H), 2.49 USD is 2.51 (m, 2H), to 3.58-of 3.60 (m, 4H), 3,88 (s, 3H), 3,98 (s, 3H), 4,25 (t, J=6.3 Hz, 2H), 4,27-or 4.31 (m, 2H), 4,62 with 4.64 (m, 1H), at 6.84 (DD, J=2.7 Hz, 8,8 Hz, 1H), 7,03-7,07 (m, 2H), 7,28-7,34 (m, 1H), 7,38 (s, 1H), 7,55 (s, 1H), 8,11-8,17 (m, 2H), 8,55 (s, 1H), total of 8.74 (s, 1H), 9,18 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 596 (M++1).

Example 173 N-(2-Methoxy-4-{[6-methoxy-7-(3-morpholine-propoxy)-4-chinolin]oxy}phenyl)-N’-proprotein

The original compound (N-{4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]-2-methoxyphenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and 1,3-dibromopropane (0.10 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-disappear to the ol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving the intermediate connection. The intermediate compound, potassium carbonate (138 mg) and morpholine (0,040 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol, receiving 74 mg (71%yield) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 0.95 (t, J=1,6 Hz, 3H), 1,52 was 1.69 (m, 2H), 2.06 to to 2.15 (m, 2H), 2,43-2,49 (m, 4H), to 2.55 (t, J=7,3 Hz, 2H), 3,23 (DD, J=6,1 Hz, 12.9 Hz, 2H), 3,67-and 3.72 (m, 4H), 3,81 (s, 3H), of 4.00 (s, 3H), 4,24 (t, J=6,8 Hz, 2H), 6,44 (d, J=5,1 Hz, 1H), of 6.68 (d, J=2.4 Hz, 1H), 6,76 (DD, J=2,4 Hz and 8.8 Hz, 1H), 7,40 (s, 1H), 7,53 (s, 1H), 8,12 (d, J=8,8 Hz, 1H), 8,44 (d, J=5,1 Hz, 1H).

Example 174 N-(2-Methoxy-4-{[6-methoxy-7-(4-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-proprotein

The original compound (N-{4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]-2-methoxyphenyl}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg), and hydrochloride of 4-chloromethylpyridine (48 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred PR is room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol getting 65 mg (yield 67%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 0.95 (t, J=7,3 Hz, 3H), 1,52 was 1.69 (m, 2H), 3,24 (DD, J=7,3 Hz, 12.9 Hz, 2H), 3,82 (s, MN), 4,06 (s, 3H), 4.63 to-4,69 (m, 1H), 5,32 (s, 2H), 6,46 (d, J=5.4 Hz, 1H), of 6.68 (d, J=2.7 Hz, 1H), 6,77 (DD, J=2,4 Hz, 8.5 Hz, 1H), 7,37 (s, 1H), 7,42 (d, J=6,1 Hz, 2H), to 7.59 (s, 1H), 8,14 (d, J=8.5 Hz, 1H), 8,43 (d, J=5.4 Hz, 1H), 8,61 (d, J=6,1 Hz, 2H).

Example 175 N-Ethyl-N’-(4-{[6-methoxy-7-(2-morpholinoethoxy)-4-chinolin]oxy}-2,5-dimetilfenil)urea

The original connection (N-ethyl-N’-{4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]-2,5-dimetilfenil}urea, 76 mg), potassium carbonate (138 mg) and 1,2-dibromethane (of 0.085 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, obtaining an intermediate compound (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-chinolin]oxy}-2,5-dimetilfenil)-N’-utilmately). Interim connected to the e, potassium carbonate (138 mg) and morpholine (0,044 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 72 mg (yield 73%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 1,10 (t, J=7,3 Hz, 3H), 2,07 (s, 3H), of 2.16 (s, 3H), 2,53 at 2.59 (m, 4H), 2,88 (t, J=5,9 Hz, 2H), 3,20-3,30 (m, 2H), 3,66-3,71 (m, 4H), 3.96 points (C, ZN), 4.26 deaths (t, J=5,9 Hz, 2H), 4,73-4,82 (m, 1H), 6,16 (s, 1H), 6,23 (d, J=5.4 Hz, 1H), to 6.88 (s, 1H), 7,35 (s, 1H), 7,40 (s, 1H), 7,50 (s, 1H), scored 8.38 (d, J=5,1 Hz, 1H).

Example 176 N-[4-({6-Methoxy-7-[3-(4-methylpiperazin)-propoxy]-4-chinolin}oxy)-2,5-dimetilfenil]-N’-proprotein

The original compound (N-{4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-propylbetaine, 80 mg), potassium carbonate (138 mg) and 1,3-dibromopropane (0.10 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, olucha intermediate compound (N-(4-{[7-(3-bromopropane)-6-methoxy-4-chinolin]oxy}-2,5-dimetilfenil)-N’-propylacetic). The intermediate compound, potassium carbonate (138 mg) and 1-methylpiperazine (by 0.055 ml) dissolved in N,N-dimethylformamide (1 ml), and the mixture is stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 33 mg (yield 31%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 0.91 (t, J=1,6 Hz, 3H), 1,50 is 1.58 (m, 2H), 2,07-of 2.20 (m, 2H), 2,12 (s, 3H), of 2.23 (s, 3H), of 2.28 (s, 3H), 2,33-2,70 (m, 10H), 3,21 (DD, J=7,3 Hz, and 13.4 Hz, 2H), 4.00 points (s, 3H), 4,24 (t, J=6,6 Hz, 2H), with 4.64 was 4.76 (m, 1H), 5,95-6,05 (m, 1H), 6,27 (d, J=5,1 Hz, 1H), 6,95 (s, 1H), 7,39-the 7.43 (m, 2H), 7,54 (s, 1H), 8,42 (d, J=5,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 536 (M++1).

Example 177 N-(2,4-Differenl)-N’-[4-({6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)ethoxy]-4-chinolin}oxy)-2,5-dimetilfenil]urea

The original connection (N-(2,4-differenl)-N’-{4-[(7-hydroxy-6-methoxy-4-chinolin)oxy]-2,5-dimethyl-phenyl}urea, 93 mg), potassium carbonate (138 mg) and 2-(1H-1,2,H-triazole-1-yl)ethyl 4-methyl-1-benzene-sulfonate (52 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for 5 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sulfate n is sodium, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 33 mg (30%yield) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,10 (s, 3H), 2,19 (s, 3H), 4,01 (s, 3H), 4,51 (t, J=4.9 Hz, 2H), is 4.93 (t, J=5.4 Hz, 2H), 4,94 (s, 1H), 6,28 (d, J=5,1 Hz, 1H), 6.75 in-to 6.88 (m, 2H), 6.90 to (s, 1H), was 7.36 (s, 1H), 7,58 (s, 1H), 7,60 (s, 1H), 7,73 (s, 1H), to 7.99 (s, 1H), 8,08 (DD, J=9,3 Hz, 15.1 Hz, 1H), to 8.41 (d, J=5,1 Hz, 1H).

Example 178: N’-(2-Chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-hintline]oxy}phenyl)-N,N-dimethylation

The original connection (N’-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N,N-dimethylation, 80 mg), potassium carbonate (138 mg) and 1,2-dibromethane (of 0.085 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, obtaining an intermediate compound (N’-(4-{[7-(2-bromoethoxy)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N,N-dimethylation).

The intermediate compound, potassium carbonate (138 mg) and morpholine (0,043 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature overnight. To the reaction with the art, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 72 mg (yield 72%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ 2,58-of 2.66 (m, 4H), 2,90 are 2.98 (m, 2H), is 3.08 (s, 6N), 3,70-with 3.79 (m, 4H), was 4.02 (s, 3H), 4,29-4,37 (m, 2H), 6,97 (s, 1H), 7,15 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7.24 to 7,26 (m, 1H), 7,29 (s, 1H), 5 7,49 (s, 1H), at 8.36 (d, J=9,3 Hz, 1H), at 8.60 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 502 (M++1).

Example 179: N’-(2-Chloro-4-{[6-methoxy-7-(4-morpholinoethoxy)-4-hintline]oxy}phenyl)-N,N-dimethylation

The original connection (N’-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N,N-dimethylation, 80 mg), potassium carbonate (138 mg) and 1,4-dibromobutane (0,12 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, obtaining an intermediate compound (N’-(4-{[7-(4-bromobutoxy)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N,N-dimethylation).

The intermediate compound, potassium carbonate (138 mg) and morpholine (0,043 ml) dissolved in N,N-dimethylformamide (1 ml) and the solution stirred at room temperature overnight. To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 47 mg (yield 44%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 1,67-to 1.77 (m, 2H), 1.93 and-2,03 (m, 2H), 2,39-of 2.50 (m, 4H), to 3.67 (s, 6N), 3,64 of 3.75 (m, 4H), was 4.02 (s, 3H), is 4.21 (t, J=6.6 Hz, 2H), 35 6,97 (s, 1H), 7,16 (DD, J=2.7 Hz, 9.3 Hz, 1H), 7,26 (s, 1H), 7,28 (s, 1H), 7,29 (d, J=2.7 Hz, 1H), of 7.48 (s, 1H), at 8.36 (d, J=9,3 Hz, 1H), 8,59 (s, 1H).

Example 180: N’-(2-Chloro-4-{[6-methoxy-7-(4-pyridyloxy)-4-hintline]oxy}phenyl)-N,N-dimethylation

The original connection (N’-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N,N-dimethylation, 50 mg), potassium carbonate (138 mg), and hydrochloride of 4-chloromethylpyridine (49 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added, and the mixture is extracted with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 37 mg (yield 60%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 3.07 (s, 6 who), 4,07 (s, 3H), 5,32 (s, 2H), 6,97 (s, 1H), 7,15 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,26 (s, 1H), 7,29 (d, J=2.7 Hz, 1H), 7,41 (d, J=6,1 Hz, 1H), 7,55 (s, 1H), of 8.37 (d, J=9, 0 Hz, 1H), 8,58 (s, 1H), 8,63 (d, J=6,1 Hz, 1H).

Determination of molecular mass (ESI-MS, m/z): 480 (M++1).

Example 181: Methyl-2-{[4-(3-chloro-4-{[(dimethylamino)-carbonyl]amino}phenoxy)-6-methoxy-7-hintline]oxy}acetate

The original connection (N’-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N,N-dimethylation, 50 mg), potassium carbonate (138 mg) and Bromeliaceae (49 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is purified by HPLC, elwira a mixture of chloroform/methanol, receiving 37 mg (yield 60%) specified in the connection header.

1H NMR (CDCl3, 400 MHz): δ of 3.07 (s, 6N), 3,82 (s, 3H), 4,06 (s, 3H), to 4.87 (s, 2H), 6,97 (s, 1H), 7,14 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,18 (s, 1H), 7,29 (d, J=2.7 Hz, 1H), 7,54 (s, 1H), at 8.36 (d, J=9.0 Hz, 1H), 8,60 (, 1H).

Example 182: N’-[2-Chloro-4-({6-methoxy-7-[3-(4-Meile-perazin)propoxy]-4-hintline}oxy)phenyl]-N,N-dimethylation

The original connection (N’-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N,N-dimethylation, 400 mg), potassium carbonate (966 mg) and 1,3-dibromopropane (,51 ml) dissolved in N,N-dimethylformamide (5 ml), and the solution is stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 398 mg (yield 78%) of intermediate compound (N’-(4-{[7-(3-bromopropane)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N,N-dimethylation). The intermediate compound (51 mg), potassium carbonate (138 mg) and 1-methylpiperazine (by 0.055 ml) dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 46 mg (yield 85%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2.06 to of 2.16 (m, 2H), to 2.29 (s, 3H), 2,30-2,60 (m, 10H), of 3.07 (s, 6N), was 4.02 (s, 3H), 4,25 (t, J=6,8 Hz, 2H), of 6.96 (s, 1H), 7,15 (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,29 (d, J=2.7 Hz, 1H), 7,30 (s, 1H), of 7.48 (s, 1H), at 8.36 (d, J=9.0 Hz, 1H), 8,59 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 529 (M++1).

Example 183: N’-{2-Chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]propoxy}-6-methoxy-4-hintline)oxy]-phenyl}-N,N-dimethylation

The source is connected to the e (N’-{2-chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]phenyl}-N,N-dimethylation, 400 mg), potassium carbonate (966 mg) and 1,3-dibromopropane (0.51 ml) dissolved in N,N-dimethylformamide (5 ml), and the mixture is stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 398 mg (yield 78%) of intermediate compound (N’-(4-{[7-(3-bromopropane)-6-methoxy-4-hintline]oxy}-2-chlorophenyl)-N,N-dimethylation).

The intermediate compound (51 mg), potassium carbonate (138 mg) and 2-(methylamino)ethanol (0,040 ml) dissolved in N,N-dimethylformamide (1 ml). The mixture is stirred at room temperature for 18 hours To the reaction mixture, water is added and the extraction is carried out with a mixture of chloroform-propanol (3/1). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The residue is washed with ether, receiving 49 mg (yield 97%) specified in the connection header.

1H NMR (Dl3, 400 MHz): δ 2,01-2,11 (m, 2H), of 2.25 (s, 3H), 2,52 (t, J=5,1 Hz, 2H), 2,61 (t, J=7,1 Hz, 2H), 3,03 (C, 6N), of 3.57 (t, J=5,1 Hz, 2H), 3,98 (s, 3H), 4,23 (t, J=6.6 Hz, 2H), 6,92 (s, 1H), 7,10 (DD, J=2,7 Hz and 9.3 Hz, 1H), 7,24 (d, J=2.7 Hz, 1H), 7,31 (s, 1H), 7,44 (s, 1H), 8,31 (d, J=9.0 Hz, 1H), 8,54 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 504 (M++1).

Example 184 N-(2-the ENT-4-{[6-methoxy-7-(3-piperidinyloxy)-4-hintline]oxy}phenyl)-N’-metalmachine

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]-phenyl}-N’-metalmachine (2.0 g) is dissolved in N,N-dimethylformamide (50 ml), and to the solution was added triphenylphosphine (2.8 g), piperidinemethanol (0.9 g) and diethylazodicarboxylate (1.9 grams). The mixture is stirred at room temperature for 2 hours To the reaction solution was again added triphenylphosphine (2.8 g), piperidinemethanol (0.6 g) and diethylazodicarboxylate (1,9 g), then stirred at room temperature for another 10 hours the Solvent is removed by distillation under reduced pressure. The residue is purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (20/1)to give 650 mg (yield 25%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ 1,37 was 1.43 (m, 2H), 1,43-of 1.53 (m, 4H), 1,96 is 2.00 (m, 2H), 2,29-of 2.50 (m, 6N), 2,68 (d, J=4,6 Hz, 3H), of 3.97 (s, 3H), 4,23 (t, J=6.3 Hz, 2H), 6,82-6,85 (m, 1H), 7.23 percent (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,38 (s, 1H), 7,47 (d, J=2.7 Hz, 1H), 7,54 (s, 1H), 8,07 (s, 1H), 8,17 (d, J=9.0 Hz, 1H), 8,55 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 500 (M++1).

Example 185 N-(2-Chloro-4-{[6-methoxy-7-(3-piperidinyloxy)-4-hintline]oxy}phenyl)-N’-atilmotin

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-hintline)oxy]-phenyl}-N’-utilmately (2.7 g) was dissolved in N,N-dimethylformamide (30 ml), and to the solution was added triphenylphosphine (3.6 g), piperidinemethanol (1.2 g) and diethylazodicarboxylate (2.4 g). The mixture is stirred at room is temperature for 2 hours To the reaction solution was again added triphenylphosphine (3.6 g), piperidinemethanol (0.8 g) and diethylazodicarboxylate (1.9 grams). The mixture is stirred at room temperature for another 10 hours the Solvent is removed by distillation under reduced pressure, and the residue purified by chromatography on silica gel, elwira a mixture of chloroform/methanol (20/1)to give 1.5 g (yield 42%) specified in the connection header.

1H NMR (DMSO-d6, 400 MHz): δ a 1.08 (t, J=7.0 Hz, 3H), 1,38-of 1.41 (m, 2H), 1,47-of 1.53 (m, 4H), 1,95-2,00 (m, 2H), 2,31 is 2.46 (m, 6N), 3,10-3,17 (m, 2H), of 3.97 (s, 3H), 4,23 (t, J=6.3 Hz, 2H), of 6.96 (t, J=5,6 5 Hz, 1H), 7.23 percent (DD, J=2.7 Hz, 9.0 Hz, 1H), 7,37 (s, 1H), 7,47 (d, J=2.7 Hz, 1H), 7,54 (s, 1H), 8,02 (s, 1H), 8,19 (d, J=9,3 Hz, 1H), 8,55 (s, 1H).

Determination of molecular mass (ESI-MS, m/z): 514 (M++1).

Example 186 N-(2-Chloro-4-{[6-methoxy-7-(4-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea

N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-chinolin)-oxy]-phenyl}-N’-(2,4-differenl)urea (55 mg), potassium carbonate (62 mg) and the hydrochloride of 4-(chloromethyl)pyridine (22 mg) was dissolved in N,N-dimethylformamide (1 ml)and the solution stirred at 80°C for one hour. The solvent is removed by distillation under reduced pressure. To the residue is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed by distillation and under reduced pressure. The residue is washed with ether, receiving 35 mg (yield 55%) specified in the connection header.

1H NMR (DMSO-d6, 400MHz): δ 3,98 (s, 3H), 5,41 (s, 2H), 6,56 (d, J=5,1 Hz, 1H),? 7.04 baby mortality-7,10 (m, 1H), 7,25-7,37 (m, 2H), 7,47 (s, 1H), 7,49-7,52 (m, 4H), 7,55 (s, 1H), 8,08-of 8.15 (m, 1H), 8,24 (d, J=9.0 Hz, 1H), 8,49 30 (d, J=5.4 Hz, 1H), 8,60-8,63 (m, 1H), 8,81-8,83 (m, 1H), of 9.30-9,31 (m, 1H).

Determination of molecular mass (ESI-MS, m/z): 563 (M++1).

Compounds described in the examples, have the following structure.

Example pharmacological test 1: Measurement of inhibitory activity against activation MARK in the endothelial cells of blood vessels, caused by stimulation under the action of VEGF

Canaliculi venous the vascular endothelial cells (obtained from Chronetics) were cultured in medium EGM-2 (obtained from Chronetics) in the incubator, containing 5% of carbon dioxide, up to 50-70% confluence and culture contribute to the wells containing the same medium in 96-well flat-bottomed plate in a quantity of 1.5×105on the hole. After culturing at 37°during the night Wednesday to replace environment computers-2 containing 0.5% fetal calf serum (obtained from Chronetics), and then cultured for 24 h To each well is added a solution of test compound in dimethyl sulfoxide, and cultivation continued at 37°C for one hour. Human recombinant growth factor vascular endothelial (referred to below as "VEGF") is added to a final concentration of 50 ng/ml and stimulation of cells was performed at 37°C for 8 minutes Medium is removed, cells are washed with saline phosphate buffer (pH 7.4), and then add 10 ál solubilizing buffer (saline solution with Tris-buffer (pH 7.4)containing 1% Triton X100, 2 mm orthovanadate sodium and 1 mm disodium ethylenediaminetetraacetate). The mixture was shaken at 4°C for one hour to solubilize the cells. To the solution add an equal amount of physiological solution with Tris-buffer containing 1% sodium dodecyl sulfate, and mix thoroughly. Spend the adsorption of this solution (2 μl) on a PVDF filter by dot-blotting, and the filter is subjected to Western blot turns with ISOE what Itanium antibodies against tyrosine-phosphorylated MARK (obtained from Daiichi Pure Chemicals). The level of phosphorylated MARK quantitatively determined with a densitometer, and the percentage of phosphorylated MARK in the presence of test compounds to determine, taking account of the level of phosphorylated MARK adding VEGF in the absence of test compounds at 100%, and the level of phosphorylated MARK in the absence of the test compound and VEGF for 0%. The concentration of the test compound (IC50)required for 50% inhibition of activation MARK, calculated on the basis of the percentage of phosphorylated MARK. The results are shown in table 1.

Table 1
ConnectionIC50(nm)ConnectionIC50(nm)ConnectionIC50(nm)
11,8452,0850,7
42,1464,3860,6
52,9474,08758,0
75,2480,58945,0
811,0494,390 42,0
95,1500,59246,0
107,8524,49314,0
1115,0535,9941,8
132,2540,5952,7
140,7552,896<1
162,9565,197518,0
1711,0576,598450,0
180,6585,1998,8
190,6595,81005,2
208,56216,0102150,0
213,46370,010353,0
220,46442,01045,3
23of 5.46536,01052,3
240,66621,0106<1
25a 3.967345,010710,2
265,36845,0  
284,06967,0  
294,4706,8  
301,771750,0  
312,572a 3.9  
327,373<2  
333,5746,0  
344,2751,2  
353,7768,0  
363,37771,0  
372,37841   
40to 12.07930,0  
41a 4.98013,0  
425,982the 3.8  
43the 3.883>1000  

Example pharmacological test 2: Measurement of inhibitory activity against the phosphorylation of KDR ELISA method

NIH T cells (A. Sawano et al., Cell Growth &Differentation, 1, 213-221 (1996), "Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor"), resulting from transfection KDR, were cultured in DMEM (obtained from GIBCO BRL)containing 10% fetal calf serum in an incubator with 5% carbon dioxide up to 50-70% confluence. The collected cells contribute to the wells containing the same medium in 96-well flat-bottomed tablet collagen type with one coating amount of 1.5×104per well, and then cultured at 37°With during the night. The medium is then replaced with a DMEM containing 0.1% fetal calf serum. To each well is added a solution of test compound in dimethyl sulfoxide, and the cultivation continued p and 37° C for one hour. Human recombinant growth factor vascular endothelial (referred to below as "VEGF") is added to a final concentration of 100 ng/ml, and stimulation of cells was performed at 37°C for 2 minutes Medium is removed, cells are washed with saline phosphate buffer (pH 7.4), and then add 50 ál solubilizing buffer (20 mm HEPES (pH 7.4), 150 mm NaCl, 0.2% Triton X-100, 10% glycerol, 5 mm orthovanadate sodium, 5 mm disodium ethylenediaminetetraacetate, and 2 mm Na4P2O7). The mixture was shaken at 4°C for 2 hours to obtain a cell extract.

Separately to the microplate for conducting ELISA (Maxisorp; obtained from NUNC) add saline solution with phosphate buffer (50 μl, pH 7.4)containing 5 μg/ml antiphosphotyrosine antibody (PY20; obtained from Transduction Laboratories), and then leave over night at 4°for education to the wells of the solid phase. After washing tablet add 300 μl of a blocking solution, and then left for 2 hours at room temperature for blocking. After washing the whole cell extract was transferred into the wells, and the tablet then left to stand at 4°With during the night. After washing at room temperature for one hour to carry out the interaction with antibodies against KDR (obtained from Santa Cruz), and after washing p. and room temperature for one hour spend interaction with peroxidase labeled antibodies against rabbit Ig (obtained from Amersham). After washing to initiate the reaction type chromophore substrate peroxidase (obtained from Sumitomo Bakelite Co., Ltd.). After reaching a suitable level of staining to stop reaction, add stop solution measure absorbance at 450 nm using an apparatus for reading a microplate. Fosforiliruyusciye activity of KDR for each well determined, taking account of the absorption of adding VEGF in the absence of a medicinal product for 100% fosforiliruyusciye activity of KDR and absorption in the absence of drug and VEGF for 0% fosforiliruyusciye activity of KDR. The concentration of the tested compounds varies on several levels, the inhibition (%) of KDR phosphorylation determined for each case and calculate the concentration of test compound required for 50% inhibition of KDR phosphorylation (IC50). The results are shown in table 2.

Table 2
ConnectionIC50(nm)ConnectionIC50(nm)ConnectionIC50(nm)
6211,010378,01461,0
63150,0104a 3.91471,0
64150,01052,014815,0
6527,01061,51491,6
6615,010711,01501,8
6763,01085,01510,5
6824,0110>10001520,8
6964,0111>10001531,5
7032,0112>10001541,5
71350,0113>10001552,1
723,5114>10001560,8
731,0115>10001570,4
7411,0116>10001581,6
751,411724,01591,9
763,5118>10000,9
776,01193,6161a 3.9
783,4120a 3.91621,0
7918,012112,51631,4
802,71225,81640,9
814,11238,91650,6
828,41241,91662,2
83840,01252,61672,1
850,5126>10001684,0
861,51271,11693,7
87110,0131>10001701,1
8861,0132>1000175the 4.7
8924,01338,31763,7
9057,01345,0 1772,3
9263,01351,0178>1000
9337,0136160,0179>1000
942,313724,0180>1000
95the 3.813840,0181>1000
960,413915,0182>1000
97490,014036,0183>1000
98330,014114,01840,2
9925,01422,61850,5
10013,01433,51866,3
1013,01441,6 
102105,01450,8

Example pharmacological test 3: Test karyomorphs

Cells of human melanoma A (2×104) (derived from the Japanese Foundation for Cancer Research) plated on culture is selecting & playing voices glass (Falcon) and cultured at 37° C. After 5 h after the start of culturing add test compound to obtain a concentration of 10 μm and 1 μm, and the cultivation continued for 48 hours After fixation of cells for staining nuclei add a solution of 50 μg/ml of iodide of propecia containing ribonuclease (200 (μg/ml). Stained nuclei observed under fluorescent microscope for the analysis of nuclei in violation karyomorphs. The change in the process karyomorphs for the tested compounds was evaluated as (2+), if the change in the process karyomorphs cells takes place at a concentration of 1 μm; evaluated as (+)if the change in the process karyomorphs cells takes place at a concentration of 10 μm; and estimated as (-)if the change in the process karyomorphs of missing cells at 10 μm.

The results are shown in table 3.

Table 3
No. of connectionsThe change in the MorphosisNo. of connectionsThe change in the Morphosis
13(-)37(-)
14(-)38(-)
15(-)39(-)
16(-)40(-)
17(-)41 (-)
18(-)42(-)
20(-)43(-)
21(-)44(-)
22(-)45(-)
24(-)46(-)
25(-)47(-)
26(-)48(-)
28(-)49(-)
29(-)52(-)
30(-)53(-)
31(-)55(-)
32(-)58(-)
33(-)59(-)
34(-)60(-)
35(-)61(-)
36(-)62(-)

Example pharmacological test 4: Antitumor effect on glioma cells human (GL07)

Glioma person GL07 (obtained from Central Laboratories for Experimental Animals transplanted naked mice. When the volume of the tumor is approximately 100 mm 3mice are placed into groups. In this case the distribution of the groups is carried out so that each group consisted of four mice and the mean tumor volume was similar for all groups. Test the connection, enter the investigated groups orally or administered intraperitoneally at a dose component 20 mg/kg, daily, once a day, for 9 days, while the control group is administered the environment in the same way as the studied groups. The degree of inhibition of tumor growth (TGIR) calculated as follows: rate of inhibition of tumor growth (TGIR)=(1-TX/CX)×100, where CX denotes the tumor volume on day x for the control group, if the tumor volume on the first day of introduction are for 1; and T indicates tumor volume for teams that enter the test connection.

The degree of inhibition of tumor growth for typical examples of groups of compounds of the present invention shown in table 4.

Table 4
Number exampleRoute of administrationTGIR, %Number exampleRoute of administrationTGIR, %Number exampleRoute of administrationTGIR, %
4Oral61102P is Moralny 24147Oral34
5Oral59103Oral23148Oral54
9Intraperitoneally59104Oral22149Oral47
13Intraperitoneally52105Oral20150Oral22
14Intraperitoneally81107Oral49151Oral44
16Intraperitoneally77109Oral71152Oral44
17Intraperitoneally85110Oral26153Oral53
18Oral57111Oral78 Oral34
24Oral63112Oral81155Oral29
25Intraperitoneally68113Oral61156Oral24
28Intraperitoneally84114Oral60157Oral44
29Oral64115Oral74158Oral39
37Intraperitoneally70116Oral83159Oral40
48Intraperitoneally90119Oral40160Oral43
50Oral59120Oral30161Oral 39
51Oral65121Oral22162Oral40
54Oral59122Oral21163Oral52
62Oral78123Oral31164Oral55
64Oral37124Oral27165Oral44
66Oral26125Oral30166Oral27
TGIR, % - Degree of inhibition of tumor growth (%)

Table 4 (continued)
Number exampleRoute of administrationTGIR,%Number exampleRoute of administrationTGIR, %Number exampleRoute of administrationTGIR, %
67Oral30126Oral52167Oral28
68Oral57127Oral25168Oral42
69Oral26128Oral21169Oral55
71Oral67129Oral25170Oral64
73Oral34130Oral32171Oral13
74Oral28131Oral31172Oral42
77Oral26132Oral24173Oral21
78Oral21 133Oral20174Oral19
79Oral28134Oral29175Oral17
80Oral52135Oral62176Oral22
82Oral27136Oral23177Oral35
83Oral31137Oral20178Oral28
85Oral26138Oral21179Oral33
89Oral40139Oral27180Oral45
93Oral29140Oral21181 Oral21
94Oral29141Oral28182Oral31
97Oral48142Oral48183Oral22
98Oral38143Oral53184Oral48
99Oral33144Oral56185Oral59
100Oral36145Oral57186Oral47
101Oral44146Oral48   
TGIR, %=the Degree of inhibition of tumor growth (%)

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

where

X represents CH or N;

Z represents CH;

R1represents a hydrogen atom;

R2and R3that may be the same or different, represent a C1-6alkoxy, which is optionally substituted by halogen atom, hydroxyl, C1-4alkoxy, C1-4alkoxycarbonyl, amino group, one or two hydrogen atoms which is optionally substituted C1-4alkyl, which is optionally substituted by hydroxyl or C1-4alkoxy group, R12R13N-C (=O)-O-, where R12and R13that may be the same or different and represent a hydrogen atom or a C1-4alkyl, optionally substituted by hydroxyl or C1-4alkoxy, or the group R14-(S)m-where R14represents phenyl or a saturated or unsaturated five-semicolony heterocyclic group, optionally substituted C1-4the alkyl, m is 0 or 1;

R4represents a hydrogen atom;

R5, R6, R7and R8that may be the same or different, represent a hydrogen atom, a halogen atom, a C1-4alkyl, C1-4alkoxy or nitro, provided that R5, R6, R7and R8at the same time do not represent a hydrogen atom;

R10represents a hydrogen atom or a C1-6alkyl;

R11represents a C1-6alkyl, C2-6alkenyl or2-6quinil (where each C1-6alkyl, C2-6alkenyl and C2-6quinil optionally substituted by a halogen atom or C1-6alkoxy), or R15-(CH2)n-where n is an integer from 0 to 3, and R15represents naphthyl or six-membered saturated or unsaturated carbocyclic or saturated or unsaturated five-semicolony heterocyclic group which is optionally substituted by a halogen atom, a C1-6the alkyl or C1-6alkoxy.

2. The compound according to claim 1, where R9and R10represent a hydrogen atom.

3. The compound represented by formula (la), or its pharmaceutically acceptable salt or MES:

where X represents CH or N;

R21and R22that may be the same or different, represent an unsubstituted C1-6alkoxy or the group R31-(CH2)p-O-, where R31represents at the m halogen, hydroxyl, C1-4alkoxy, C1-4alkoxycarbonyl, the amino group in which one or two hydrogen atoms optionally substituted C1-4the alkyl, which is optionally substituted by hydroxyl or C1-4alkoxy group, R12R13N-C(=O)-O-, where R12and R13that may be the same or different, represent a hydrogen atom or a C1-4alkyl, where alkyl optionally substituted by hydroxyl or C1-4alkoxy, or the group R14-(S)m-where R14represents phenyl or a saturated or unsaturated five-semicolony heterocyclic group, optionally substituted C1-4the alkyl and m is 0 or 1; p is an integer from 1 to 6;

R23, R24, R25and R26that may be the same or different, represent a hydrogen atom, a halogen atom, a C1-4alkyl, C1-4alkoxy or nitro, provided that R23, R24, R25and R26at the same time do not represent a hydrogen atom;

R27represents a hydrogen atom, a C1-6alkyl or C1-4alkylsulphonyl, where the alkyl fragment specified C1-6the alkyl or C1-4alkylsulphonyl optionally substituted C1-4alkoxy;

R28represents a hydrogen atom or a C1-6alkyl; R29represents a C1-6Ala is l, With2-6alkenyl or2-6quinil (each of these C1-6of alkyl, C2-6alkenyl or2-6the quinil optionally substituted by a halogen atom or C1-4alkoxy), or R32-(CH2)q-where q is an integer from 0 to 4, R32represents a naphthyl or a saturated or unsaturated six-membered carbocyclic or heterocyclic group which is optionally substituted by a halogen atom, a C1-4the alkyl or C1-4alkoxy.

4. The compound according to claim 3, where R21and R22represent unsubstituted C1-4CNS group.

5. The compound according to claim 3, where one of R21and R22represents unsubstituted C1-4CNS group and the other represents a group R31-(CH2)p-O-.

6. The compound according to claim 3, where at least one of R23, R24, R25and R26represents a halogen atom.

7. The compound according to claim 3, where at least one of R23, R24, R25and R26represents a chlorine atom or a fluorine atom.

8. The compound according to claim 3, where at least one of R23, R24, R25and R26represents a C1-4alkyl.

9. The compound according to claim 3, where two of R23, R24, R25and R26represent methyl and the other two represent a hydrogen atom.

23, R24, R25and R26represents nitro or C1-4alkoxy.

11. The compound according to claim 3, where R23, R25and R26represent a hydrogen atom, and R24represents a halogen atom, a C1-4alkyl, C1-4alkoxy or nitro.

12. The compound according to claim 3, where both R27and R28represent a hydrogen atom.

13. The compound according to claim 3, where

X represents CH or N;

R21and R22represent unsubstituted C1-4alkoxy;

R23, R25and R26represent a hydrogen atom;

R24represents a halogen atom, a C1-4alkyl, C1-4alkoxy or nitro;

R27and R28represent a hydrogen atom; R29represents a C1-6alkyl, C2-6alkenyl or2-6quinil (where each of C1-6of alkyl, C2-6alkenyl and C2-6the quinil optionally substituted by a halogen atom or C1-4alkoxy), or -(CH2)q-R32where q is an integer of 0 or 1, and R32represents phenyl, pyridyl or naphthyl, where phenyl, pyridyl and naphthyl optionally substituted by a halogen atom, a C1-4the alkyl or C1-4alkoxy.

14. The compound according to claim 1, which is connected to the tion, selected from the group consisting of the following compounds or a pharmaceutical salt or MES:

(1) N-(2,4-diferensial)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}urea;

(2) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-(2-foradil)urea;

(3) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-(2-pyridylmethyl)urea;

(4) N-allyl-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal)urea;

(5) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-proprotein;

(6) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-(4-terbutyl)urea;

(7) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-(2-PROPYNYL)urea;

(8) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-atilmotin;

(9) N-butyl-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}urea;

(10) N-(fluoro-butyl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}urea;

(11) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-isobutylamine;

(12) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-forfinal}-N’-(1,2-dimethylpropyl)urea;

(13) N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-

N’-proprotein;

(14) N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N’-(4-fluoro-2-were)urea;

(15) N-(5-bromo-6-methyl-2-pyridyl)-N’-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}urea;/p>

(16) N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N’-(5-chloro-2-pyridyl)urea;

(17) N-(5-bromo-2-pyridyl)-N’-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}urea;

(18) N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N’-(2-methoxyphenyl)urea;

(19) N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N’-(2-were)urea;

(20) N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N’-(5-methyl-2-pyridyl)urea;

(21) N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N’-(6-methyl-2-pyridyl)urea;

(22) of the hydrochloride of N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N’-(4-methoxyphenyl)urea;

(23) N-{2-chloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N’-(1-naphthyl)urea;

(24) N-(2,4-differenl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea;

(25) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(4-fluoro-2-were)urea;

(26) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-

dimetilfenil}-N’-(3-fluoro-2-methoxyphenyl)urea;

(27) N-(5-bromo-6-methyl-2-pyridyl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea;

(28) N-(5-chloro-2-pyridyl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea;

(29) N-(5-bromo-2-pyridyl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea;

(30) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(2-methox is phenyl)urea;

(31) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(2-were)urea;

(32) N-(4-chloro-2-were)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}urea;

(33) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(2-pyridyl)urea;

(34) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(5-methyl-2-pyridyl)urea;

(35) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(6-methyl-2-pyridyl)urea;

(36) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,3-dimetilfenil}-N’-(4-methoxyphenyl)urea;

(37) N-(2,4-differenl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}urea;

(38) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-proprotein;

(39) N-(4-chloro-2-were)-N’-{4-[(6,7-dimethoxy-4-

hinely)oxy]-2,5-dimetilfenil}urea;

(40) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-(4-fluoro-2-were)urea;

(41) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-(3-fluoro-2-methoxyphenyl}urea;

(42) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-(2-were)urea;

(43) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-(2-methoxyphenyl)urea;

(44) N-(5-bromo-6-methyl-2-pyridyl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}urea;

(45) N-(2,6-dimethoxy-3-pyridyl)-N’-{4-[(6,7-dime the XI-4-chinolin)oxy]-2,5-dimetilfenil}urea;

(46) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2,5-dimetilfenil}-N’-(4-methoxyphenyl)urea;

(47) N-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-nitrophenyl}-N’-proprotein;

(48) N-(2,4-differenl)-N’-{4-[(6,7-dimethoxy-4-chinolin)oxy]-2-nitrophenyl}urea;

(49) N-{3,5-dichloro-4-[(6,7-dimethoxy-4-chinolin)oxy]phenyl}-N’-(2,4-differenl)urea;

(50) N-(2,4-differenl)-N’-(2-fluoro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-chinolin]oxy}phenyl)urea;

(51) N-(2-chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea;

(52) N-(2,4-differenl)-N’-(4-{[6-methoxy-7-(2-

morpholinoethoxy)-4-chinolin]oxy}-2,5-dimethyl-phenyl)urea;

(53) N-(4-{[6-methoxy-7-(2-morpholinoethoxy)-4-chinolin]oxy}-2,5-dimetilfenil)-N’-(2-methoxyphenyl)urea;

(54) N-(2-chloro-4-{[6-methoxy-7-(2-methoxyethoxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea;

(55) N-(2-chloro-4-{[6-methoxy-7-(2-methoxyethoxy)-4-chinolin]oxy}phenyl)-N’-(2-methoxyphenyl)urea;

(56) N-(2,4-differenl)-N’-(4-{[6-methoxy-7-(2-methoxyethoxy)-4-chinolin]oxy}-2,3-dimetilfenil)urea;

(57) N-(4-{[6-methoxy-7-(2-methoxyethoxy)-4-chinolin]oxy}-2,3-dimetilfenil)-N’-(2-methoxyphenyl)urea;

(58) N-(2,4-differenl)-N’-(4-{[6-methoxy-7-(2-methoxyethoxy-4-chinolin]oxy}-2,5-dimetilfenil)urea;

(59) N-(4-{[6-methoxy-7-(2-Metacritic and)-4-chinolin]oxy}-2,5-dimetilfenil)-N’-(2-methoxyphenyl)urea;

(60) N-(4-{[7-(benzyloxy)-6-methoxy-4-chinolin]oxy}-2,3-dimetilfenil)-N’-(2-methoxyphenyl)urea;

(61) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-(2,4-differenl)urea;

(76) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-atilmotin;

(77) N-butyl-N’-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}urea;

(78) N-{2-xnop-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-pencilmation;

(79) N-(sec-butyl)-N’-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}urea;

(80) N-allyl-N’-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}urea;

(81) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-(2-PROPYNYL)urea;

(82) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-(2,4-diferensial)urea;

(83) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-(2-pyridylmethyl)urea;

(85) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-(4-forfinal)urea;

(86) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-(2-methoxyphenyl)urea;

(87) N-{2-xnop-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-(5-chloro-2-pyridyl)urea;

(88) N-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-forfinal}-N’-proprotein;

(89) N-butyl-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-forfinal}urea;

(90) N-(sec-butyl)-N’-{4-[(6,7-dimethoxy-4-indolinyl)oxy]-2-forfinal}urea;

(91) N-allyl-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-forfinal}urea;

(92) N-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-forfinal}-N’-(2-PROPYNYL)urea;

(93) N-(2,4-diferensial)-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-forfinal}urea;

(94) N-(2,4-differenl)-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-forfinal}urea;

(95) N-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-forfinal}-N’-(2-were)urea;

(96) N-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-forfinal}-N’-(2-methoxyphenyl)urea;

(97) N-{4-[(6,7-dimethoxy-4-hintline)oxy]-3-were}-N’-proprotein;

(98) N-butyl-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-3-were}urea;

(99) N-(2,4-differenl)-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-3-were}urea;

(100) N-{4-[(6,7-dimethoxy-4-hintline)oxy]-3-were)-N’-(4-forfinal)urea;

(101) N-{4-[(6,7-dimethoxy-4-hintline)oxy]-3-were}-N’-(2-methoxyphenyl)urea;

(102) N-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-were}-N’-proprotein;

(103) N-butyl-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-were}urea;

(104) N-(2,4-differenl)-N’-(4-[(6,7-dimethoxy-4-hintline)oxy]-2-were}urea;

(105) N-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-were}-N’-(4-forfinal)urea;

(106) N-{4-[(6r7-di is ethoxy-4-hintline)oxy]-2-were}-N’-(2-methoxyphenyl)urea;

(107) N-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-nitrophenyl}-N’-proprotein;

(108) N-butyl-N’-{4-[(6,7-dimethoxy-4-hintline)oxy]-2-nitrophenyl}urea;

(117) N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-metalmachine;

(119) N-(2-chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-proprotein;

(120) N-(2-chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-proprotein;

(121) N-(2-chloro-4-{[7-(3-hydroxypropoxy)-6-methoxy-4-hintline]oxy}phenyl)-N’-proprotein;

(122) N-(2-chloro-4-{[7-(2-hydroxyethoxy)-6-methoxy-4-hintline]oxy}phenyl)-N’-proprotein;

(123) N-(2-chloro-4-{[6-methoxy-7-(4-pyridyloxy)-4-hintline]oxy}phenyl)-N’-proprotein;

(124) N-[2-chloro-4-({6-methoxy-7-[(5-morpholinomethyl)oxy]-4-hintline}oxy)phenyl]-N’-proprotein;

(125) N-{2-chloro-4-[(6-methoxy-7-{[5-(1H-1,2,3-triazole-1-yl)pentyl]oxy]-4-hintline)oxy]phenyl}-N’-proprotein;

(127) N-(2-chloro-4-{[6-methoxy-7-(4-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-proprotein;

(128) N-[2-chloro-4-({6-methoxy-7-[2-(4-methylpiperazin)-ethoxy]-4-hintline}oxy)phenyl]-N’-proprotein;

(129) N-{2-chloro-4-[(7-{2-[(2-hydroxyethyl)(methyl)-amino]ethoxy}-6-methoxy-4-hintline)oxy]phenyl}-N’-proprotein;

(130) N-[2-chloro-4-({6-methoxy-7-[3-(4-methylpiperid is in)propoxy]-4-hintline}oxy)phenyl]-N’-proprotein;

(133) N-[2-chloro-4-({6-methoxy-7-[3-(4-pyridylthio)propoxy]-4-hintline}oxy)phenyl]-N’-proprotein;

(134) N-{2-chloro-4-[(6-methoxy-7-{3-[(1-methyl-1H-1,2,3,4-tetrazol-5-yl)thio]propoxy}-4-hintline)oxy]phenyl}-N’-proprotein;

(135) N-(2-chloro-4-{[6-methoxy-7-(3-piperidinyloxy)-4-hintline]oxy}phenyl)-N’-proprotein;

(136) N-[2-chloro-4-({7-methoxy-6-[2-(4-methylpiperazin)-ethoxy]-4-hintline}oxy)phenyl]-N’-proprotein;

(137) N-[2-chloro-4-({7-methoxy-6-[3-(4-methylpiperazin)propoxy]-4-hintline}oxy)phenyl]-N’-proprotein;

(138) N-(2-chloro-4-{[7-methoxy-6-(2-pyridyloxy)-4-hintline]oxy}phenyl)-N’-proprotein;

(139) N-(2-chloro-4-{[7-methoxy-6-(3-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-proprotein;

(140) N-{2-chloro-4-[(6-{3-(2-hydroxyethyl)-(methyl)-amino]propoxy}-7-methoxy-4-hintline)oxy]phenyl}-N’-proprotein;

(141) N-(2-chloro-4-{[6-methoxy-7-(2-pyridyl-methoxy)-4-chinolin]oxy}phenyl)-N’-proprotein;

(142) N-(2-chloro-4-{[6-methoxy-7-(3-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-proprotein;

(143) N-(2-chloro-4-{[6-methoxy-7-(4-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-proprotein;

(144) N-(2-chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-chinolin]oxy}phenyl)-N’-proprotein;

(145) N-[2-chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)ethoxy]-4-chinolin}oxy)phenyl]-N’-propyl who Icewine;

(146) N-[2-chloro-4-({7-[2-(1H-1-imidazolyl)ethoxy]-6-methoxy-4-chinolin}oxy)phenyl]-N’-proprotein;

(147) N-(2-chloro-4-{[7-(3-hydroxypropoxy)-6-methoxy-4-chinolin]oxy}phenyl)-N’-proprotein;

(148) N-[2-chloro-4-({6-methoxy-7-[2-(4-methylpiperazin)-ethoxy]-4-chinolin}oxy)phenyl]-N’-proprotein;

(149) N-(2-chloro-4-{[7-(2-hydroxyethoxy)-6-methoxy-4-chinolin]oxy}phenyl)-N’-proprotein;

(150) N-{2-chloro-4-[(7-{2-[(2-hydroxyethyl)-(methyl)-amino]ethoxy}-6-methoxy-4-chinolin)oxy]phenyl}-N’-proprotein;

(151) N-(2-chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-chinolin]oxy}phenyl)-N’-proprotein;

(152) N-[2-chloro-4-(6-methoxy-7-{[3-(4-methylpiperazin)propoxy]-4-chinolin}oxy)phenyl]-N’-proprotein;

(153) N-[2-chloro-4-(6-methoxy-7-{[3-(1H-1,2,3-triazole-1-yl)propoxy]-4-chinolin}oxy)phenyl]-N’-proprotein;

(154) N-[2-chloro-4-({7-[3-(1H-1-imidazolyl)propoxy]-6-methoxy-4-chinolin}oxy)phenyl]-N’-proprotein;

(155) N-{2-chloro-4-[(7-{2-[di(2-hydroxyethyl)amino]-ethoxy}-6-methoxy-4-chinolin)oxy]phenyl}-N’-proprotein;

(156) N-{2-chloro-4-[(7-{3-[di(2-hydroxyethyl)amino]-propoxy}-6-methoxy-4-chinolin)oxy]phenyl}-N’-proprotein;

(157) N-{2-chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]-propoxy}-6-methoxy-4-chinolin)oxy]phenyl}-N’-proprotein;

(158) N-[2-chloro-4-({6-methoxy-7-[4-(1H-1,2,3-triazole-1-yl)butoxy]-4-chinolin}oxy)Hairdryer is l]-N’-proprotein;

(159) N-{2-chloro-4-[(6-methoxy-7-{[5-(1H-1,2,3-triazole-1-yl)pentyl]oxy}-4-chinolin)oxy]phenyl}-N’-proprotein;

(160) N-[2-chloro-4-({7-[4-(1H-1-imidazolyl)butoxy]-6-methoxy-4-chinolin}oxy)phenyl]-N’-proprotein;

(161) N-(2-chloro-4-{[6-methoxy-7-(4-pyridyloxy)-4-hintline]oxy}phenyl)-N’-(2,4-debtor-phenyl)urea;

(162) N-(2-chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-(2,4-differenl)urea;

(163) N-(2-chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-(2,4-differenl)urea;

(164) N-[2-chloro-4-({6-methoxy-7-[3-(4-methylpiperazine)propoxy]-4-hintline}oxy)phenyl)-N’-(2,4-differenl)urea;

(165) N-{2-chloro-4-[(7-{3-[(2-hydroxyethyl)-(methyl)amino]-propoxy}-6-methoxy-4-hintline)oxy]phenyl}-N’-(2,4-differenl)urea;

(166) N-[2-chloro-4-({6-methoxy-7-[2-(4-methylpiperazine)-ethoxy]-4-chinolin}oxy)phenyl]-N’-(2,4-differenl)urea;

(167) N-{2-chloro-4-[(7-{2-[(2-hydroxyethyl)-(methyl)-amino]ethoxy}-6-methoxy-4-chinolin)oxy]phenyl}-N’-(2,4-differenl)urea;

(168) N-(2-chloro-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea;

(169) N-(2-chloro-4-{[6-methoxy-7-(3-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea;

(170) N-(2-chloro-4-({6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)ethoxy]-4-chinolin}oxy)phenyl]-N’-(2,4-differenl)mochaui is a;

(171) N-(2-methoxy-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline]oxy}phenyl)-N’-proprotein;

(172) N-(2,4-differenl)-N’-(2-methoxy-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-hintline]oxy}-phenyl)urea;

(173) N-(2-methoxy-4-{[6-methoxy-7-(3-morpholinoethoxy)-4-chinolin]oxy}phenyl)-N’-proprotein;

(174) N-(2-methoxy-4-{[6-methoxy-7-(4-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-proprotein;

(175) N-ethyl-N’-(4-{[6-methoxy-7-(2-morpholinoethoxy)-4-chinolin]oxy}-2,5-dimetilfenil)urea;

(176) N-[4-({6-methoxy-7-[3-(4-methylpiperazin)propoxy]-4-chinolin}oxy)-2,5-dimetilfenil]-N’-proprotein;

(177) N-(2,4-differenl)-N’-[4-({6-methoxy-7-[2-(1H-1,2,3-triazole-1-yl)ethoxy]-4-chinolin}oxy)-2,5-dimetilfenil]urea;

(184) N-(2-chloro-4-{[6-methoxy-7-(3-piperidinyloxy)-4-hintline]oxy}phenyl)-N’-metalmachine;

(185) N-(2-chloro-4-{[6-methoxy-7-(3-piperidinyloxy)-4-hintline]oxy}phenyl)-N’-atilmotin;

(186) N-(2-chloro-4-{[6-methoxy-7-(4-pyridyloxy)-4-chinolin]oxy}phenyl)-N’-(2,4-differenl)urea.

15. The compound according to any one of claims 1 to 14 or its pharmaceutically acceptable salt or MES as an active ingredient of a therapeutic agent for the treatment of diseases selected from the group including a malignant tumor, diabetic retinopathy, chronic rheumatism, psora is AZ, atherosclerosis, and Kaposi's sarcoma.

16. The pharmaceutical composition inhibiting the activation of mitogen-activated protein kinase, containing as active ingredient a compound according to any one of claims 1 to 14 or its pharmaceutically acceptable salt or MES.

17. The pharmaceutical composition according to article 16, for the treatment of diseases selected from the group including a malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma.

18. The method of treatment of a disease selected from the group including a malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, and Kaposi's sarcoma, comprising a stage of introduction to the mammal an effective amount of a compound according to any one of claims 1 to 14, or its pharmaceutically acceptable salt or MES, together with a pharmaceutically acceptable carrier.

19. Method of inhibiting angiogenesis target blood vessel, comprising a stage of bringing into contact connection according to any one of claims 1 to 14, or its pharmaceutically acceptable salt or MES, with endothelial cells of the target blood vessel.

20. The compound represented by formula (Ia), or pharmaceutically acceptable salt or MES:

where X represents N; R21and R22to the e may be the same or different, represent unsubstituted C1-6alkoxy; R23, R25and R26represent a hydrogen atom, R24represents a halogen atom; R27and R28represent a hydrogen atom; R29represents a C1-6alkyl, C2-6alkenyl or2-6quinil.

21. Connection claim 20, where R21and R22represent methoxy.

22. Connection claim 20, which represents a N-{2-chloro-4-[(6,7-dimethoxy-4-hintline)oxy]phenyl}-N’-propylacetic or its pharmaceutical salt or MES.



 

Same patents:

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I):

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

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

SUBSTANCE: invention relates to new derivatives of piperazinylalkylthiopyrimidine of the formula (I): wherein R1 represents hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkanoyl or di-(C1-C4-alkyl)-amino-(C1-C4-alkyl); R2 means hydrogen atom or benzyl substituted with 1-3 substitutes taken among the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy-group, di-(C1-C4-alkyl)-amino-group, hydroxyl group and halogen atom; n = 2, 3 or 4, and to its pharmaceutically acceptable acid addition salt. Also, invention describes a method for preparing compounds and pharmaceutical composition based on thereof. Compounds are useful for treatment of diseases arising as result of the central nervous system injury.

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

14 cl, 3 tbl, 26 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to substituted cyclic aminoven compounds of formula (I)

< / BR>
where Ar represents thienyl, substituted pyridine, phenyl unsubstituted or substituted with halogen, hydroxy, alkoxy, C1-C4the alkyl, phenyloxy, NO2or phenyl; R1is NHOR2where R2is hydrogen; W is one or more hydrogen atoms; Y is independently one or more members of the group consisting of hydroxy, SR3, alkoxy, NR6R7where R6and R7independently selected from hydrogen, alkyl, pyridylethyl, SO2R8, COR9or R6and R7can be combined with the formation of the ring containing the nitrogen to which they relate, formulas

< / BR>
where Y' is CH2OH , SO2; R3represents hydrogen, alkyl, aryl, benzothiazolyl, pyrazinyl, N-methylimidazole; R8represents C1-C4alkyl, phenyl; R9represents hydrogen, alkyl, phenyl; Z is hydrogen; n = 1, and its optical isomer, diastereoisomer, or enantiomer, or its pharmaceutically acceptable salt

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new heterocyclic compounds corresponding to general formulas: (I) , (II) , (Ia) and (Ib) wherein substitutes have values given in the description. Such compounds are reversible inhibitors of cathepsins S, K, F, L and B. Also, invention relates to a method for preparing these compounds, pharmaceutical composition eliciting inhibitory activity with respect to cysteine proteases and to a method for modulation of autoimmune diseases, treatment of Alzheimer's disease and osteoporosis.

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

42 cl, 106 ex

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new compound: N-[2-hydroxy-3(1-piperidinyl)-propoxy]-pyridine-1-oxyde-3-carboxyimidoyl chloride, stereoisomers thereof acid additional salts useful in treatment of pathological insulin resistance.

EFFECT: new compound useful in medicine.

5 cl, 10 tbl, 10 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

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

SUBSTANCE: invention proposes two variants of the improved method for preparing anti-ulcerous therapeutic agents of the formula (I): wherein radicals R1-R6 have values given in cl. 1 and cl. 2 of the invention claim. Method involves interaction of corresponding sulfides with m-chloroperoxybenzoic acid in acetone or a mixture acetone/water as a solvent. According to the first variant pH value of the reaction mixture is increased to the value above 7 after the reaction interaction and solvent is removed and crystals of compound of the formula (I) are separated. According to the second variant the interaction is carried out at pH ≥ 7.0 followed by addition of water if necessary and compound of the formula (I) crystals are separated. Invention is directed for preparing omeprazole or pantoprazole preferably. Invention provides preparing the end products of high purity and with high yield.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

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

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

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