UA79455C2 - 4-(n-phenylamino)quinazolines or -quinolines as tyrosine kinase inhibitors - Google Patents

Abstract

The invention relates to the bicyclic heterocycles of the general formula (I), wherein Ra, Rb, Rc, Rd and X are defined as in claim 1, the tautomers, stereoisomers, mixtures and salts thereof, especially the physiologically acceptable salts thereof with inorganic or organic acids, which have valuable pharmacological properties, especially an inhibitory effect on tyrosine kinase-mediated signal transduction. The invention also relates to the use of the bicyclic heterocycles in the treatment of diseases, especially cancer diseases and of benign prostate hyperplasia (BPH), of diseases of the lung and the respiratory system, and further to the production of the bicyclic heterocycles. (I)

Description

Description of the invention

The present invention relates to bicyclic heterocycles of the general formula

E and "5 75 of their tautomers, their stereoisomers, their mixtures and their salts, primarily their physiologically compatible salts with inorganic or organic acids or bases, which have valuable pharmacological properties, primarily the inhibitory effect on signal transduction mediated by tyrosine kinases, their use for the treatment of various diseases, primarily tumor diseases, as well as benign prostatic hyperplasia (BPH), lung and respiratory tract diseases, and the method of obtaining them.

In the above general formula I, the substituents have the following meanings:

KU means a hydrogen atom or C. dalalkyl group,

VE? means a phenyl or 1-phenylethyl group, in each of which the phenyl nucleus is substituted by residues B 1-23, where

In and in? can have identical or different values and mean an atom of hydrogen, fluorine, chlorine, bromine or iodine, He

C. dalalkyl group, hydroxy group, Si lalkoxy group, Co-alkenyl group, Co-alkynyl group, aryl group, o aryloxy group, arylmethyl group, arylmethoxy group, heteroaryl group, heteroaryloxy group, heteroarylmethyl group, heteroarylmethoxy group, substituted by 1-3 fluorine atoms, metal or methoxy group or a cyano-, nitro- or amino group and

VZ means a hydrogen, fluorine, chlorine or bromine atom, a metal or trifluoromethyl group,

KO means a cyclobutyl, cyclopentyl or cyclohexyl group, each of which is substituted by

B7-M-B, where Z

B" means a hydrogen atom or a C. alkyl group, and (22) vo means a hydrogen atom, C. alkyl group, aminocarbonyl-C. alkyl group, p

S. dalkylaminocarbonyl-S. alkyl group, di(Cu alkyl)aminocarbonyl-C to alkyl group, pyrrolidine-1-ylcarbonyl-C 4 alkyl group, piperidine-1-ylcarbonyl-C. alkyl group, homopiperidine-1-ylcarbonyl-C 4 alkyl group, morpholine-4-ylcarbonyl-C. alkyl group, homomorpholin-4-ylcarbonyl-C to alkyl group, piperazine-1-ylcarbonyl-C. alkyl group, "4-C alkylpiperazine-1-ylcarbonyl-C 1 alkyl group, homopiperazine-1-ylcarbonyl-C. and alkyl group, SHO with 4-C. zalkylhomopiperazine-1-ylcarbonyl-C 4 alkyl group, hydroxy-C» dalalkyl group, c C 1 alkyloxy-C 1 alkyl group, C . (C-.alkyl)uamino-Co alkyl group, C. alkylcarbonylamino-C» alkyl group, aminocarbonylamino-C» alkyl group, Su alkylaminocarbonylamino-C» alkyl group, dDY(C. alkyl)aminocarbonylamino-C» alkyl group, pyrrolidine -1-ylcarbonylamino-C» alkyl group, -I piperidine-1-ylcarbonylamino-C» alkyl group, morpholine-4-ylcarbonylamino-C» alkyl group,

Su alkylsulfonyl-C" dalalkyl group, Su alkylsulfonylamino-C" dalalkyl group, and (2-oxopyrrolidin-1-yl)-C" alkyl group, (2-oxopiperidin-1-yl)-C" dalalkyl group, "" ( 3-oxomorpholin-4-yl)-C» alkyl group, (2-oxoimidazolidin-1-yl)-Co dalalkyl group, (2-oxo-3-C 4 alkylimidazolidin-1-yl)u-Co alkyl group, ( 2-oxohexahydropyrimidin-1-yl)-Soalkyl group, i-th (2-oxo-3-C 4 alkylhexahydropyrimidin-1-yl)-C» alkyl group, C dalalkylsulfonyl group, c chloro-Ci.alkylsulfonyl group, bromo- C..alkylsulfonyl group, amino-C.i.alkylsulfonyl group,

Su alkylamino-C4 alkylsulfonyl group, di(Ci alkyl)amino-C4 alkylsulfonyl group, (pyrrolidin-1-yl)-C 4 alkylsulfonyl group, (piperidin-1-yl)-C3 alkylsulfonyl group, (homopiperidin-1-yl) -C 1. alkylsulfonyl group, (morpholin-4-yl)-C- alkylsulfonyl group, (homomorpholin-4-yl)-C 4 alkylsulfonyl group, (piperazin-1-yl)-C- alkylsulfonyl group, iF) (4 -C.alkylpiperazin-1-yl)-C3 alkylsulfonyl group, (homopiperazin-1-yl)-C1 alkylsulfonyl group, co (4-C; alkylhomopiperazin-1-yl)-C1.alkylsulfonyl group, C..alkyloxycarbonyl group , formyl group, C..alkylcarbonyl group, C..alkyloxy-C-alkylcarbonyl group, tetrahydrofuranylcarbonyl group, tetrahydropyranylcarbonyl group, amino-C. an alkylcarbonyl group,

Su zalkylamino-S. lalkylcarbonyl group, di(Su.alkyl)amino-Si dalkylcarbonyl group, pyrrolidin-1-yl-C. lalkylcarbonyl group, piperidin-1-yl-C lalkylcarbonyl group, (homopiperidin-1-yl)-C 1 lalkylcarbonyl group, morpholin-4-yl-C. alkylcarbonyl group, (homomorpholin-4-yl)-C 4 lalkylcarbonyl group, (piperazin-1-yl)-C alkylcarbonyl group, 65 (4-C1 alkylpiperazin-1-yl)-C 4 alkylcarbonyl group, (homopiperazine-1- yl)-C lalkylcarbonyl group, (4-C; zalkylhomopiperazin-1-yl)-C 1 lalkylcarbonyl group, Su. alkylsulfonyl-C. an alkylcarbonyl group,

cyano group, aminocarbonyl group, C alkylaminocarbonyl group, di(C alkyl)aminocarbonyl group, (Ci alkyloxy-C» alkyl)aminocarbonyl group, M-(Ci alkyl)-M-(C4 alkyloxy-Co alkyl)aminocarbonyl group, arylaminocarbonyl group, pyrrolidin-1-ylcarbonyl group, piperidin-1-ylcarbonyl group, homopiperidin-1-ylcarbonyl group, morpholin-4-ylcarbonyl group, homomorpholin-4-ylcarbonyl group, 2-oxa-5-azabicyclo|2.2.1)hept -5--ylcarbonyl group, 3-oxa-8-azabicyclo|3.2.1|oct-8-ylcarbonyl group, 8-oxa-3-azabicyclo|3.2.1|oct-33-ylcarbonyl group, piperazin-1-ylcarbonyl group, 4-C. zalkylpiperazin-1-ylcarbonyl group, homopiperazin-1-ylcarbonyl group, 4-С3 zalkylhomopiperazin-1-ylcarbonyl group, aminosulfonyl group, Si. alkylaminosulfonyl group, 7/0. Bi(Cu alkyl)aminosulfonyl group, pyrrolidin-1-yl-sulfonyl group, piperidin-1-ylsulfonyl group, homopiperidin-1-ylsulfonyl group, morpholin-4-ylsulfonyl group, homomorpholin-4-ylsulfonyl group, piperazin-1-ylsulfonyl group group, 4-C. alkylpiperazin-1-ylsulfonyl group, homopiperazin-1-ylsulfonyl group or 4-C) alkylhomopiperazin-1-ylsulfonyl group, cyclobutyl, cyclopentyl or cyclohexyl group, each of which is substituted by a K.E group, where

U means 2-oxopyrrolidin-1-yl group, 2-oxopiperidin-1-yl group, 3-oxomorpholin-4-yl group, 2-oxoimidazolidin-1-yl group, 2-oxo-3-C1 alkylimidazolidin-1-yl group group, 2-oxohexahydropyrimidin-1-yl group or 2-oxo-3-C; zalkylhexahydropyrimidin-1-yl group, azetidin-Z-yl group, which in position 1 is replaced by the residue E Z, where BE? has the above values, a pyrrolidine-Z-yl group, which in position 1 is replaced by a KB Z residue, where BC? has the values indicated above, a piperidine-Z-yl group, which in position 1 is replaced by a B U residue, where BK? has the values indicated above, a piperidin-4-yl group, which in position 1 is replaced by residue B 7, where KO has the values indicated above, or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

BZ means a hydrogen, fluorine, chlorine or bromine atom, a hydroxy group, a C dalalkyloxy group substituted by 1-3 fluorine atoms, a methoxy group substituted by 1-5 fluorine atoms, an ethyloxy group, Co. dalalkyloxy group, which is substituted by the residue 5 or B", where o 2? has the above values, and

B/ means a hydroxy group, a C 1 -alkyloxy group, a C 3 -cycloalkyloxy group, an amino group, a C 6 alkylamino group, a di(C 1 alkyl)amino group, a bis(2-methoxyethyl)amino group, a pyrrolidin-1-yl group, a piperidin-1-yl group, M) homopiperidine -1-yl group, morpholin-4-yl group, homomorpholin-4-yl GROUP, 2-oxa-5-azabicyclo|2.2.1)hept-5-yl group, 3-oxa-8-azabicyclo!/3.2. oct-8-yl group, 8-oxa-3-azabicyclo|3.2.1|oct-Z-yl group, piperazin-1-yl group, 4-C.i alkylpiperazin-1I-yl group, Z homopiperazin-1- yl group, Su alkylhomopiperazin-1-yl group, formylamino group, Fo

Si dalalkylcarbonylamino group, Su. zalkyloxy-S. alkylcarbonylamino group, Cu dalalkyloxycarbonylamino group, aminocarbonylamino group, Cu alkylaminocarbonylamino group, di(Si alkyl)aminocarbonylamino group, c. pyrrolidine-1-ylcarbonylamino group, piperidine-1-ylcarbonylamino group, piperazin-1-ylcarbonylamino group, 4-C. alkylpiperazine-1-ylcarbonylamino group, morpholine-4-ylcarbonylamino group or

Si dalalkylsulfonylamino group, Cz 7cycloalkyloxy group, Cz.7cycloalkyl-C. dalalkyloxy group, "tetrahydrofuran-3-yloxy group, tetrahydropyran-3-yloxy group, tetrahydropyran-4-yloxy group, tetrahydrofuranyl-C 3 dalyloxy group, tetrahydropyranyl-Si lalyloxy group, t c C daloxy group, which is substituted by the substituted in position 1 by the VK Z pyrrolidinyl residue, piperidinyl z" or homopiperidinyl group, where KZ means a hydrogen atom or a C. alkyl group, or a C. daloxy group, which is substituted by a morpholinyl group substituted in position 4 by a KZ residue, where KU has the above values, and - 35 X means a methine group substituted by a cyano group or a nitrogen atom, while the aryl groups mentioned in the definitions of the above-mentioned residues in each case mean a phenyl group that is mono- or disubstituted by a KU residue, where in the case of double substitution, the substituents can have identical or different values and where

BO means a hydrogen, fluorine, chlorine, bromine or iodine atom, a sisalalkyl group, a hydroxy group, about C, an alkyloxy group, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, or a cyano group, by the heteroaryl groups mentioned in the definitions of the above residues, we mean pyridyl, pyridazinyl, pyrimidinyl, or pyrimidinyl group, and the above-mentioned heteroaryl groups are in each case mono- or disubstituted by a KU residue, where in the case of double substitution, the substituents may have

Gee! identical or different values and where is RE? has the above values, each of the above pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups may be substituted by one or two C. alkyl groups and the above alkyl groups, unless otherwise specified, may be straight or branched, 60 except for 4 -1(3-chloro-4-fluorophenyl)amino|-6-(5)-tetrahydrofuran-3-yloxy)-7-hydroxyquinazoline.

To the preferred compounds of the above general formula | belong to compounds in which

KU means hydrogen atom,

IN? means a phenyl group substituted by K-2EZ residues, where

B" means a hydrogen, fluorine, chlorine or bromine atom, a metal group, a trifluoromethyl group, an ethynyl group, or a phenyloxy group or a phenylmethoxy group, where the phenyl fragment of the above groups is optionally substituted by a fluorine or chlorine atom, or a pyridyloxy or pyridinylmethoxy group, where the pyridinyl fragment of the above groups optionally substituted with a methyl or trifluoromethyl group,

IN? means a hydrogen, fluorine or chlorine atom or a metal group and

VZ stands for hydrogen atom,

IN? means the cyclopentyl group, which is substituted by the K7-M-B group in position C? where

B" means a hydrogen atom or a C. alkyl group, and vo means a hydrogen atom, a C. alkyl group, an aminocarbonyl-C. an alkyl group,

S. dalkylaminocarbonyl-S. an alkyl group, di(Cu alkyl)aminocarbonyl-C into an alkyl group, then pyrrolidine-1-ylcarbonyl-C 4 an alkyl group, piperidine-1-ylcarbonyl-C. alkyl group, piperazin-1-ylcarbonyl-C 4 alkyl group, 4-C. alkylpiperazine-1-ylcarbonyl-C / alkyl group, morpholine-4-ylcarbonyl-C. an alkyl group, a hydroxy-Soalkyl group, a C 1 alkyloxy-Co alkyl group,

C dalalkyloxycarbonylamino-C alkyl group, amino-C alkyl group, C alkylamino-C alkyl group, di(C alkyl)amino-C alkyl group, C alkylcarbonylamino C alkyl group, aminocarbonylamino C 5 alkyl group, C alkylaminocarbonylamino-C 5. dalalkyl group, di(S.sub.alkyl)aminocarbonylamino-C o. alkyl group, morpholine-4-ylcarbonylamino-C» alkyl group,

Su alkylsulfonyl-C» alkyl group, Su alkylsulfonylamino-C» alkyl group, (2-oxopyrrolidin-1-yl)-C» alkyl group, (2-oxopiperidin-1-yl)-C» alkyl group, (3-oxomorpholine -4-yl)-C » alkyl group, (2-oxoimidazolidin-1-yl)-C 4alkyl group, (2-oxo-3-methylimidazolidin-1-yl)-C » dalalkyl group, (2-oxohexahydropyrimidine-1 -yl)-Co alkyl group, (2-oxo-3-methylhexahydropyrimidin-1-yl)-C» alkyl group, C 1 alkylsulfonyl group, chloro-C 10 alkylsulfonyl group, bromo-C 10 alkylsulfonyl group, amino-C 10 alkylsulfonyl group,

Cu alkylamino-Co alkylsulfonyl group, di(Ci alkyl)amino-C» alkylsulfonyl group, (pyrrolidin-1-yl)-C» alkylsulfonyl group, (piperidin-1-yl)-Co lalkylsulfonyl group, ch 29 (morpholine-4 -yl)-C » laalkylsulfonyl group, Su dalalkyloxycarbonyl group, formyl group, OU)

C alkylcarbonyl group, C. alkyloxy-C. and alkylcarbonyl group, tetrahydrofuranylcarbonyl group, tetrahydropyranylcarbonyl group, amino-C. alkylcarbonyl group, Su. alkylamino-C.; alkylcarbonyl group, di(Si alkyl)amino-C.4 alkylcarbonyl group, pyrrolidin-1-yl-C alkylcarbonyl group, piperidin-1-yl-C. alkylcarbonyl group, piperazin-1-yl-C. alkylcarbonyl group, and 4-C. alkylpiperazin-1-yl-C to the alkylcarbonyl group, morpholin-4-yl-C. alkylcarbonyl group, Yu

Su alkylsulfonyl-S. alkylcarbonyl group, cyano group, aminocarbonyl group, Su. alkylaminocarbonyl group, di(Ci alkyl)aminocarbonyl group, (Ci.alkyloxy-C» alkyl)aminocarbonyl group, C

M-(C4.alkyl)-M-(Ci alkyloxy-C»lalkyl)aminocarbonyl group, phenylaminocarbonyl group,, FI pyrrolidin-1-ylcarbonyl group, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl group, ! pl! : dust ! and -

C1 alkylmorpholin-4-ylcarbonyl group, di(C1.alkyl)ummorpholin-4-ylcarbonyl group, homomorpholin-4-ylcarbonyl group, 2-oxa-5-azabicyclo|2.2.1|)hept-5-ylcarbonyl group, 3- oxa-8-azabicyclo|3.2.1|oct-8-ylcarbonyl group, 8-oxa-3-azabicyclo|3.2.1|oct-3-ylcarbonyl group, piperazin-1-ylcarbonyl group, 4-(C3 alkyl)piperazine -1-ylcarbonyl group, aminosulfonyl group, "du C alkylaminosulfonyl group, di(C. alkyl)uaminosulfonyl group, pyrrolidin-1-yl-sulfonyl group, c piperidin-1-ylsulfonyl group or morpholin-4-ylsulfonyl group, c cyclopentyl group, which in position Z is replaced by group KU, where ;" 9 means 2-oxopyrrolidin-1-yl group, 2-oxopiperidin-1-yl group, 3-oxomorpholin-4-yl group, 2-oxoimidazolidin-1-yl group, 2-oxo-3-methylimidazolidin-1-yl group , 2-oxohexahydropyrimidin-1-yl

A group or 2-oxo-3-methylhexahydropyrimidin-1-yl group, -I cyclohexyl group, which in position З or in position 4 is replaced by group B 7-M-BE?, where B7 and B? have c the values indicated above, a cyclohexyl group, which in position C or position 4 is replaced by a group B ZU, where K5 has the values indicated above, a pyrrolidine-Z-yl group, which in position 1 is replaced by a residue B C, where B? has the above values, a piperidin-3-yl group, which in position 1 is replaced by the residue B?, where K? has the indicated axis 20 higher values, a piperidin-4-yl group, which in position 1 is replaced by the residue ЕВ?, where КЕ? has the above values, or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, with VU means a hydrogen atom, C. an alkyloxy group, a methoxy group substituted by one to three fluorine atoms, an ethyloxy group that is in position 2 replaced by the residue of КЗ or В", where 2? has the values indicated above, and

B/ means a hydroxy group, C is an alkyloxy group, an amino group, C). alkylamino group, di(C. alkyl)amino group,

F, bis(2-methoxyethyl)amino group, pyrrolidin-1-yl group, piperidin-1-yl group, morpholin-4-yl group, homomorpholin-4-yl group, 2-oxa-5-azabicyclo|2.2.1 )hept-5-yl group, 3-oxa-8-azabicyclo|3.2.1|oct-d-yl group, 8-oxa-3-azabicyclo|3.2.1|oct-Z-yl group, piperazin-1- yl group, 4-C)3 alkylpiperazin-1-yl group, formylamino group, C. dalalkylcarbonylamino group,

Su zalkyloxy-S. alkylcarbonylamino group, C. dalalkyloxycarbonylamino group, aminocarbonylamino group,

Su alkylaminocarbonylamino group, di(Su. alkyl)aminocarbonylamino group, pyrrolidine-1-ylcarbonylamino group, piperidin-1-ylcarbonylamino group, piperazin-1-ylcarbonylamino group, 4-C. alkylpiperazine-1-ylcarbonylamino group, morpholin-4-ylcarbonylamino group or 65 C.alkylsulfonylamino group, propyloxy group, which in position C is replaced by residue 25 or B", where VK5 and KE" have the above values,

or a butyloxy group, which in position 4 is replaced by a KZ or B" residue, where B and B" have the above values, and

X means a nitrogen atom, while the above alkyl groups, unless otherwise specified, can have a straight or branched chain, their tautomers, their stereoisomers, their mixtures and their salts.

To the more preferred compounds of the above general formula | belong to compounds in which

VK? means a hydrogen atom, vo means a 3-ethynylphenyl group, a 3-bromophenyl group, a 3,4-difluorophenyl group,

3-chloro-4-fluorophenyl group, 3-chloro-4-benzyloxyphenyl group, 3-chloro-4-(3-fluorobenzyl)oxy|phenyl group, 10. 4-(pyridin-3Z-yloxy)phenyl group, 4- (b-methylpyridin-3-yl)oxy|phenyl group,

3-methyl-4-(pyridin-3-yloxy)phenyl group, 3-methyl-4-((b-methylpyridin-3-yl)oxy|phenyl group,

C-chloro-4-(pyridin-3-yloxy)phenyl group or C-chloro-4-((b-methylpyridin-3-yl)oxy|phenyl group,

B: means a cyclohexyl group, which is substituted in position C or in position 4 by the group B7-M-B2U, where

B" means a hydrogen atom, a metal group or an ethyl group, and "B" means a hydrogen atom, a metal group, an aminocarbonylmethyl group, a methylaminocarbonylmethyl group, a dimethylaminocarbonylmethyl group, a pyrrolidin-1-ylcarbonylmethyl group, a piperidin-1-ylcarbonylmethyl group, a piperazine-1- ylcarbonylmethyl group, 4-methylpiperazin-1-ylcarbonylmethyl group, morpholin-4-ylcarbonylmethyl group, 2-(morpholin-4-ylcarbonyl)ethyl group,

C-(morpholin-4-ylcarbonyl)upropyl group, oethyl group, propyl group, 2-hydroxyethyl group,

C-hydroxypropyl group, 2-methoxyethyl group, C-methoxypropyl group, 2-(butyloxycarbonylamino)ethyl group, 2-aminoethyl group, C-aminopropyl group, 2-acetylamino)dethyl group, C-(acetylamino)propyl group, 2 -(ethylcarbonylamino)ethyl group, 3-(ethylcarbonylamino)propyl group, 2-(propylcarbonylamino)ethyl group, 3-(propylcarbonylamino)propyl group, 2-(ethylaminocarbonylamino)ethyl group, 3-(ethylaminocarbonylamino)propyl group, ch 29 2 -(dimethylaminocarbonylamino)detyl group, 33-(dimethylaminocarbonylamino)propyl group, OO) 2-(morpholin-4-ylcarbonylamino)detyl group, 3-(morpholin-4-ylcarbonylamino)propyl group, 2-(methylsulfonyl)ethyl group, З3 -(methylsulfonyl)propyl group, 2-(methylsulfonylamino)ethyl group,

C-(methylsulfonylamino)propyl group, 2-(2-oxopyrrolidin-1-yl)ethyl group, 2-(2-oxopiperidin-1-yl)ethyl group, 2-(3-oxomorpholin-4-yl)ethyl group, and 30 2-(2-oxoimidazolidin-1-yl)ethyl group, 2-(2-oxo-3-methylimidazolidin-1-yl)ethyl group, Y 2-(2-oxohexahydropyrimidin-1-yl)ethyl group, 2 -(2-oxo-3-methylhexahydropyrimidin-1-yl)ethyl group, 3-(2-oxopyrrolidin-1-yl)upropyl group, 3-(2-oxopiperidin-1-yl)upropyl group, C 3-(3 -oxomorpholin-4-yl)propyl group, 3-(2-oxoimidazolidin-1-yl)upropyl group,, FI 3-(2-oxo-3-methylimidazolidin-1-yl)upropyl group, 3-(2-oxohexahydropyrimidine -1-yl)upropyl group, 3-(2-oxo-3-methylhexahydropyrimidin-1-yl)upropyl group, methyl sulfonyl group, ethyl sulfonyl group, 3-chloropropylsulfonyl group, 2-(morpholin-4-yl )"'ethylsulfonyl group,

C-(morpholin-4-yl)upropylsulfonyl group, propyloxycarbonyl group, butyloxycarbonyl group, formyl group, acetyl group, ethylcarbonyl group, propylcarbonyl group, methoxyacetyl group, di (2-methoxyethyl)carbonyl group, (3-methoxypropyl)carbonyl group , tetrahydrofuran-2-ylcarbonyl group, c tetrahydropyran-4-ylcarbonyl group, aminoacetyl group, methylaminoacetyl group, c dimethylaminoacetyl group, morpholin-4-ylacetyl group, (|2-(morpholin-4-yl)ethylcarbonyl group, :z» I3-(morpholin-4-yl)/propyl|carbonyl group, methylsulfonylacetyl group, cyano group, aminocarbonyl group, methylaminocarbonyl group, dimethylaminocarbonyl group, ethylaminocarbonyl group, diethylaminocarbonyl group, propylaminocarbonyl group, (2-methoxyethyl)aminocarbonyl group, - 15 M- methyl-M-(2-methoxyethyl)aminocarbonyl group, (3-methoxypropyl)aminocarbonyl group,

M-methyl-M-(3-methoxypropyl)aminocarbonyl group, phenylaminocarbonyl group, pyrrolidin-1-ylcarbonyl (Ce) group, piperidin-1-ylcarbonyl group, morpholin-4-ylcarbonyl group, 2-methylmorpholin-4-ylcarbonyl 1» group, 2,6-dimethylmorpholin-4-ylcarbonyl group, homomorpholin-4-ylcarbonyl group, 2-oxa-5-azabicyclo|2.2.1|)hept-b--ylcarbonyl group, 3-oxa-8-azabicyclo|3.2 .1|oct-B-ylcarbonyl group, 1 50 8-oxa-3-azabicycloi|3.2.1|oct-33-ylcarbonyl group, 4-methylpiperazin-1-ylcarbonyl group, sp aminosulfonyl group, methylaminosulfonyl group, dimethylaminosulfonyl group or a morpholin-4-ylsulfonyl group, a cyclohexyl group, which in position C or in position 4 is replaced by a group P, where 55 U means a 2-oxopyrrolidin-1-yl group, a 2-oxopiperidin-1-yl group, a C-oxomorpholin-4- yl group, 2-oxoimidazolidin-1-yl group, 2-oxo-3-methylimidazolidin-1-yl group, 2-oxohexahydropyrimidin-1-yl

F) group or 2-oxo-3Z-methylhexahydropyrimidin-1-yl group, or pyrrolidin-Z-yl group, which in position 1 is replaced by residue B 9, where KE? has the above values, a piperidine-Z-yl group, which in position 1 is replaced by the BC 7 residue, where B? has the above values, 60 piperidin-4-yl group, which in position 1 is replaced by the EC 7 residue, where BC? has the above values, a tetrahydrofuran-3-yl group, a tetrahydropyran-3Z-yl group or a tetrahydropyran-4-yl group,

BZ means a hydrogen atom, a methoxy group, a difluoromethoxy group, an ethyloxy group, an ethyloxy group, which in position 2 is replaced by a P or B residue", where it has the above values, and

B means a phydroxy group, a methoxy group, an ethoxy group, an amino group, a dimethylamino group, a diethylamino group,

bis(2-methoxyethyl)amino group, pyrrolidin-1-yl group, piperidin-1-yl group, morpholin-4-yl group, homomorpholin-4-yl group, 2-oxa-5-azabicyclo|2.2.1)hept- 5-yl group, 3-oxa-8-azabicyclo/3.2.1|oct-Z-yl group, 8-oxa-3-azabicyclo|3.2.1)oct-Z-yl group, piperazin-1-yl group, 4-methylpiperazin-1-yl group, 4-ethylpiperazin-1-yl group, acetylamino group, ethylcarbonylamino group, propylcarbonylamino group, butylcarbonylamino group, methoxyacetylamino group, butyloxycarbonylamino group, ethylaminocarbonylamino group, dimethylaminocarbonylamino group, pyrrolidine-1-ylcarbonylamino group, pyrrolidine-4-pyroylcarbonylamino group ylcarbonylamino group, methylsulfonylamino group, ethylsulfonylamino group or butylsulfonylamino group, 70 propyloxy group, which in position C is substituted by residue 5 or B", where KZ and VK" have the above values, or butyloxy group, which in position 4 is substituted by residue KZ or B", where B and B" " have the values indicated above, and

X means a nitrogen atom, while the above alkyl groups, unless otherwise specified, can have a straight or branched chain, their tautomers, their stereoisomers, their mixtures and their salts.

Particularly preferred compounds of the above general formula I include compounds in which

KU means hydrogen atom,

VE? means 3-bromophenyl group, 3,4-difluorophenyl group, 3-chloro-4-fluorophenyl group, 3-ethynylphenyl group, 3-chloro-4-benzyloxyphenyl group, 3-chloro-4-((3-fluorobenzyl)oxy| phenyl group, 4-(pyridin-3-yloxy)phenyl group, 4-(b-methylpyridin-3-yl)oxy|phenyl group,

3-methyl-4-(pyridin-33-yloxy)phenyl group, 3-methyl-4-((b-methylpyridin-3-yl)oxy|phenyl group,

C-chloro-4-(pyridin-3-yloxy)phenyl group or C-chloro-4-((b-methylpyridin-3-yl)oxy|phenyl group,

KO means a cyclohexyl group, which in position C is substituted by an amino-, acetylamino-, tert-butyloxycarbonylamino- or methylsulfonylamino group, a cyclohexyl group, which is substituted in position 4 by amino-, methylamino-, ethylamino-, dimethylamino-, aminocarbonylmethyl amino-, c 29 methylaminocarbonylmethylamino -, dimethylaminocarbonylmethylamino-, morpholin-4-ylcarbonylmethylamino-, (U

3-(morpholin-4-ylcarbonyl)propylamino-, (2-(methylsulfonyl)ethylamino-, (3-(methylsulfonyl)propylamino- or (2-(methylsulfonylamino)ethylamino), cyclohexyl group, which is in position 4 substituted (2-(2-oxopyrrolidin-1-yl)ethyl|amino-, (2-(2-oxopiperidin-1-yl)ethylamino-, (2-(2-oxoimidazolidin-1-yl)ethyl|amino-, (2-(2-oxo-3-methylimidazolidin-1-yl)ethyl|amino-, o (2-(2-oxohexahydropyrimidin-1-yl)ethyl|amino- or u (2-(2-oxo-3- methylhexahydropyrimidin-1-ylethylamino group, cyclohexyl group, which is substituted in position 4

3-(2-oxopyrrolidin-1-yl)propyl|amino-, 3-(2-oxopiperidin-1-yl)propyl| amino-, M

3-(2-oxoimidazolidin-1-yl)propylamino-, 3-(2-oxo-3-methylimidazolidin-1-yl)propyl)amino-, He»!

3-(2-oxohexahydropyrimidin-1-yl)ipropyl)amino- or

Zo IZ-(2-oxo-3-methylhexahydropyrimidin-1-yl)upropylamino group, cyclohexyl group, which in position 4 is substituted by acetylamino-, M-(acetyl)methylamino-, aminomethylcarbonylamino-, methylaminomethylcarbonylamino-, dimethylaminomethylcarbonylamino-, morpholine-4 -ylmethylcarbonylamino-, methoxyacetylamino-,

M-(methoxyacetyl)methylamino-, tetrahydropyran-4-ylcarbonylamino-, "

M-(tetrahydropyran-4-ylcarbonyl)methylamino-, tert-butyloxycarbonylamino-, - t0 M-(tert-butyloxycarbonyl)methylamino-, aminocarbonylamino-, methylaminocarbonylamino-, c M-(ethylaminocarbonyl)methylamino-, dimethylaminocarbonylamino-, M-( dimethylaminocarbonyl)methylamino-, c» M-(piperidin-1-ylcarbonyl)methylamino-, morpholin-4-ylcarbonylamino-, M-(morpholin-4-ylcarbonyl)methylamino- or

M-(4-methylpiperazin-1-ylcarbonyl)methylamino group, cyclohexyl group substituted in position 4 with 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl, 2-oxoimidazolidin-1 -yl, 2-oxo-3-methylimidazolidin-1-yl, 2-oxohexahydropyrimidin-1-yl or 2-oxo-3-methylhexahydropyrimidin-1-yl group, cyclohexyl group, which in position 4 is substituted by (Ce) methylsulfonylamino- , M-(methylsulfonyl)methylamino-, ethylsulfonylamino-, M-(ethylsulfonyl)methylamino-, dimethylaminosulfonylamino-, M-(dimethylaminosulfonyl)methylamino-, morpholin-4-ylsulfonylamino-, and M-(morpholin-4-ylsulfonyl)methylamino- . , which is substituted in position 1 by methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, sl-morpholin-4-ylcarbonyl or methylsulfonyl group, piperidin-3-yl group, piperids n-Z-yl group, which in position 1 is substituted by methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl group, piperidin-4-yl group, which in position 1 29 is substituted by methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl,

HF) 3-methoxypropyl, 2-(methylsulfonyl)ethyl, 3-("methylsulfonyl)propyl, 2-(tert-butyloxycarbonylamino)detyl, 2-aminoethyl, 2-(acetylamino)ethyl, o 2-(ethylcarbonylamino)detyl, 2 -(propylcarbonylamino)ethyl, 2-(ethylaminocarbonylamino)detyl, 2-(dimethylaminocarbonylamino)detyl, 2-(morpholin-4-ylcarbonylamino)detyl, 3-(acetylamino)propyl, 60 3-(ethylcarbonylamino)propyl, 3-(propylcarbonylamino) )propyl, 3-(ethyl aminocarbonylamino)propyl, 3-(dimethylaminocarbonylamino)propyl, 3-(morpholin-4-ylcarbonylamino)propyl, 2-(methylsulfonylamino)ethyl, 3-("methylsulfonylamino)propyl, (aminocarbonyl)umethyl, ( methylaminocarbonyl)methyl, (dimethylaminocarbonyl)methyl, (pyrrolidin-1-ylcarbonyl)umethyl, (morpholin-4-ylcarbonyl)umethyl, 2-(morpholin-4-ylcarbonyl)ethyl or 3-(morpholin-4-ylcarbonyl)upropyl group , a piperidin-4-yl group, which is substituted in position 1

2-(2-oxopyrrolidin-1-yl)ethyl, 2-(2-oxopiperidin-1-yl)ethyl, 2-(33-oxomorpholin-4-yl)ethyl, 2-(2-oxoimidazolidin-1-yl) uethyl, 2-(2-oxo-3-methylimidazolidin-1-yl)ethyl, 2-(2-oxohexahydropyrimidin-1-yl)ethyl or 2-(2-oxo-3-methylhexahydropyrimidin-1-yl)ethyl group, piperidin-4-yl group, which in position 1 is substituted by 3-(2-oxopyrrolidin-1-yl)upropyl, 3-(2-oxopiperidin-1-yl)upropyl, 3-(3Z-oxomorpholin-4-yl)upropyl , 3-(2-oxoimidazolidin-1-yl)upropyl, 3-(2-oxo-3-methylimidazolidin-1-yl)upropyl, 3-(2-oxohexahydropyrimidin-1-yl)upropyl or 3-(2-oxo -3-methylhexahydropyrimidin-1-yl)upropyl group, piperidin-4-yl group substituted in position 1 by formyl, acetyl, methoxyacetyl, (2-methoxyethyl)carbonyl, 70 (3-methoxypropyl)/carbonyl, methylsulfonylacetyl, aminoacetyl, methylaminoacetyl, (dimethylamino)acetyl, (morpholin-4-yl acetyl, (2-(morpholin-4-yl)ethyl)carbonyl,

3-(morpholin-4-yl)/propylcarbonyl, tetrahydrofuran-2-ylcarbonyl or tetrahydropyran-4-ylcarbonyl group, piperidin-4-yl group, which in position 1 is substituted by a cyano group, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, (2-methoxyethyl) aminocarbonyl,

M-methyl-M-(2-methoxyethyl)aminocarbonyl, (3-methoxypropyl)iaminocarbonyl,

M-methyl-M-(3-methoxypropyl)aminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 2-methylmorpholin-4-ylcarbonyl, 2,6 -dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-azabicyclo|2.2.1)hept-5--ylcarbonyl, 33-oxa-8-azabicyclo/|3.2.1|oct-8-ylcarbonyl . (2-(morpholin-4-yl)ethyl|isulfonyl, 3-(morpholin-4-yl)propyl|sulfonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl group, tetrahydrofuran-3-yl group, tetrahydropyran -3-yl group or tetrahydropyran-4-yl group,

BZ means a hydrogen atom, a methoxy group, a difluoromethoxy group, an ethyloxy group, a 2-(morpholin-4-yl)ethyloxy group, and)

C-(morpholin-4-yl)propyloxy group, 4-(morpholin-4-yl)butyloxy group, C-(dimethylamino)propyloxy group,

C-(diethylamino)propyloxy group, 3-(bis(2-methoxyethyl)amino|propyloxy group,

C-(piperazin-1-yl)propyloxy group, 3-(4-methylpiperazin-1-yl)upropyloxy group,

3-(4-ethylpiperazin-1-yl)propyloxy group, 3-(homomorpholin-4-yl)propyloxy group, 3-(2-oxa-5-azabicyclo|2.2.1)hept-5-yl)propyloxy group, o 3- (3-oxa-8-azabicycloI3.2.oct-8-yl)propyloxy group, 3-(8-oxa-3-azabicyclo|3.2.1|oct-3-yl)propyloxy group, "His 2-(2-oxopyrrolidine -1-yl)ethyloxy group, 2-(2-oxopiperidin-1-yl)ethyloxy group, 2-(3-oxomorpholin-4-yl)ethyloxy group, 2-(2-oxoimidazolidin-1-yl)ethyloxy group, o 3z5 2- (2-oxo-3-methylimidazolidin-1-yl)ethyloxy group, 2-(2-oxohexahydropyrimidin-1-yl)ethyloxy group, rch- 2-(2-oxo-3-methylhexahydropyrimidin-1-yl)ethyloxy group, 3-( 2-oxopyrrolidin-1-yl)upropyloxy group, 3-(2-oxopiperidin-1-yl)upropyloxy group, 3-(33-oxomorpholin-4-yl)propyloxy group, 3-(2-oxoimidazolidin-1-yl)propyloxy group, C -(-2-oxo-3-methylimidazolidin-1-yl)upropyloxy group, « 3-(2-oxohexahydropyrimidin-1-yl)upropyloxy group, 3-(2-oxo-3-methylhexahydropyrimidin-1-yl)upropyloxy group, 2 -(methoxy)ethyloxy group, 2-(tert-butyloxycarbonylamino)ethyloxy group, 2-(amino) ethyloxy group, WHAT is 2-(acetylamino)ethyloxy group, 2-(ethylcarbonylamino)ethyloxy group, 2-(propylcarbonylamino)ethyloxy group, is 2-(isobutylcarbonylamino)ethyloxy group, 2-(methoxyacetylamino)ethyloxy group, "» 2-(ethylaminocarbonylamino)ethyloxy group, 2 -(dimethylaminocarbonylamino)ethyloxy group, 2-(pyrrolidin-1-ylcarbonylamino)ethyloxy group, 2-(piperidin-1-ylcarbonylamino)ethyloxy group, 2-(morpholin-4-ylcarbonylamino)ethyloxy group, 2-(methylsulfonylamino)ethyloxy group, -I 2- "ethylsulfonylamino)ethyloxy group, 2-(butylsulfonylamino)ethyloxy group,

3-(tert-butyloxycarbonylamino)propyloxy group, 3-(amino)propyloxy group, 3-(acetylamino)propyloxy group or 1-o 3-("methylsulfonylamino)propyloxy group and "" X means a nitrogen atom, their tautomers, their stereoisomers, their mixtures and their salts. i-th The most preferred compounds of the general formula I include compounds in which sl VK? means a hydrogen atom,

IN? preferably means a 3-chloro-4-fluorophenyl group or a 3-ethynylphenyl group,

KO means a cyclohexyl group which is substituted in position C with an amino-, acetylamino-, 22-tert-butyloxycarbonylamino- or methylsulfonylamino group, a cyclohexyl group which is in position 4

HF) substituted amino-, methylamino-, dimethylamino-, acetylamino-, M-(acetyl)methylamino-, methoxyacetylamino-,

M-(methoxyacetyl)methylamino-, tetrahydropyran-4-ylcarbonylamino-, M-(tetrahydropyran-4-ylcarbonyl)methyl de amino-, tert-butyloxycarbonylamino-, M-(tert-butyloxycarbonyl)methylamino-,

M-(ethylaminocarbonyl)methylamino-, dimethylaminocarbonylamino-, M-(dimethylaminocarbonyl)methylamino-, 60 M-(piperidin-1-ylcarbonyl)methylamino-, morpholin-4-ylcarbonylamino-, M-(morpholin-4-ylcarbonyl)methylamino- ,

M-(4-methylpiperazin-1-ylcarbonyl)methylamino-, methylsulfonylamino-, M-(methylsulfonyl)methylamino-, ethylsulfonylamino-, M-(ethylsulfonyl)methylamino-, dimethylaminosulfonylamino-,

M-(dimethylaminosulfonyl)methylamino-, morpholin-4-ylsulfonylamino-,

M-(morpholin-4-ylsulfonyl)methylamino-, 3-chloropropylsulfonylamino- or 3-(morpholin-4-yl)/propylsulfonylamino group, pyrrolidin-3-yl group, pyrrolidin-3-yl group, which is in position 1 substituted by a tert-butyloxycarbonyl or methylsulfonyl group, a piperidin-3-yl group, a piperidin-Z-yl group, which in position 1 is substituted by a tert-butyloxycarbonyl or methylsulfonyl group, a piperidin-4-yl group, a piperidin-4-yl group, which in position 1 position 1 is substituted with methyl, (aminocarbonyl)umethyl, (dimethylaminocarbonyl)methyl, (morpholin-4-ylcarbonyl)umethyl, 2-(tert-butyloxycarbonylamino)deethyl, 2-aminoethyl, 2-(acetylamino)ethyl, 2-(methylsulfonylamino)ethyl group, cyano group, acetyl, methoxyacetyl, (dimethylamino)acetyl, (morpholin-4-ylluacetyl, tetrahydropyran-4-ylcarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl, dimethylaminocarbonyl, 70 diethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1 -ylcarbonyl, morpholin-4-ylcarbonyl, 2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, methylsulfonyl, dimethylaminosulfonyl or a morpholin-4-ylsulfonyl group, a tetrahydrofuran-3-yl group, a tetrahydropyran-3-yl group or a tetrahydropyran-4-yl group, c means a hydrogen atom, a methoxy group, an ethyloxy group, a 2-(morpholin-4-yl)ethyloxy group,

C-(morpholin-4-yl)/propyloxy group, 4-(morpholin-4-yl)butyloxy group, 2-(3-methyl-2-oxohexahydropyrimidin-1-yl)ethyloxy group, 2-(methoxy)ethyloxy group, 2-( tert-butyloxycarbonylamino)ethyloxy group, 2-aminoethyloxy group, 2-(acetylamino)ethyloxy group, 2-(methylsulfonylamino)ethyloxy group, 3-(tert-butyloxycarbonylamino)propyloxy group, 3-aminopropyloxy group, 3-acetylamino)propyloxy group or 3-(methylsulfonylamino) propyloxy group and

X means a nitrogen atom, their tautomers, their stereoisomers, their mixtures and their salts.

Among the above-mentioned bicyclic heterocycles of the general formula I, as well as among those mentioned above as preferred, more preferred, especially preferred and most preferred subgroups of compounds, it is especially worth noting those compounds in which (a) K7 means a cyclohexyl group substituted in position 4, o ( b) BO means optionally substituted in position 1 pyrrolidin-3-yl group, (c) EB" means optionally substituted in position 1 piperidin-3-yl group, (d) K7 means optionally substituted in position 1 piperidin-4-yl group, o 3o (e) KO means tetrahydrofuran-3-yl group, Io) (e) KU means tetrahydropyran-3-yl or group « (e) KO means tetrahydropyran-4-yl group, and Ka , VR, VU and X in each case have the above values

As an example of the most preferred compounds of the general formula I, the following can be named: rch- (1). 4-(3-chloro-4-fluorophenyl)amino|-6-((5)-tetrahydrofuran-3-yloxy)-7-methoxyquinazoline, (2). 4-((3-chloro-4-fluorophenyl)amino|-6-(tetrahydropyran-4-yloxy)-7-methoxyquinazoline, (3). 4-(3-chloro-4-fluorophenyl)amino|-6-( K)-tetrahydrofuran-3-yloxy)-7-methoxyquinazoline, "(4). 4-((3-chloro-4-fluorophenyl)amino|-6-(trans-4-aminocyclohexan-1-yloxy)-7-methoxyquinazoline, (5). 4-KHZ-chloro-4-fluorophenyl)amino|- 6-(trans-4-methanesulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline, - c (6). 4-KZ-chloro-4-fluorophenyl)amino|-6-(piperidin-4-yloxy)-7-methoxyquinazoline, with" (7). 4-(3-chloro-4-fluorophenyl)amino|-6-(1-methanesulfonylpiperidin-4-yloxy)-7-methoxyquinazoline, " (8) 4-(3-chloro-4-fluorophenyl)amino)|-6 -(cis-4-13-(morpholin-4-yl)upropyl|sulfonylamino)cyclohexan-1-yloxy)-7-methoxy quinazoline, -I (9). 4-(3-chloro-4-fluorophenyl)amino| -6-(tetrahydropyran-3-yloxy)-7-methoxyquinazoline, (10) i-o 4-(3-chloro-4-fluorophenyl)amino)|-6-(trans-4-4I3-("morpholine-4 -yl)upropyl|Isulfonylamino)cyclohexane-1-yloxy)-7-metho "g"xyquinazoline, (11). 4-KZ-chloro-4-fluorophenyl)amino|-6-(1-methylpiperidin-4-yloxy) -7-methoxyquinazoline, i-th (12). 4-((3-chloro-4-fluorophenyl)amino!|-6-41-(morpholin-4-yl)carbonyl|piperidin-4-yloxy)-7- methoxyquinazoline, cl (13). 4-(3-chloro-4-fluorophenyl)amino|-6-71-(methoxymethyl)carbonyl|piperidin-4-yloxy)-7-methoxyquinazoline, (143. 4-К(З- chloro-4-fluorophenyl)amino|-6-(1-cyanopiperidin-4-yloxy)-7-methoxyquinazoline, (153. 4-K(3-chloro-4-fluorophenyl)amino|-6-41-Kmorpholine-4 -yl)sulfonyl|piperidin-4-yloxy)-7-methoxyquinazoline, (16). 4-(3-chloro-4-fluorophenyl)amino)-6-(1-(2-acetylaminoethyl)pip eridin-4-yloxy|-7-methoxyquinazoline, 17

Ф, 4-(3-chloro-4-fluorophenyl)amino)|-6--trans-4-(dimethylamino)sulfonylamino|cyclohexan-1-yloxy)-7-methoxyquinazolim)in, (18) bo A-KZ -chloro-4-fluorophenyl)amino|-6-"trans-4-((morpholin-4-yl)carbonylamino|cyclohexan-1-yloxy)-7-methoxyquinazolin, (19) 4-(3-chloro-4 -fluorophenyl)amino|-6--trans-4-Kmorpholin-4-yl)usulfonylamino|cyclohexan-1-yloxy)-7-methoxyquinazolin, 65 (20). 4-((3-chloro-4-fluorophenyl) amino)-6-(tetrahydropyran-4-yloxy)-7-(2-acetylaminoethoxy)quinazoline, (21). 4-(3-chloro-4-fluorophenyl)amino)|-6-(tetrahydropyran-4-yloxy) -7-(2-methanesulfonylaminoethoxy)quinazoline and

(22). 4-(3-chloro-4-fluorophenyl)amino|-6-(tetrahydropyran-4-yloxy)-7-(2-methoxyethoxy)quinazoline, as well as their salts.

Compounds of the general formula | can be obtained, for example, by the following methods. a) In this version, the compound of the general formula y oo in which KU, РЕ, VU Her X have the values indicated at the beginning of the description, is subjected to interaction with the compound of the general formula 21-vo (1) in which BU has the values indicated at the beginning of the description, and 7 means a leaving group such as a halogen atom such as a chlorine or bromine atom, a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group, or a hydroxy group.

The interaction with the compound of the general formula I, in which 7 is a hydroxy group, is carried out in the presence of a dehydrating agent, preferably in the presence of phosphine and a derivative of azodicarboxylic acid, for example, triphenylphosphine/diethyl ether of azodicarboxylic acid, preferably in a solvent, for example, methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or diethyl ether of ethylene glycol, at (o) a temperature from -50 to 1502C, preferably, however, at a temperature from -20 to 8026. b) In this variant, for obtaining compounds of the general formula I, in which B 9 means one of the above optionally substituted alkyloxy groups, a compound of the general formula oyu - I c) « (o) and - their derivatives; Я Я є є ди " " in which K2, КО, КО and Х have the values indicated at the beginning of the description, are subjected to interaction with a compound of the general formula - 72-вЯ (М)

I.Y and? in which BZ means a C dalalkyl group substituted by 1-3 fluorine atoms, a methyl group substituted by 1-5 fluorine atoms, an ethyl group substituted by a KZ residue or B" C" a dalalkyl group, where KZ and Kk" have the values indicated at the beginning of the description, C 1.alkyl group which is substituted by the BV residue substituted in position 1 with a pyrrolidinyl, piperidinyl or homopiperidinyl group, or C. dalalkyl group which is substituted by the BZ residue substituted in position 4 with a morpholinyl group, where C in each case has the indicated at the beginning description of the value, and 72 means a leaving group, such as a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group, or a hydroxy group.

If the group to be removed is a halogen atom, for example a chlorine, bromine or iodine atom, or a alkylsulfonyloxy or arylsulfonyloxy group, for example a methanesulfonyloxy or p-toluenesulfonyloxy group, then the reaction is preferably carried out in the presence of an organic or inorganic base, for example potassium carbonate, hydride sodium or M-ethyldisopropylamine. If the group that is removed is a hydroxy group, then the reaction is carried out in the presence of a dehydrating agent, preferably in the presence

HF) of phosphine and a derivative of azodicarboxylic acid, for example, triphenylphosphine/diethyl ether of azodicarboxylic acid. c) In this version, for the preparation of compounds of the general formula I, in which B C means one of the alkyloxy groups indicated at the beginning of the description, which is substituted by an optionally substituted amino-, alkylamino- or dialkylamino group or an optionally substituted imino group attached through a nitrogen atom a heterocyclic group, a compound of the general formula b5 chi bos tag sp in which 2, BR, BZ and X have the values indicated at the beginning of the description, and 7 means a group that is removed, for example a halogen atom, in particular a chlorine or bromine atom, or a sulfonyloxy group, for example methanesulfonyloxy - or p-toluenesulfonyloxy group, are subjected to interaction with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or with an imino compound or their acceptable salts or derivatives, for example, morpholine. t d) In this version, for obtaining compounds of the general formula I, in which B. Z means a hydroxy group, from a compound of the general formula ev (SUPU C - o in which B2, B?, BZ | X have the values indicated at the beginning of the description, and BU means a group that is converted into a hydroxy group, for example an optionally substituted benzyloxy group, benzylethylsilyloxy group, acetyloxy group, benzoyloxy group, methoxy group, ethoxy group, tert-butoxy group or trityloxy group, the protective group is removed. iv)

The protecting group is removed, for example, hydrolytically in an aqueous solvent such as water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence of an alkali metal base, such as sodium hydroxide or potassium hydroxide, or aprotonically, for example in the presence of phoiodotrimethylsilane, at a temperature from 0 to 1202C, preferably at a temperature from 10 to 10090.

Benzyl or methoxybenzyl group is cleaved off, for example, by hydrogenolysis, in particular using hydrogen in the presence of a catalyst, such as palladium on carbon, in a solvent suitable for this purpose, such as methanol, ethanol, ethyl acetic acid or glacial acetic acid, neobov necessarily with the addition of an acid, such as hydrochloric acid, at a temperature from 0 to 100 C, preferably, "however, at close to room temperatures from 20 to 602 C, and at a hydrogen pressure from 1 to 7 bar, preferably from 70 C to B5 bar. The 2,4-dimethoxybenzyl group is preferably cleaved, however, in trifluoroacetic acid in the presence of anisole.

The tert-butyl or benzyl group is removed, for example, by treatment with an acid such as trifluoroacetic acid, hydrochloric acid, or hydrobromic acid, or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol, or diethyl ether. -1 395 d) In this version, to obtain compounds of the general formula I, in which K C means the group -МН-, from the compound of the general formula se) another 50 8 steps (steps from t)

ГФ) in which B2, 2, BU and X have the values indicated at the beginning of the description, and B has the values indicated at the beginning of the description for VZ with the condition that K: contains a protected nitrogen atom, the protective group is cleaved off.

Examples of common protecting groups for an amino, alkylamino, or imino group include a formyl group, an acetyl group, a trifluoroacetyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, a methoxybenzyl group, or a 2,4-dimethoxybenzyl group, and for amino groups - you can additionally call the phthalic group.

The protecting group is removed, for example, hydrolytically in an aqueous solvent, such as water, isopropanol/water, acetic acid/water, tetrahydrofuran/water, or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid, or in in the presence of an alkali metal base, such as sodium hydroxide or potassium hydroxide, or aprotonically, for example in the presence of iodotrimethylsilane, at a temperature from 0 to 1202C, preferably at a temperature from 10 to 10020.

However, the benzyl, methoxybenzyl or benzyloxycarbonyl group is removed, for example, by hydrogenolysis, in particular using hydrogen in the presence of a catalyst such as palladium on carbon, in a suitable solvent such as methanol, ethanol, ethyl acetic acid or glacial acetic acid, optionally with the addition of an acid, such as hydrochloric acid, at a temperature of from 0 to 100 2C, preferably, however, at close to room temperatures from 20 to 602C, and at a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar. The 2,4-dimethoxybenzyl group is preferably cleaved, however, in trifluoroacetic acid in the presence of anisole. 70 tert-Butyl or tert-butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, or treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The trifluoroacetyl group is preferably removed by treatment with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid, at a temperature of 50 to 120 C, or by treatment with caustic sodium, optionally in the presence of a solvent such as tetrahydrofuran, at temperature from O to 5090.

The phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at a temperature of 20 to 5026. e) In this embodiment for obtaining compounds of the general formula I, in which K C contains an optionally substituted amino, alkylamino, or dialkylamino group or an alkyl group attached through a nitrogen atom, optionally substituted by a heterocyclic group, a compound of the general formula

IS) where (ho, yu in which КУ, ЕР, КУ and Х have the values indicated at the beginning of the description, 7? means a group that is removed, for example, a halogen atom, in particular a chlorine or bromine atom, or a sulfonyloxy group, for example, methanesulfonyloxy- or Ф ) with a p-toluenesulfonyloxy group, and KO provided that the hydrogen atom M attached to the aliphatic carbon atom is replaced by group 73, has the values indicated at the beginning of the description for K 7, are subjected to interaction with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or with an imino compound or their acceptable salts or derivatives, for example, morpholine.

When obtaining by the method proposed in the invention a compound of the general formula I, which contains an amino-, " alkylamino- or imino group, such a compound can be converted into a corresponding acyl compound, cyano compound or sulfonyl compound of the general formula by means of acylation, cyanation or sulfonylation, using as acylating agent, for example, isocyanates, carbamoyl chlorides, carboxylic acid halides, carboxylic acid anhydrides and carboxylic acids together with activators such as

M,M'-carbonyldiimidazole, M,M'-dicyclohexylcarbodiimide or tetrafluoroborate

O-(benzotriazol-1-yl)M,M,M',M'-tetramethyluronium, as a sulfonylation agent - sulfonyl halides, and as an agent -I of cyanation - chloro- or bromocyanide, and/or when obtaining a compound of the general formula I, which contains an amino-, alkylamino- or imino group, such a compound can be converted by alkylation or hydroalkylation into the corresponding alkyl compound of the general formula I and/or by obtaining a compound of the general formula I, which contains a chloro-Ci.alkylsulfonyl group or bromo-C . alkylsulfonyl group, such a compound can be converted into a corresponding amino-C-alkylsulfonyl compound by interaction with an amine and/or by obtaining a compound of the general formula 1, which contains tert-butyloxycarbonylamino-, M-alkyl-M-(tert-butyloxycarbonyl)amino- or with an M-tert-butyloxycarbonylimino group, such a compound can be converted into a corresponding amino-, alkylamino- or imino compound of the general formula |

When carrying out the reactions described above, reactive groups such as hydroxy-, amino-, alkylamino- or imino groups present under certain conditions can be protected during the course of the reaction by conventional protective groups and cleaved off again after the reaction is complete. (F) Trimethylsilyl, acetyl, trityl, cobenzyl or tetrahydropyranyl group can be mentioned as an example of a protecting group for a hydroxy group.

An example of a protective group for an amino, alkylamino, or imino group is a formyl, acetyl, v-trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl, or 2,4-dimethoxybenzyl group.

The protecting group used in the reaction is subsequently removed, if necessary, for example by hydrolysis in an aqueous solvent such as water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water in the presence of an acid such as trifluoroacetic acid acid, hydrochloric db Acid or sulfuric acid, either in the presence of an alkali metal base, such as sodium hydroxide or potassium hydroxide, or by an aprotic pathway, such as in the presence of iodotrimethylsilane, at a temperature from 0 to 1202C, preferably at a temperature from 10 to 10020.

However, the benzyl, methoxybenzyl or benzyloxycarbonyl group is removed, for example, by hydrogenolysis, in particular using hydrogen in the presence of a catalyst such as palladium on carbon, in a suitable solvent such as methanol, ethanol, ethyl acetic acid or glacial acetic acid, optionally with the addition of an acid, such as hydrochloric acid, at a temperature of from 0 to 100 2C, preferably, however, at close to room temperatures from 20 to 602C, and at a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar. The 2,4-dimethoxybenzyl group is preferably cleaved, however, in trifluoroacetic acid in the presence of anisole. 70 tert-Butyl or tert-butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, or treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The trifluoroacetyl group is preferably cleaved by treatment with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid, at a temperature of 50 to 120 C, or by treatment with caustic sodium, optionally in the presence of a solvent such as tetrahydrofuran or methanol , at a temperature from O to 5096.

In addition, compounds of the general formula | can be divided, as already mentioned above, into their enantiomers and/or diastereomers. Thus, for example, cis-/trans-mixtures can be separated into their individual cis- and trans-isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.

Thus, in particular, the obtained cis-/trans-mixtures can be separated by chromatography into their separate cis- and trans-isomers, the obtained compounds of the general formula I, which are formed in the form of racemates, can be separated by known methods, see E. AiShpdeg and E.Yi. ЕЕеей, "Торисв ип 5иегеоспетивигу", ed. УМиеу Ипегвзсиепсе, 1971, etc. into their optical antipodes, and compounds of the general formula I with at least 2 asymmetric carbon atoms SM can be separated based on the differences in their physicochemical properties by known methods , for example by chromatography and/or fractional crystallization, into their diastereomers, which, when formed in racemic form, can then be separated, as described above, into enantiomers.

Separation into enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by interaction with an optically active substance, such as M) a racemic compound forms salts or derivatives, such as esters or amides, primarily by interaction with acids and their activated derivatives or alcohols, and separation of the resulting mixture of diastereomeric salts or derivatives, for example, on the basis of differences in their solubility, while free antipodes can be released from pure Ж diastereomeric salts or derivatives under the influence of an agent suitable for this purpose. As an example of optically active acids, which are most often used for the above purposes, we can name ХО- and I-forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. An example of an optically active alcohol is (h)- or (-U-menthol), and an example of an optically active acyl residue in amides is (t)- or (-)U-menthyloxycarbonyl.

The obtained compounds of the formula | can, in addition, be converted into their salts, primarily for pharmaceutical use into their physiologically compatible salts, with inorganic or organic acids. Examples of suitable acids for this purpose include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Compounds of the general formulas 1I-IX, which are used as starting products, are partially known from the literature or can be obtained by methods known from the literature (see examples I-XXII) or by the methods described above, if necessary with additional introduction of protective groups ( see, for example, the compounds of the formulas M, respectively MI! and MP).

The compounds of the general formula !/ and their physiologically compatible salts proposed in the invention have, as already noted at the beginning of the description, valuable pharmacological properties, primarily an inhibitory effect on signal transduction mediated by the sl 50 receptor of the epidermal growth factor (ESF-K), which can be caused by , for example, by inhibiting ligand binding, receptor dimerization, or tyrosine kinase itself. In addition, there is also an opportunity to block signal transduction to components located at a deeper level.

The biological properties of the new compounds were studied according to the method described below.

Inhibition of human ESBE receptor kinase was determined using the cytoplasmic domain of the tyrosine kinase (fragment from methionine at position 664 to alanine at position 1186 based on the sequence,

Gee! published in Maishge 309, 1984, p. 4181). For this purpose, the protein in the form of a fusion with (57 (glutathione-5-transferase) protein was expressed in 5th cells of insects using a baculovirus expression system.

Enzymatic activity was determined in the presence or absence of the tested compounds by the method of serial 60 dilutions. Polymer pEM (4:1) from 5ZISMA was used as a substrate. Biotinylated pEM polymer (bio-pEM) was added as a labeled (indicator) substrate. Each 100 μl of the reaction solution contained 1 μl of the inhibitor in 5096 DMSO, 20 μl of the substrate solution (200 μM NEREZ (M-2-hydroxyethylpiperazine-M'-2-ethanesulfonic acid) with pH 7.4, 5 μM magnesium acetate, 2.5 mg/ml polymer pEM, 5μg/ml bio-pEM) and 20μl of enzymatic preparation. The enzymatic reaction was initiated by adding 5 μl of a 100 micromolar ATP solution in 65 10 millimolar magnesium chloride. The parameters of the process of diluting the enzymatic preparation were selected in such a way that the incorporation of phosphate into the bio-pREM occurred in a linear dependence on time and enzyme consumption. The enzyme preparation was diluted in a mixture of 20 mm NEREZ with pH 7.4, 1 mm EDTC, 130 mm table salt, 0.595 triton X-100, 1 mm dithiothreitol (DTT) and 1095 glycerol.

Experiments with enzymes were carried out at room temperature for 30 h, stopping the reaction by adding

ZOml of stop solution (250 MM EDTC in 20 MM NEREZ with pH 7.4). A sample with a volume of 100 μl was transferred to a streptavidin-coated titration microplate and incubated for 2 hours at room temperature. After this tablet was washed with 200 μl of washing solution (50MM Tris, 0.0595 Tween 20). After adding 10 μl of horseradish peroxidase-labeled (NKRO) antibodies to pRU (РУ2ОН Apii-RTusNKR company Tgapzdisiyop I arogaifgiev, 25 ng/ml) were incubated for 2h. After that, the titration microplate was washed three times with a 7/0 washing solution in portions of 200 μl. Then the samples were mixed with 100 μl of TMB-peroxidase solution (А:В-1:1, firm

Kiiedaaga Reitu Iarogayugiev). After 1 Ohv, the reaction was stopped. The optical density of OG was measured using a tablet reader for EI IZA analysis. All experimental data were determined in three replicates.

Data were fitted by iterative calculations using a sigmoidal curve analysis program (Ogari Ray R'gist program, version 3.0) with a variable Hill slope. The correlation coefficient of all allowed data obtained by iteration exceeded 0.9, and the upper and lower values of the curves differed by a factor equal to at least 5. Based on these curves, the concentration of the active substance was determined at which the activity of the ECE receptor kinase inhibited at 5095 (ISvo). At the same time, the following results were obtained:

F zv ev m « 0 Z s g shchi t se)

It follows from the above results that the compounds of the general formula I! inhibit signal transduction mediated by tyrosine kinases, as illustrated by the example of the human g 20 EOSE receptor, and are therefore suitable for the treatment of pathophysiological processes caused by hyperfunction of tyrosine kinases. An example of such processes is the formation of benign and malignant tumors, first of all tumors of epithelial and neuroepithelial origin, metastasis, as well as abnormal proliferation of vascular endothelial cells (neoangiogenesis).

The compounds proposed in the invention are also suitable for the prevention and treatment of diseases of the respiratory tract and lungs associated with excessive or altered mucus formation caused by stimulation

GF! tyrosine kinases, for example in inflammatory diseases of the respiratory tract, such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, d1-antitrypsin deficiency or in cough, pulmonary emphysema, pulmonary fibrosis and increased reactivity respiratory tract. 60 The compounds proposed in the invention are also suitable for the treatment of diseases of the gastrointestinal tract, as well as bile ducts and gall bladder, associated with a violation of the activity of tyrosine kinases, as occurs, for example, in chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis and gastrointestinal ulcers, or as occurs in gastrointestinal disorders associated with hypersecretion, such as Menetriere's disease, adenoma of the secretory glands, and protein-wasting syndrome. because Compounds of the general formula! and their physiologically compatible salts can be used, in addition, for the treatment of other diseases caused by the aberrant function of tyrosine kinases, such as, for example, epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, as well as for the treatment of nasal polyps, etc.

Due to their biological properties, the compounds proposed in the invention can be used individually or in combination with other pharmacologically active compounds, for example, for the therapeutic treatment of tumors in monotherapy or in combination with other antitumor therapeutic agents, for example, in combination with topoisomerase inhibitors (for example, etoposide), with antimitotic agents (for example, vinblastine), with compounds interacting with nucleic acids (for example, cis-platinum, 7/0 Cyclophosphamide, Adriamycin), with hormone antagonists (for example, tamoxifen), with inhibitors of metabolic processes (for example, 5-RSh, etc.), with cytokines (for example, interferons), with antibodies, etc.

For the treatment of diseases of the respiratory tract, these compounds can be used individually or in combination with other drugs intended for the treatment of the respiratory tract, such as, for example, substances that have an expectorant effect (in particular, ambroxol, M-acetylcysteine), broncholytic effect (in particular, 7/5 Tiotropium or ipratropium or fenoterol, salmeterol or salbutamol) and/or action that suppresses the inflammatory process (in particular theophylline or glucocorticoids). For the treatment of diseases in the gastrointestinal tract, these compounds can also be prescribed individually or in combination with substances that affect peristalsis or secretion. In such combinations, the active substances can be administered either simultaneously or sequentially.

The compounds proposed in the invention can be used individually or in combination with other active substances

Administer intravenously, subcutaneously, intramuscularly, intraperitoneally, nasally, by inhalation or percutaneously or orally, while aerosol preparations are primarily suitable for inhalation.

For pharmaceutical use, the compounds proposed in the invention are administered, as a rule, to warm-blooded vertebrates, primarily to humans, in doses from 0.01 to 100 Ω/kg of body weight, preferably from 0.1 to 15 mg/kg.

For the preparation of medicinal products, such compounds are processed together with one or more common inert carriers and/or diluents, such as corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water /ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose, or fatty substances such as solid fat, or acceptable mixtures thereof, into conventional galenic forms such as tablets, dragees, capsules, powders, suspensions, oral solutions, sprays or suppositories.

Below, the invention is illustrated by non-limiting examples. at

Preparation of starting compounds "E

Example

Hydrochloride 4-((3-chloro-4-fluorophenyl)amino)|-6-(tetrahydropyran-4-yloxy)-7-benzyloxyquinazoline Me

A mixture of 10.84 g of 4-chloro-6-(tetrahydropyran-4-yloxy)-7-benzyloxyquinazoline and 4.50 g of 3-chloro-4-fluoroaniline in M

Zb0Oml of isopropanol is refluxed for four hours and then left to stand overnight at room temperature. The precipitate formed is separated by vacuum filtration, washed with isopropanol and mixed with 150 ml of methanol. The resulting suspension is stirred for half an hour at room temperature and then subjected to vacuum filtration. The precipitate on the filter is washed several times with methanol and dried. "

Yield: 9.07g (60905 from theory), sshc value of K, 0.27 (silica gel, cyclohexane/ethyl acetate in a ratio of 1:1), there is a mass spectrum (EBIU: t/:2 - 478, 480 M-NO . "» Similarly to example I, the following compounds are obtained: (1) 4-Y(3-chloro-4-fluorophenyl)amino|-6-(5)-tetrahydrofuran-3-yloxy)-7-benzyloxyquinazoline hydrochloride: value of K, : 0.34 (silica gel, cyclohexane/ethyl acetate in a ratio of 1:1), -and mass spectrum (ESI"): t/2 - 466, 468 MANI"; (2) hydrochloride 4-Y(Z-chloro-4 -fluorophenyl)amino|-6-"-1-trifluoroacetylpiperidin-4-yloxy)quinazoline: its LC value is 0.17 (ready-made plates for reverse-phase TLC (firm E. MegskK), t" acetonitrile/water/trifluoroacetic acid in ratios 50:50:1), hundred 20 mass spectrum (E5I"): t/2 - 469471 MANI"; (3) hydrochloride 4-((3-chloro-4-fluorophenyl)amino|-6-"-1 -trifluoroacetylpiperidin-4-yloxy)-7-acetoxyquinazoline: sl Ku value, 0.70 (silica gel, methylene chloride/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), mass spectrum (E5I"): t/ 2 - 527, 529 MANI"; (4) 4-(Z-ethyne ylphenyl)amino)|-6-acetoxy-7-methoxyquinazoline: 29 K value: 0.59 (silica gel, ethyl acetate),

F! mass spectrum (E5BI"): t/2 - 334 MANI".

Example II about 4-chloro-6-(tetrahydropyran-4-yloxy)-7-benzyloxyquinazoline

The title compound is obtained by reacting 60 b-(tetrahydropyran-4-yloxy)-7-benzyloxy-ZH-quinazolin-4-one with thionyl chloride in the presence

of M,M-dimethylformamide in acetonitrile under reflux.

K value: 0.90 (silica gel, ethyl acetate/methanol in the ratio 9:1).

Similarly to example II, the following compounds are obtained: (1). 4-chloro-6-((5)-tetrahydrofuran-3-yloxy)-7-benzyloxyquinazoline: K value: 0.85 (silica gel, ethyl acetate/methanol in a ratio of 9:1);

(2) 4-chloro-6-(1-trifluoroacetylpiperidin-4-yloxy)quinazoline: K value: 0.92 (silica gel, ethyl acetate); (3). 4-chloro-6-(1-trifluoroacetylpiperidin-4-yloxy)-7-acetoxyquinazoline.

Example II b-(tetrahydropyran-4-yloxy)-7-benzyloxy-ZN-quinazolin-4-one

A mixture of 15.08 g of 2-amino-4-benzyloxy-5-(tetrahydropyran-4-yloxy)benzoic acid and 14 40 g of formamidine acetate in 250 ml of absolute ethanol is refluxed overnight.

The cooled reaction mixture is mixed with 250 ml of water. The precipitate that has fallen out is separated by vacuum filtration and 7/0 is stirred at 70C in a drying cabinet.

Yield: 10.00 Ω (6590 from theory), LC value 0.40 (ready plates for TLC with reversed phase (E. MegskK company), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (EBI"): t/2 - 353 MANI".

Similarly to example III, the following compounds are obtained: (1). 6-(5)-tetrahydrofuran-3-yloxy)-7-benzyloxy-ZN-quinazolin-4-one: LC value 0.60 (ready-made reverse-phase TLC plates (E. MegskK company), acetonitrile/water/ trifluoroacetic acid in a ratio of 50:50:1), mass spectrum (EBI"): t/2 - 339 ME"; (2). 6-(1-(tert-butyloxycarbonyl)piperidin-4-yloxy|-ZN-quinazolin-4-one: K value: 0.48 (silica gel, ethyl acetate/methanol in a ratio of 9:1), mass spectrum (EBI "): m/2 - 346 MANI"; (3). 6-P1-(tert-butyloxycarbonyl)piperidin-4-yloxy)-7-hydroxy-ZN-quinazolin-4-one: K value: 0.35 (silica gel, methylene chloride/methanol in a ratio of 9:1), with mass spectrum (EVI7): t/2 - 362 MANI". o

Example HIM 2-amino-4-benzyloxy-5-(tetrahydropyran-4-yloxy)benzoic acid 16.40 g. 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)benzoic acid is hydrogenated in the presence of 1.64 g of Raney nickel in 800 ml of methanol at 552 until the calculated amount of hydrogen is absorbed. After this catalyst is filtered off and the filtrate is concentrated, which is accompanied by crystallization of the target product. yu

Yield: 15.08 g (10095 from theory), LC value 0.60 (ready-made reverse-phase TLC plates (E. MegskK company), with acetonitrile/water/trifluoroacetic acid in a ratio of 50:50:1). Ge")

Similarly to the IM example, the following compounds are obtained:

Zo (1) benzyl ether of 2-amino-4-benzyloxy-5-(5)-tetrahydrofuran-3-yloxy)benzoic acid: t value of K, 0.70 (silica gel, cyclohexane/ethyl acetate in a ratio of 1:1), wt - spectrum (EBI"): t/2 - 420 MANI"; (2) 2-amino-5-(1-(tert-butyloxycarbonyl)piperidin-4-yloxy|benzoic acid: " du value of K,: 0.43 (silica gel, methylene chloride/methanol in the ratio 9:1), - c mass spectrum (E5I"): m/2 - 337 MANI"; (3) 2-amino-4-hydroxy-5-(/1-(tert-butyloxycarbonyl)piperidin-4-yloxy|benzoic acid: :z» K value: 0.23 (silica gel, methylene chloride/methanol/acetic acid in the ratio 90:10:1).

Example M 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)benzoic acid -I The compound specified in the title is obtained by saponification of the benzyl ether of 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)benzoic acid others caustic sodium in methanol at room temperature. from the value of LC and 0.20 (ready-made plates for reverse-phase TLC (E. MegskK company), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), o mass spectrum (E5I"): t/2 - 374 MANI". with Example MI

Benzyl ether of 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)benzoic acid

Two 42.60 g of potassium tert-butznolate are added to 1 ml of tetrahydrofuran-4-ol in 228 ml of M,M-dimethylformamide while cooling in an ice bath. The mixture is stirred for an hour at room temperature, after which 22.90 g of b-nitrobenzo|1,3|dioxol-5-carboxylic acid is added. After 1.5 hours, the reaction according to the data

F) of thin-layer chromatography is completed, and 28.94 ml of benzyl bromide is added dropwise to the mixture while cooling in an ice bath. The reaction mixture is stirred overnight at room temperature, mixed with 100 ml of 1096 citric acid and stirred at room temperature during the next day. After that, the reaction mixture is concentrated in a vacuum at 602C and its volume is brought up to 80 Oml by adding a mixture of water and ice. The aqueous phase is extracted with ethyl acetate, after which the combined extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is mixed with diethyl ether, followed by crystallization of 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)benzoic acid as a by-product. This acid is filtered off and the filtrate is concentrated. As the main product 65 remains the benzyl ether of 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)benzoic acid, which is saponified to carboxylic acid without further purification (see example M).

Analogous to example MI, the following compounds are obtained: (1) 2-nitro-4-benzyloxy-5-(5)-tetrahydrofuran-3-yloxy)benzoic acid benzyl ether: K value, 0.75 (silica gel, cyclohexane/ethyl acetate in the ratio 1:1), mass spectrum (EBI"): t/2 - 450 MANI"; (2) 2-nitro-4-hydroxy-5-(/1-(tert-butyloxycarbonyl)piperidin-4-yloxy|benzoic acid: no interaction with benzyl bromide, value K,: 0.40 (silica gel, methylene chloride/methanol/ acetic acid in a ratio of 90:10:1), mass spectrum (EBIU: t/2 - 381 M-NO.

Example MY 4-(3-chloro-4-fluorophenyl)amino!|-6-41-(2-(tert-butyloxycarbonylamino)ethyl|piperidin-4-yloxy)-7-methoxyquinase olin

A mixture of 410 mg of 4-((3-chloro-4-fluorophenyl)amino|-6-(piperidin-4-yloxy)-7-methoxyquinazoline dihydrochloride, 2400 mg of M-(tert-butyloxycarbonyl)-2-bromomethylamine and 300 mg of potassium carbonate in bml of M,M-dimethylformamide 75 is stirred overnight at room temperature.

M-(tert-butyloxycarbonyl)-2-bromomethylamine in a portion of 8Omg and the reaction mixture is stirred for the next four hours at room temperature. For processing, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed on a silica gel column using ethyl acetate/methanol (in a ratio varying from 95:5 to 90:1) as an eluent.

Yield: 37Omg (7995 from theory): LC value 0.33 (ready plates for reverse-phase TLC (E. MegskK company), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (EI ): t/2 - 544, 546 |M-NO. with

Analogously to the example of MYI, the following compound is obtained: o (1). 4-KZ-chloro-4-fluorophenyl)amino|-6-11-(2-(tert-butyloxycarbonylamino)ethyl|piperidin-4-yloxy)quinazoline: LC value 0.38 (ready plates for reverse-phase TLC ( firm E. MegskK), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (E5I"): t/2 - 516, 518 MANI. o

An example of MI! yu

4-((3-chloro-4-fluorophenyl)amino|-6-(piperidin-4-yloxy)-7-methoxyquinazoline dihydrochloride

The title compound is obtained by processing - 4-(3-chloro-4-fluorophenyl)amino1-6-(/1-(tert-butyloxycarbonyl)piperidin-4-yloxy)|-7-methoxyquinazoline Ge! concentrated hydrochloric acid in dioxane at room temperature.

З Value of LC K 0.53 (ready-made plates for reverse-phase TLC (E. MegskK company), acetonitrile/water/trifluoroacetic acid in a ratio of 50:50:1), mass spectrum (E5I"): t/2 - 403, 405 MONEY".

Similarly to the MI example, the following compounds are obtained: "(1) 6-(piperidin-4-yloxy)-ZN-quinazolin-4-onex2 trifluoroacetic acid: the reaction is carried out with trifluoroacetic acid - 70 in methylene chloride, with mass spectrum (ESI") : t/2 - 246 MANI"; :z" (2) 6-(piperidin-4-yloxy)-7-hydroxy-ZN-quinazolin-4-one: the reaction is carried out with trifluoroacetic acid in methylene chloride, the LC value is 0.60 (ready-made plates for reversed-phase TLC (firm E. MegskK), -1 acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (EBI"): t/2 - 262 MANI". 4-(3-Chloro-4-fluorophenyl)amino-1-6-((1-(tert-butyloxycarbonyl)piperidin-4-yloxy)|-7-methoxyquinazoline

To a mixture of 10.00 g of 4-(3-chloro-4-fluorophenyl)amino)-6-hydroxy-7-methoxyquinazoline, 9.40 g of 1 1-(tert-butyloxycarbonyl)-4-hydroxypiperidine and 12.40 g of triphenylphosphine in 40 Oml of methylene chloride at room temperature, a solution of 7.800 ml of diethyl ether of azodicarboxylic acid in 100 ml of methylene chloride is added dropwise. The resulting suspension is stirred for three days at room temperature and then subjected to vacuum filtration. The filtrate is concentrated and chromatographed on a silica gel column using methylene chloride/methanol (in a ratio varying from 98:2 to 95:5) as an eluent. The obtained crude product is mixed with diisopropyl ether, stirred in it overnight, subjected to vacuum filtration and dried. ratios 9:1), in the mass spectrum (EBI"): t/2 - 503, 505 MANI.

Example X 4-(3-chloro-4-fluorophenyl)amino)|-6-(tetrahydropyran-4-yloxy)-7-(4-bromo-butyloxy)quinazoline

A mixture of 5O0mg of 4-(3-chloro-4-fluorophenyl)amino)|-6-(tetrahydropyran-4-yloxy)-7-hydroxyquinazoline, 1b5bmcl of 1-bromo-4-chloropropane and 3b0omg of potassium carbonate in ml of M,M- of dimethylformamide is stirred overnight at 65,802C. For processing, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is used in the next reaction without further purification.

Output: 65Ω (9795 from theory). . 1

Similarly to example X, the following compounds are obtained: (1). 4-((3-chloro-4-fluorophenyl)amino1-6-(5)-tetrahydrofuran-z-yloxy)-7-(4-bromobutyloxy)quinazoline: K value: 0.84 (silica gel, ethyl acetate/methanol in ratios 9:1); (2). 4-(3-chloro-4-fluorophenyl)amino|-6-"1-trifluoroacetylpiperidin-4-yloxy)-7-ethoxyquinazoline: mass spectrum (E5I"): m/2 - 513, 515 MANI"; ( 3). 4-(3-chloro-4-fluorophenyl)amino|-6-"1-trifluoroacetylpiperidin-4-yloxy)-7-(2-methoxyethoxy)quinazoline: 70 values of K,. 0.38 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (EBI"): t/2 - 543, 545 (MANI.

Example XI 1-(2-hydroxyethyl)-3-methyltetrahydropyrimidin-2-one

The title compound was obtained by cleavage of 75. 1-(2-benzyloxyethyl)-3-methyltetrahydropyrimidin-2-one by hydrogenolysis in the presence of palladium on activated carbon in methanol at room temperature.

Value of K. 0.23 (silica gel, ethyl acetate/methanol/conc. aqueous solution of ammonia in the ratio 90:10:1), mass spectrum (E5BI"): t/2 - 159 MANI".

Example XII 1--2-benzyloxyethyl)-3-methyltetrahydropyrimidin-2-one

The title compound is prepared by reacting 1-(2-benzyloxyethyl)tetrahydropyrimidin-2-one with methyl iodide in the presence of potassium tert-butanolate in M,M-dimethylformamide at room temperature.

The value of CC. 0.62 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), mass spectrum (ESI"): t/2 - 249 MANI". with

An example of HIA! o 1--2-benzyloxyethyl)tetrahydropyrimidin-2-one

The title compound is prepared by treating /1-(2-benzyloxyethyl)-3-(3-chloropropyl)urea with potassium tert-butanolate in M,M-dimethylformamide at room temperature.

CI value: 0.42 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), o 3o mass spectrum (EBI7): t/2 - 235 MEI".

Example CHEM 1--2-benzyloxyethyl)-tetrahydropyrimidin-2-one h

The compound indicated in the title is obtained by the interaction of 2-benzyloxyethylamine with 3-chloropropyl isocyanate in FU tetrahydrofuran m

Value of K. 0.73 (silica gel, ethyl acetate/methanol/conc. aqueous solution of ammonia in the ratio 90:10:1), mass spectrum (E5BI"): t/2 - 271, 273 MANI".

Example of HM

3-(tert-butyloxycarbonylamino)cyclohexanol « 20 The title compound is prepared by reacting 3-aminocyclohexanol with di-tert-butyl ether in pyrocarbonic acid in the presence of triethylamine in a mixture of dioxane/water (2:1 ratio) at 5026.

The value of CC. 0.34 (silica gel, methylene chloride/methanol/concentrated aqueous solution of ammonia in the ratio 90:10:1), ;" mass spectrum (E5IU: t/2 - 214 IM-NO"

Analogous to the example of XM, the following compound is obtained: (1) cis-4-IM-(tert-butyloxycarbonyl)-M-methylamino|cyclohexanol: -I reaction is carried out in methanol, value K,: 0.70 (silica gel, ethyl acetate), and -o mass spectrum (E5I"): t/2 - 230 MANI". g» Example of KMI sl 50 6-(1-trifluoroacetylpiperidin-4-yloxy)-ZN-quinazolin-4-one

The title compound is obtained by reacting 6b-(piperidin-4-yloxy)-ZH-quinazolin-4-one 2 sl of trifluoroacetic acid with trifluoroacetic anhydride in the presence of triethylamine in tetrahydrofuran.

K value: 0.48 (silica gel, ethyl acetate/methanol in a ratio of 9:1), mass spectrum (ESI"): t/2 - 342 MANI"

Similarly to the example of KMI, the following compound is obtained:

GF! (1). 6-"1-trifluoroacetylpiperidin-4-yloxy)-7-hydroxy-ZN-quinazolin-4-one: the reaction is carried out with the methyl ether of trifluoroacetic acid in the presence of Hünig's base in methanol, where the value of K,: 0.80 (silica gel, methylene chloride /methanol in a ratio of 4:1), mass spectrum (E5I"): m/2 - 358 MANI".

To 25.14 g of 1-(tert-butyloxycarbonyl)piperidin-4-ol in 120 ml of M,M-dimethylformamide, while cooling in an ice bath, add 21.00 g of potassium tert-butanolate in portions, while maintaining the temperature below 1026.

Next, the mixture is stirred for another 30 minutes while cooling in an ice bath, after which 11.60 g of 5B-fluoro-2-nitrobenzoic acid are added. After the next three hours, the reaction mixture is poured into water,

the pH value is set to 1 using concentrated hydrochloric acid and extracted with ethyl acetate.

The combined organic phases are washed with a dilute solution of citric acid, dried over magnesium sulfate and concentrated. The residue is triturated with diethyl ether, subjected to vacuum filtration and dried. An additional amount of product crystallizes from the filtrate during its long standing, which is also separated by vacuum filtration and dried.

Yield: 9.58g (42905 from theory), value of K,. 0.43 (silica gel, methylene chloride/methanol/acetic acid in the ratio 90:10:1), mass spectrum (E5I"): t/z2 - 367|M ANI". 70 Example XM 4-(3-chloro-4-fluorophenyl)amino|-6-(1-bromoacetylpiperidin-4-yloxy)quinazoline and 4-(3-chloro-4-fluorophenyl)amino)|-6-(1- chloroacetylpiperidin-4-yloxy)quinazoline

The title compounds are prepared by reacting 4-(3-chloro-4-fluorophenyl)amino|-6-(piperidin-4-yloxy)quinazoline with bromoacetic acid chloride in the presence of Hunig's base in tetrahydrofuran at room temperature. As a result, a mixture of bromine- and chlorine-substituted compounds is formed.

Value of K,: 0.43 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (ESI"): t/2 - 493, 495, 497 MINI" and 449, 451, 453 (M2ZhNI.

Similarly to the example of KhMIII, the following compound is obtained: (1). 4-(3-chloro-4-fluorophenyl)amino)|-6-(1-chloroacetylpiperidin-4-yloxy)-7-methoxyquinazoline: the reaction is carried out with chloroacetyl chloride, Kk value 0.59 (silica gel, ethyl acetate/methanol/conc. aqueous solution of ammonia in the ratio 90:10:1), mass spectrum (EI): t/:2 - 477, 479, 481 IM-NO.

Example XIX with 1-methyl-3-(11,Zoxazepan-4-yl)carbonyl|-ZN-imidazol-1-yl iodide

The title compound is obtained by reacting 3-((1,Shoxazepan-4-yl)/carbonyl|-ZH-imidazole with methyl iodide in acetonitrile at room temperature. The crude product is used in the next reaction without further purification.

Similarly to example XIX, the following compounds are obtained: IF) (1). 1-Methyl-3-(cis-2,6-dimethylmorpholin-4-yl)carbonyl|-ZN-imidazol-1-yl iodide: the value of CC". 0.12 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 90:10:1); (2). 1-methyl-3-(2-methylmorpholin-4-yl)carbonyl|-ZH-imidazol-1-yl iodide: Kk value 0.02 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in a ratio of 90:10: 1). Fo

Example XX 3 3-K11,Zoxazepan-4-yl)carbonyl|-ZH-imidazole v.

The title compound is obtained by reacting (|1,Tsoxazepane with M,M'-carbonyldiimidazole in the presence of triethylamine in tetrahydrofuran at room temperature.

K value: 0.30 (silica gel, ethyl acetate/methanol/concentrated aqueous ammonia solution in the ratio 90:10:1), "mass spectrum (E5BI"): t/2 - 196 MANI"

Analogously to example XX, the following compounds are obtained: C c (1) 3-Kcis-2,6-dimethylmorpholin-4-yl)carbonyl|-ZH-imidazole: "» Kk value 0.46 (silica gel, ethyl acetate/methanol/conc. aqueous solution of ammonia in a ratio of 90:10:1); " (2) 3-(2-methylmorpholin-4-yl)carbonyl|-ZH-imidazole: Kk value 0.43 (silica gel, ethyl acetate/methanol/conc. aqueous solution ammonia in the ratio 90:10:1).

Example XXI sh- 4-(3-chloro-4-fluorophenyl)amino|-6-(1-trifluoroacetylpiperidin-4-yloxy)-7-hydroxyquinazoline so The compound specified in the title is obtained by treating the hydrochloride of 4-(3-chloro-4- fluorophenyl)amino|-6-(1-trifluoroacetylpiperidin-4-yloxy)-7-acetoxyquinazoline with a saturated solution of sodium bicarbonate in methanol at room temperature. Along with the target product, a small amount of 4-((3-chloro-4-fluorophenyl)amino|-6-(piperidin-4-yloxy)-7-hydroxyquinazoline is also isolated as a side product in c 20.

Value of K,: 0.20 (silica gel, methylene chloride/methanol - 20:1), sl mass spectrum (ESI): pt/2 - 483, 485 M-NO.

Similarly to example XXI, the following compound is obtained: (1) 4-KZ-ethynylphenyl)amino|-6-hydroxy-7-methoxyquinazoline: the reaction is carried out with 4095 sodium caustic in ethanol,

HF) value of K,.: 0.32 (silica gel, ethyl acetate), 7 mass spectrum (EBI"): t/2 - 292 MANI".

Example XXIII in 6-(1-trifluoroacetylpiperidin-4-yloxy)-7-acetoxy-ZN-quinazolin-4-one

The title compound is prepared by reacting 6-(1-trifluoroacetylpiperidin-4-yloxy)-7-hydroxy-ZN-quinazolin-4-one with acetic anhydride in pyridine at 8020.

The value of K,. 0.60 (silica gel, methylene chloride/methanol in the ratio 9:1), mass spectrum (EBI"): t/2 - 400 MANI". 65 Preparation of final compounds

Example 1

4-(3-chloro-4-fluorophenyl)amino|-6-(5)-tetrahydrofuran-3-yloxy)-7-methoxyquinazoline

30 mg of 4-(3-chloro-4-fluorophenyl)amino|-b-hydroxy-7-methoxyquinazoline in 1 ml of acetonitrile is mixed with 114 μl of (K)-3-hydroxytetrahydrofuran and 37 mg of triphenylphosphine. Next, 234 μl of diethyl ether of azodicarboxylic acid is added and the reaction mixture is stirred overnight at room temperature. For processing, the reaction mixture is filtered and the filtrate is concentrated in a vacuum. The crude product is purified by chromatography on a silica gel column using a mixture of ethyl acetate/methanol (95:5) as an eluent.

Yield: 5 Zmg (15950 from theory), melting point: 1789С, mass spectrum (E5I"): t/2 - 390, 392 MANI". high school

Similarly to example 1, the following compounds are obtained: (1). 4-(3-chloro-4-fluorophenyl)amino|-6-(tetrahydropyran-4-yloxy)-7-methoxyquinazoline: (8)

E. iv) yu « (22) m. | that | the value of K,: 0.54 (silica gel, ethyl acetate/methanol in a ratio of 9:1), . mass spectrum (E5I"): t/2 - 404, 406 MANI"; I (2) 4-(3-chloro-4-fluorophenyl)amino1|-6-Cys-4-(tert-butyloxycarbonylamino)cyclohexan-1-yloxy|-7-methoxyquinazoline: -I se) sh» sl 50 sl Her oh oh where; 60 values of CC, 0.70 (silica gel, ethyl acetate/methanol in a ratio of 9:1), mass spectrum (E5I"): t/2 - 517, 519 MANI"; (3). 4-(3-chloro-4-fluorophenyl)amino|-6-(K)-tetrahydrofuran-3-yloxy)-7-methoxyquinazoline: b5

E' value of K,: 0.64 (silica gel, ethyl acetate/methanol in the ratio 9:1), mass spectrum (E5I"): t/2 - 390, 392 MANI"; (4) 4-(3-chloro-4-fluorophenyl)amino)|-6-Itrans-4-(tert-butyloxycarbonylamino)cyclohexan-1-yloxy|-7-methoxyquinazoline: i b "i o

Fe Fl - i i yu yu « (22) 35 . with. ! - K value: 0.65 (silica gel, ethyl acetate/methanol in a 9:1 ratio), mass spectrum (ESI"): t/2 - 517, 519 MANI"; (5) 4-((3-chloro-4-fluorophenyl)amino)-6-P1-(tert-butyloxycarbonyl)piperidin-4-yloxy)-7-methoxyquinazoline: "-1 и se) и" sl 50 sl not melting point: 1845C, 59 mass spectrum (EBI7): t/x - 503, 505 MANI";

GF) (6). 4-(3-chloro-4-fluorophenyl)amino|-6-(tetrahydropyran-3-yloxy)-7-methoxyquinazoline: ime) 60 b5 what

F E i ke; y Y n F IF y y o ik. t value of K,: 0.52 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (E5I"): t/2 - 404, 406 MANI"; (7). 4-KZ-chloro-4-fluorophenyl)amino)|-6-(1-methylpiperidin-4-yloxy)-7-methoxyquinazoline:

E 4 g che Y I ' s

Mt 5, Fr

And in y: - I g sia! also iv) melting point: 2189C, mass spectrum (E5I"): t/2 - 417, 419 MANI"; "And (8). 4-((3-chloro-4-fluorophenyl)amino1|-6-(5)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yloxy|-7-methoxyquinazoline: Fu reaction is carried out with diisopropyl ether of azodicarboxylic acid in methylene chloride, K value: 0.51 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (E5I"): t/2 - 489, 491 MANI"; (9). 4-(3-chloro -4-fluorophenyl)amino1|-6-I1-(tert-butyloxycarbonyl)piperidin-3-yloxy|-7-methoxyquinazoline: the reaction is carried out with diisopropyl ether of azodicarboxylic acid in methylene chloride, K value: 0.56 (silica gel, methylene chloride /methanol in a ratio of 9:1), mass spectrum (EI): t/x - 501, 503 (M-NI; no) s (10)

Is» 4-(3-chloro-4-fluorophenyl)amino)|-6-(5)-tetrahydrofuran-3-yloxy)-7-(2-(3-methyl-2-oxohexahydropyrimidin-1-yl)ethoxyquinazoline : the reaction is carried out with diisopropyl ether of azodicarboxylic acid in methylene chloride, melting point: 2359C,

In the mass spectrum (E5BI"): t/2 - 516, 518 MANI"; se) (11) their 4-(3-chloro-4-fluorophenyl)amino1|-6-3-"(tert-butyloxycarbonylamino)cyclohexan-1-yloxy)|-7-methoxyquinazoline: the reaction is carried out with diisopropyl ether of azodicarboxylic acid in methylene chloride, 1 50 K value: 0.68 (silica gel, ethyl acetate/methanol in the ratio 9:1), c mass spectrum (ESPIU: t/2 - 515, 517 IM-NI; (12) 4-(Z- chloro-4-fluorophenyl)amino!|-6--cis-4-IM-(tert-butyloxycarbonyl)-M-methylamino|cyclohexan-1-yloxy)-7-methoxy iquinazoline: the reaction is carried out with diisopropyl ether of azodicarboxylic acid in methylene chloride , (F; K value: 0.37 (silica gel, methylene chloride/methanol in a 9:1 ratio), mass spectrum (E5I"): t/2 - 531, 533 MANI"; (13) bo 4-I (3-chloro-4-fluorophenyl)amino)|-6-(trans-4-(M-(tert-butyloxycarbonyl)-M-methylamino|cyclohexan-1-yloxy)-7-methoxyquinazoline: the reaction is carried out with diisopropyl ether of azodicarboxylic acid in methylene chloride, melting point: 2312C, mass spectrum (E5I"): t/2 - 531, 533 MANI. 65 Example 2 4-(3-chloro-4-fluorophenyl)amino)|-6-(cis -4-aminocyclohexane-1-yloxy)-7-methoxyquinazoline xtrifluoroacetic acid l, l i i F F in g i -

The title compound was obtained by treating 75. 4-KZ-chloro-4-fluorophenyl)amino)|-6-(Icis-4-(tert-butyloxycarbonylamino)cyclohexan-1-yloxy|-7-methoxyquinazoline with trifluoroacetic acid in methylene chloride at room temperature temperature

Melting point: 221 C, mass spectrum (EBI"): t/2 - 417, 419 (MANI.

Similarly to example 2, the following compounds are obtained: (1). 4-K(3-chloro-4-fluorophenyl)amino|-6-(trans-4-aminocyclohexan-1-yloxy)-7-methoxyquinazoline: c (8)

IS) t zo and kN, oyu "mass spectrum (E5I"): t/2 - 417, 419 MANI"; ia (2) 4-((3-chloro-4-fluorophenyl)amino)|-6-(piperidin-4-yloxy)-7-methoxyquinazoline trifluoroacetic acid:

Y shi s zhh I z veshg

The melting point of Ho Ei and (Se) is 2322C, their mass spectrum (E5I"): t/2 - 403.405 MANI.

Example Z o 4-(3-chloro-4-fluorophenyl)amino)|-6-(cis-4-methanesulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline sl i F ov y and what with her (F; М о и) . and yuyu bo R SCHI "Vsh

The title compound was obtained by reacting 4-(3-chloro-4-fluorophenyl)amino)|-6-(cis-4-aminocyclohexan-1-yloxy)-7-methoxyquinazoline xtrifluoroacetic acid 65 with methanesulfonic acid chloride in the presence of Hunig's base in tetrahydrofuran at room temperature.

Value of K. 0.77 (silica gel, ethyl acetate/methanol/conc. aqueous solution of ammonia in the ratio 40:10:1), mass spectrum (E5I"): t/2 - 495.497 MANI.

Similarly to example C, the following compounds are obtained: (1). 4-KZ-chloro-4-fluorophenyl)amino|-6-(trans-4-methanesulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline:

E id value K,: 0.20 (silica gel, ethyl acetate), mass spectrum (E5I"): t/2 - 495.497 MANI"; (2). 4-(3-chloro-4-fluorophenyl)amino|-6-(1-methanesulfonylpiperidin-4-yloxy)-7-methoxyquinazoline: cm ; (8) о ю о ю « value of Kk 0.59 (silica gel, ethyl acetate/methanol/concentrated aqueous solution of ammonia in the ratio 90:10:1), Ge! mass spectrum (E5I"): t/2 - 481, 483 MANI"; (3) and - 4-(3-chloro-4-fluorophenyl)amino)|-6--cis-4-((3-chloropropyl)sulfonylamino|cyclohexane-1-yloxy)-7-methoxyquinazoline:

R « - s; with"

WITH

-I se) the reaction is carried out with 3-chloropropanesulfonyl chloride, and the value of K,: 0.79 (silica gel, ethyl acetate/methanol in the ratio 9:1), sl mass spectrum (EI): t/2 - 555, 557, 559 |M-NO; (4) 4-(3-chloro-4-fluorophenyl)amino)|-6--trans-4-(3-chloropropyl)sulfonylamino|cyclohexane-1-yloxy)-7-methoxyquinazoles

N:

Ф) име) 60 b5 o tr and the reaction is carried out with 3-chloropropanesulfonyl chloride, /5 value of K,: 0.42 (silica gel, ethyl acetate), mass spectrum (E5BI"): t/2 - 557, 559, 561 IMENI" ; (5). 4-(3-chloro-4-fluorophenyl)amino|-6-(1-methylcarbonylpiperidin-4-yloxy)-7-methoxyquinazoline:

R what - what ' -- - with ' Ga " and ve in o ; p what - and-

IS) the reaction is carried out with acetic anhydride, melting point: 2169C, "mass spectrum (EBI"): t/2 - 445, 447 MANI"; (6). 4-((3-chloro-4-fluorophenyl)amino|-6-41-(dimethylamino)carbonyl|piperidin-4-yloxy)-7-methoxyquinazoline: (o)

E. m. "shi s

I , and i, - but" (Te) reaction is carried out with M,M-dimethylcarbamoyl chloride, its value is 0.28 (ready-made plates for reverse-phase TLC (E. MegekK company), acetonitrile/water/trifluoroacetic acid in a ratio of 50 :50:1), sya 70 mass spectrum (EVI7): t/2 - 474, 476 MANI"; Mr. (7). 4-KZ-chloro-4-fluorophenyl)amino|-6-71-(morpholin-4-yl)carbonyl|piperidin-4-yloxy)-7-methoxyquinazoline:

The reaction is carried out with (morpholin-4-yl)carbonyl chloride in acetonitrile, the LC value is 0.37 (ready-made plates for reverse-phase TLC (E. MegskK company) , acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (E5BI"): t/2 - 516, 518 MANI"; (8). 4-((3-chloro-4-fluorophenyl)amino|-6-41-(methoxymethyl)carbonyl|piperidin-4-yloxy)-7-methoxyquinazoline:

S s - h . th r - i Tsi

E y t ni f i. The second reaction is carried out with methoxyacetic acid chloride, value of K,: 0.80 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (E5BI"): t/2 - 475, 477 MANI"; (9). 4-((3-chloro-4-fluorophenyl)amino)|-6-(1-cyanopiperidin-4-yloxy)-7-methoxyquinazoline: со т Ф ! iv) and V and yu

Xia 5 I Ge! with i m, the reaction is carried out with cyanogen bromide in methylene chloride, the LC value is 0.40 (ready-made reverse-phase TLC plates (E. MegskK company), diacetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), with c mass spectrum (EBI"): t/2 - 428, 430 MANI"; (10). 4-(3-chloro-4-fluorophenyl)amino|-6-41-(dimethylamino)sulfonyl|piperidin-4-yloxy)-7-methoxyquinazoline: ;» і- г se) із -і . і I ч че s і - і sl o 7 ne , . and the reaction is carried out with M,M-dimethylsulfamoyl chloride in acetonitrile, (Ф) value of LC and 0.24 (ready-made plates for reverse-phase TLC (E. MegskK company), g acetonitrile/water/trifluoroacetic acid in a ratio of 50:50: 1), mass spectrum (E5I"): t/2 - 510, 512 MANI"; in (11). 4-KZ-chloro-4-fluorophenyl)amino|-6-41-Cmorpholin-4-yl)sulfonyl|piperidin-4-yloxy)-7-methoxyquinazoline: b5

F shiche H 70 | in 1 o, the reaction is carried out with (morpholin-4-yl)usulfonyl chloride in acetonitrile, the value of i is 0.29 (ready-made plates for reverse-phase TLC (E. MegskK company), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1 ), mass spectrum (EBI"): t/2- 552, 554 MANI"; (12). 4-(3-chloro-4-fluorophenyl)amino|-6-(1-methanesulfonylpiperidin-3-yloxy)-7-methoxyquinazoline: LC value 0.33 (ready-made plates for reverse-phase TLC (firm E. MegskK) , acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (E5I"): t/2 - 481, 483 MANI"; (13). 4-(3-Chloro-4-fluorophenyl)amino|-6-((5)-1-methanesulfonylpyrrolidin-3-yloxy)-7-methoxyquinazoline: mp 29 melting point: 2499C, o mass spectrum (EBI"): t/2 - 467, 469 MANI"; (143. 4-K(3-chloro-4-fluorophenyl)amino|-6-(1--2-methanesulfonylaminoethyl)piperidin-4-yloxy|-7-methoxyquinazoline: LC value 0.49 (ready plates for TLC with an inverted phase (E. MegskK company), using acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (EBI"): t/2 - 524, 526 MANI"; o (153.4 -(3-chloro-4-fluorophenyl)amino)-6-(1-(2-acetylaminoethyl)piperidin-4-yloxy|-7-methoxyquinazoline: "The first reaction is carried out with acetic anhydride, its LC value is 0.51 (ready plates for reverse-phase TLC (E. MegskK company), ia

335 acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (E5I"): t/2 - 488, 490 MANI"; (16) 4-(3-chloro-4-fluorophenyl)amino)|-6--trans-4-(dimethylamino)sulfonylamino|cyclohexan-1-yloxy)-7-methoxyquinazoline: the reaction is carried out with M,M- with dimethylsulfamoyl chloride in acetonitrile, - with the value of K.. 0.69 (silica gel, ethyl acetate/methanol/conc. aqueous solution of ammonia in the ratio 90:10:1), "mass spectrum (E5I"): t/2 - 524, 526 MANY"; and? 17 4-(3-chloro-4-fluorophenyl)amino|-6--trans-4-(morpholin-4-yl)ucarbonylamino|cyclohexan-1-yloxy)-7-methoxyquinazole nn: -and the reaction is carried out with (morpholin -4-yl)carbonyl chloride in acetonitrile, with K value: 0.38 (silica gel, ethyl acetate/methanol in the ratio 9:1), mass spectrum (E5I"): t/2 - 530, 532 MANI"; e (18) g 20 A-((3-chloro-4-fluorophenyl)amino|-6-"trans-4-((morpholin-4-yl)usulfonylamino|cyclohexan-1-yloxy)-7-methoxyquinazole and others: sl reaction is carried out with (morpholin-4-yl)usulfonyl chloride in acetonitrile, melting point: 2372C, mass spectrum (EI: pt/2 - 564, 566 M-NI; (19). 4-(3-chloro-4- fluorophenyl)amino|-6-(3-methanesulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline:

HF) K value: 0.66 (silica gel, ethyl acetate/methanol in a ratio of 9:1),

HF mass spectrum (EBIU: pt/2 - 493.495 |M-NI"; (20). 4-((3-chloro-4-fluorophenyl)amino)-6-(tetrahydropyran-4-yloxy)-7-( 2-acetylaminoethoxy)quinazoline: react with acetyl chloride in acetonitrile, melting point: 2245C, mass spectrum (ESI"): t/2 - 475.477 MANI"; (21). 4-(3-chloro-4-fluorophenyl) amino)|-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonylaminoethoxy)quinazoline: melting point: 2272C, 65 mass spectrum (EBI"): t/2 - 511, 513 MANI"; (22) 4-(3-chloro-4-fluorophenyl)amino|-6-(cis-3-acetylaminocyclohexan-1-yloxy)-7-methoxyquinazoline:

the reaction is carried out with acetyl chloride in acetonitrile, the cis- and trans-isomers are separated by chromatography on a silica gel column, the Kk value is 0.43 (silica gel, methylene chloride/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), mass spectrum (E5I "): t/2 - 459461 MANI"; (23). 4-((3-chloro-4-fluorophenyl)amino)|-6-(trans-3-acetylaminocyclohexan-1-yloxy)-7-methoxyquinazoline: the reaction is carried out with acetyl chloride in acetonitrile, the cis- and trans-isomers are separated by chromatography on silica gel column, K value, 0.49 (silica gel, methylene chloride/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), 70 mass spectrum (E5I"): t/2 - 459, 461 MANI"; (24). 4-(3-chloro-4-fluorophenyl)amino|-6-(tetrahydropyran-4-yloxy)-7-(3-acetylaminopropyloxy)quinazoline: the reaction is carried out with acetyl chloride, melting point: 2259C, mass spectrum (E5I") : t/2 - 489, 491 MANI"; (25) 4-(3-chloro-4-fluorophenyl)amino)-6-(tetrahydropyran-4-yloxy)-7-(3-methanesulfonylaminopropyloxy)quinazoline: melting point: 2229C, mass spectrum (ESI"): t /2 - 525, 527 MANI"; (26). 4-(3-chloro-4-fluorophenyl)amino)|-6-(1-methanesulfonylpiperidin-4-yloxy)quinazoline: K value: 0.44 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (EBI"): t/2 - 451, 453 MANI"; (27). 4-(3-chloro-4-fluorophenyl)amino|-6-41-Kmorpholin-4-yl)carbonyl|piperidin-4-yloxy)quinazoline: the reaction is carried out with (morpholin-4-yl)carbonyl chloride in acetonitrile, in K,: 0.40 (silica gel, methylene chloride/methanol in a ratio of 9:1), ch mass spectrum (E5I"): t/2 - 486, 488 MANI"; (about) (28). 4-(3-chloro-4-fluorophenyl)amino|-6-(1-acetylpiperidin-4-yloxy)quinazoline: the reaction is carried out with acetic anhydride, the value of K,: 0.50 (silica gel, methylene chloride / methanol in the ratio of 9: 1), mass spectrum (E5I"): t/2 - 415.417 MANI"; (29). 4-(3-chloro-4-fluorophenyl)amino)|-6-41-(dimethylamino)carbonyl|piperidin-4-yloxy)quinazoline: the reaction is carried out with M,M-dimethylcarbamoyl chloride, "g value of K,: 0, 47 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (E5I"): t/2 - 444, 446 MANI"; about (30). 4-((3-chloro-4-fluorophenyl)amino|-6--trans-4-acetylaminocyclohexan-1-yloxy)-7-methoxyquinazoline: the reaction is carried out with acetic anhydride, the value of K,: 0.50 (silica gel , methylene chloride/methanol in a ratio of 9:1), mass spectrum (E5I"): t/2 - 459, 461 MANI"; (31). 4-(3-chloro-4-fluorophenyl)amino)|-6--trans-4-(dimethylamino)carbonylamino)cyclohexan-1-yloxy)-7-methoxyquinazoline: - the reaction is carried out with M,M-dimethylcarbamoyl chloride, h K value: 0.40 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (E5I"): t/2 - 488, 490 MANI"; (32)

A-((33-chloro-4-fluorophenyl)amino)-6-(trans-4-(2-methoxyacetylamino)cyclohexan-1-yloxy)|-7-methoxyquinazoline: - the reaction is carried out with methoxyacetic acid chloride, with the value of K ,: 0.35 (silica gel, methylene chloride/methanol in the ratio 9:1), mass spectrum (E5I"): t/2 - 489, 491 MANI"; that (33). 4-K(3-chloro-4-fluorophenyl)amino|-6-(1-(2-methoxyacetyl)piperidin-4-yloxy)quinazoline: in step 20, the reaction is carried out with methoxyacetic acid chloride, K value: 0.41 (silica gel, methylene chloride/methanol in a ratio of 9:1), sl mass spectrum (E5I"): t/2 - 445, 447 MANI"; (34). 4-((3-chloro-4-fluorophenyl)amino)|-6-(1-isopropyloxycarbonylpiperidin-4-yloxy)-7-methoxyquinazoline: the reaction is carried out with isopropyl ether of chloroformic acid, Kk value 0.67 (silica gel, ethyl acetate/ methanol/concentrated aqueous ammonia solution in the ratio 98:2:1),

HF) mass spectrum (E5I"): t/2 - 489, 491 MANI";

GF (35). 4-(3-Chloro-4-fluorophenyl)amino|-6-(1-cyanopiperidin-4-yloxy)quinazoline: the reaction is carried out with cyanogen bromide in methylene chloride, in the value of K,: 0.49 (silica gel, methylene chloride/methanol in the ratio 9:1), mass spectrum (E5I): t/2 - 396, 398 M-NO; (36). 4-((3-chloro-4-fluorophenyl)amino|-6-41-(dimethylamino)sulfonyl|piperidin-4-yloxy)quinazoline: the reaction is carried out with M,M-dimethylsulfamoyl chloride in acetonitrile, K value: 0.34 (silica gel, methylene chloride/methanol in a ratio of 9:1), 65 mass spectrum (E5I"): t/2 - 480,482 MANI"; (37). 4-(3-chloro-4-fluorophenyl)amino|-6--1-(morpholin-4-yl)usulfonyl|piperidin-4-yloxy)quinazoline:

the reaction is carried out with (morpholin-4-yl)usulfonyl chloride in acetonitrile, K value, 0.15 (silica gel, cyclohexane/ethyl acetate in the ratio 1:1), mass spectrum (ESI"): t/2 - 522, 524 MANI" ; (38). 4-KZ-chloro-4-fluorophenyl)amino|-6-(1--2-acetylaminoethyl)piperidin-4-yloxy|)quinazoline: the reaction is carried out with acetic anhydride in acetonitrile, melting point: 2219С, mass spectrum (E5I "): m/z - 458, 460 MANI; (39). 4-((3-chloro-4-fluorophenyl)amino|-6-71-(diethylamino)carbonyl|piperidin-4-yloxy)-7-methoxyquinazoline : the reaction is carried out with M,M-diethylcarbamoyl chloride, Kk value 0.40 (silica gel, ethyl acetate/methanol/concentrated aqueous ammonia solution in the ratio 95:5:1), mass spectrum (E5I"): t/2 - 502, 504 MANI"; (40). 4-((3-chloro-4-fluorophenyl)amino|-6-41-Kpiperidin-1-yl)carbonyl|piperidin-4-yloxy)-7-methoxyquinazoline: the reaction is carried out with ( piperidin-1-yl/ucarbonyl chloride, Ku value 0.51 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 95:5:1), mass spectrum (ESBIU: pt/2 - 512, 514 IM-NI (41). 4-((3-chloro-4-fluorophenyl)amino1|-6-71-K(pyrrolidin-1-yl)carbonyl|Ipiperidin-4-yloxy)-7-methoxyquinazoline: the reaction is carried out with (pyrrolidine -1-yl/ucarbonyl chloride, melting point: 2372C , mass spectrum (EI): t/» - 500, 502 MEI"; (42) 4-(3-chloro-4-fluorophenyl)amino!|-6-41-(4-methylpiperazin-1-yl)/ucarbonyl|Ipiperidin-4-yloxy)-7-methoxyquinazoline: the reaction is carried out with hydrochloride ( 4-methylpiperazin-1-yl)carbonyl chloride, in Ku value, 0.28 (silica gel, methylene chloride/methanol/conc. aqueous solution of ammonia in the ratio 90:10:1), mass spectrum (EBIU: t/2 - 527 , 529 |M-NI; (o) (43) 4-(3-chloro-4-fluorophenyl)amino)|-6-(cis-4--M-methanesulfonyl-M-methylamino)cyclohexane-1-yloxy| -7-methoxyquinazoline: the reaction is carried out in methylene chloride, the value of CC, 0.71 (silica gel, ethyl acetate/methanol in the ratio 9:1), iv) mass spectrum (E5I"): t/2 - 509, 511 MANI" ; "(44) 4-(3-chloro-4-fluorophenyl)amino)|-6-(cis-4-(-M-acetyl-M-methylamino)cyclohexan-1-yloxy)|-7-methoxyquinazoline: b" the reaction is carried out with acetic anhydride, M melting point: 2345C, mass spectrum (E5I"): t/z2 - 473, 475 IMENI"; (45) « 4-(3-chloro-4-fluorophenyl)amino)|-6-(cis-4-(M-(2-methoxyacetyl)-M-methylamino|cyclohexane-1-yloxy)-7-methoxyquinazoline : - c reaction is carried out with methoxyacetic acid chloride, h value of K,: 0.40 (silica gel, ethyl acetate/methanol in a ratio of 9:1), i mass spectrum (E5I"): t/: - 503, 505 IMENI"; (46)

A-(33-chloro-4-fluorophenyl)amino)-6-(cis-4-"M-dimethylaminocarbonyl-M-methylamino)cyclohexan-1-yloxy)|-7-methoxy - inazoline: the reaction is carried out with M ,M-dimethylcarbamoyl chloride, K value: 0.51 (silica gel, ethyl acetate/methanol in a 9:1 ratio), and mass spectrum (E5I"): m/z - 502, 504 MANI; g 20 (47) 4-(3-chloro-4-fluorophenyl)amino!|-6-(cis-4--M-Kmorpholin-4-yl)carbonyl|-M-methylamino)cyclohexan-1-yloxy)- 7-labeled syquinazoline: the reaction is carried out with (morpholin-4-yl)ucarbonyl chloride, value of K,: 0.50 (silica gel, ethyl acetate/methanol in the ratio 9:1), 29 mass spectrum (EBI7): t/» - 544, 546 MANI";

F. (48) 4-(3-chloro-4-fluorophenyl)amino)|-6-(cis-4-"H-((morpholin-4-yl)usulfonyl|-M-methylamino)cyclohexane-1-yloxy )-7-metho o xyquinazoline: the reaction is carried out with (morpholin-4-yl)usulfonyl chloride in acetonitrile, because the LC value is 0.24 (ready-made reverse-phase TLC plates (E. MegskK company), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (E5I"): m/2 - 580, 582 MANI"; (49) 4-(3-chloro-4-fluorophenyl)amino)|-6-(Icis- 4--"M-dimethylaminosulfonyl-M-methylamino)cyclohexan-1-yloxy)|-7-methoxy bo iquinazoline:

the reaction is carried out with M,M-dimethylsulfamoyl chloride in acetonitrile, value of K,: 0.53 (silica gel, ethyl acetate), mass spectrum (E5I"): t/2 - 538, 540 MANI"; (50). 4-(3-chloro-4-fluorophenyl)amino|-6-(trans-4-ethanesulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline: the reaction is carried out with ethanesulfonic acid chloride in methylene chloride, Kk value 0.41 (silica gel, ethyl acetate ), mass spectrum (E5I"): m/2 - 509, 511 MANI; (51). 4-((3-chloro-4-fluorophenyl)amino!|-6-71-Cmorpholin-4-yl)carbonyl |piperidin-4-yloxy)-7-ethoxyquinazoline: the reaction is carried out with (morpholin-4-yl)ucarbonyl chloride, K value: 0.48 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (E5I" ): m/2 - 530, 532 MANI"; (52). 4-(3-chloro-4-fluorophenyl)amino|-6-(1-methanesulfonylpiperidin-4-yloxy)-7-ethoxyquinazoline: value of K,: 0.50 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (ESI"): t/2 - 495, 497 MANI"; 19 (53). 4-(3-chloro-4-fluorophenyl) amino)|-6-(1-(2-methoxyacetyl)piperidin-4-yloxy|-7-ethoxyquinazoline: the reaction is carried out with methoxyacetic acid chloride, K value: 0.40 (silica gel, methylene chloride/methanol - 20:1) , mass spectrum (E5I"): t/2 - 489, 4 91 MANI"; (54). 4-I(3-chloro-4-fluorophenyl)amino|-6-(1-methanesulfonylpiperidin-4-yloxy)-7-(2-methoxyethoxy)quinazoline: K value: 0.47 (silica gel, methylene chloride/methanol in ratios 9:1), mass spectrum (E5I"): t/2 - 525, 527 MANI"; (55) 4-(3-chloro-4-fluorophenyl)amino|-6-71-(morpholin-4-yl)carbonyl|piperidin-4-yloxy)-7-(2-methoxyethoxy)quinazoline: the reaction is carried out with ( with morpholin-4-yl)ucarbonyl chloride, the average value of K: 0.48 (silica gel, methylene chloride/methanol in the ratio 9:1), Ge) mass spectrum (E5I"): t/2 - 560, 562 MANI"; (56). 4-I(3-chloro-4-fluorophenyl)amino|-6-(1-(2-methoxyacetyl)piperidin-4-yloxy|-7-(2-methoxyethoxy)quinazoline: the reaction is carried out with methoxyacetic acid chloride, the value K,: 0.48 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (E5I"): t/2 - 519, 521 MANI"; o (57). 4-(3-chloro-4 -fluorophenyl)amino|-6-(cis-4-acetylaminocyclohexan-1-yloxy)-7-methoxyquinazoline: "E reaction is carried out with acetic anhydride, melting point: 2812С, Me mass spectrum (EBI"): t/2 - 459, 461 MANI"; - (58). 4-(3-chloro-4-fluorophenyl)amino|-6-(cis-4-(2-methoxyacetylamino)cyclohexan-1-yloxy|-7-methoxyquinazoline: the reaction is carried out with methoxyacetic acid chloride, melting point: 2645C, "mass spectrum (E5I"): t/2 - 489, 491 MANI"; (59) 4-(3-chloro-4-fluorophenyl)amino!|-6 -(cis-4--M-K(piperidin-1-yl)/ucarbonyl|-M-methylamino)cyclohexan-1-yloxy)-7-metho "» xyquinazoline: " the reaction is carried out with (piperidin-1-yl/ ucarbonyl chloride, melting point: 2539С, mass spectrum (ЕБИ7): t/2 - 542, 544 TO ME";

B. (60) (se) 4-(3-chloro-4-fluorophenyl)amino1|-6-(cis-4--M-(4-methylpiperazin-1-yl)/ucarbonyl|-M-methylamino)cyclohexane -1-yloxy) -i-methoxyquinazoline: the reaction is carried out with (4-methylpiperazin-1-yl)carbonyl chloride hydrochloride, 4! 20 melting point: 2629C, sp mass spectrum (EBI"): t/2 - 557, 559 |MANI"; (61) 4-(3-chloro-4-fluorophenyl)amino)|-6-(cis-4-(MI-ethanesulfonyl-M-methylamino)cyclohexan-1-yloxy|-7-methoxyquinazole n: 59 the reaction is carried out with ethanesulfonic acid chloride in methylene chloride,

HF) value of LC and 0.19 (ready-made plates for reversed-phase TLC (E. MegskK company), with acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (EBI"): t/2 - 523, 525 |MANI"; in (62) 4-(3-chloro-4-fluorophenyl)amino|-6--cis-4-Cmorpholin-4-yl)/ucarbonylamino|cyclohexan-1-yloxy)-7-methoxyquinazoline: the reaction is carried out with (morpholin -4-yl)ucarbonyl chloride, LC value 0.33 (ready-made reverse-phase TLC plates (E. MegskK company), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), 65 mass spectrum (E5I" ): t/2 - 530, 532 MANI"; (63)

4-(3-chloro-4-fluorophenyl)amino)|-6--cis-4-(morpholin-4-yl)usulfonylamino|cyclohexan-1-yloxy)-7-methoxyquinazoline: the reaction is carried out with (morpholin-4- by yl)usulfonyl chloride in acetonitrile, K value: 0.81 (silica gel, ethyl acetate/methanol in a ratio of 9:1), mass spectrum (E5I"): t/2 - 566, 568 MANI"; (64). 4-(3-ethynylphenyl)amino|-6-«-1-acetylpiperidin-4-yloxy)-7-methoxyquinazoline: the reaction is carried out with acetic anhydride, Kk value 0.30 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia in the ratio 90:10:1), mass spectrum (EBI"): t/2 - 417 MANI"; 710 (65). 4-KZ-ethynylphenyl)amino1|-6-(1-(2-methoxyacetyl)piperidin-4-yloxy|-7-methoxyquinazoline: the reaction is carried out with methoxyacetic acid chloride, Kk value 0.37 (silica gel, methylene chloride/methanol/conc . aqueous solution of ammonia in the ratio 90:10:1), mass spectrum (ESI"): t/2 - 447 MANI"; (66). 4-K(3-ethynylphenyl)amino|-6-(1-methanesulfonylpiperidine) -4-yloxy)-7-methoxyquinazoline: Kk value 0.59 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), mass spectrum (E5I"): t/2 - 453 | MANI"; (67). 4-KZ-ethynylphenyl)amino|-6-41-(morpholin-4-yl)carbonyl|piperidin-4-yloxy)-7-methoxyquinazoline: the reaction is carried out with (morpholin-4-yl) ucarbonyl chloride, K value: 0.43 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), mass spectrum (E5I"): t/2 - 488 MANI"; (68) 4-(3-chloro-4-fluorophenyl)amino)|-6-(trans-4-(M-methanesulfonyl-M-methylamino)cyclohexan-1-yloxy)|-7-methoxyquinase olin: K value, : 0.50 (silica gel, methylene chloride/methanol in a ratio of 9:1), c 29 mass spectrum (EVI7): t/g - 509, 511 MEI"; o (69) 4-((3Z-chloro-4- fluorophenyl)amino)|-6-(trans-4-(-M-Kmorpholin-4-yl)ucarbonyl|-M-methylamino)cyclohexan-1-yloxy)-7-methoxyquinazoline: the reaction is carried out with (morpholin-4- by yl)ucarbonyl chloride, K value: 0.54 (silica gel, methylene chloride/methanol in a ratio of 9:1), IS o) mass spectrum (ESI"): t/2 - 544, 546 (MANI. "

Example 4 4-(3-chloro-4-fluorophens)amino)|-6-(cis-4-13-(morpholin-4-yl)upropyl|isosulfonylamino)cyclohexane-1-yloxy)-7-meth (e) oxyquinazoline

In sh. F « i - in "y y: i sh ' :" Z i ; a in, : -I (Se) Do bomg 4-(3-chloro-4-fluorophenyl)amino)|-6--cis-4- ((3-Chloropropyl)sulfonylamino|cyclohexan-1-yloxy)-7-methoxyquinazoline and 2 ml of acetonitrile add 233 μl of morpholine and the reaction mixture is boiled overnight with a reflux os 20 refrigerator. For processing, the mixture is dissolved in ethyl acetate and washed with water. The phase is dried over magnesium sulfate and concentrated.

Yield: 18 mg (2795 from theory): K value: 0.36 (silica gel, methylene chloride/methanol in a ratio of 9:1), mass spectrum (EVI7): t/» - 608, 610 ME".

HF) Analogously to example 4, the following compounds are obtained: -1-yloxy)-7-metho xyquinazoline: 60 b5

E 4 k chi and sv n |! B is 5 o value of Kk 0.16 (silica gel, ethyl acetate/methanol/conc. aqueous solution of ammonia in the ratio 90:10:1), mass spectrum (E5I"): t/2 - 608, 610 (MANI; 19 (2). 4-(3-chloro-4-fluorophenyl)amino)-6-(tetrahydropyran-4-yloxy)-7-(14-(morpholin-4-yl)butyloxy|)quinazoline: the reaction is carried out in the presence of sodium carbonate and sodium iodide in M-methylpyrrolidone at 1002C, CC value, 0.18 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 40:10:0.5), mass spectrum (E5I"): t /2 - 531, 533 MANI"; (3). 4-(3-chloro-4-fluorophenyl)amino)-6-(5)-tetrahydrofuran-3-yloxy)-7-I(I4-(morpholine-4 -yl)butyloxy|)quinazoline: the reaction is carried out in the presence of sodium carbonate and sodium iodide in M-methylpyrrolidone at 1002С, Kk value 0.32 (silica gel, ethyl acetate/methanol/concentrated aqueous ammonia solution in the ratio 80:20:1), mass spectrum (ESI"): t/2 - 517, 519 MANI"; (4). 4-(3-chloro-4-fluorophenyl)amino|-6-71-Cmorpholin-4-yl)uacetyl|piperidin- 4-yloxy) quinazoline: the reaction is carried out in the presence of Hünig's base v tetrahydrofuran at room temperature, K value: 0.30 (silica gel, methylene chloride/methanol in a ratio of 9:1), i) mass spectrum (E5I"): t/2 - 500, 502 MANI"; (5). 4-(3-chloro-4-fluorophenyl)amino)|-6-(1-dimethylaminoacetylpiperidin-4-yloxy)quinazoline, the reaction is carried out in the presence of Hünig's base in tetrahydrofuran at room temperature, with a Ku value of 0.11 (silica gel, methylene chloride /methanol/concentrated aqueous solution of ammonia in the ratio 90:10:1), mass spectrum (E5I"): t/2 - 458, 460 MANI"; i (6). 4-(3-chloro-4-fluorophenyl)amino|-6--1-dimethylaminoacetylpiperidin-4-yloxy)-7-methoxyquinazoline: And the reaction is carried out in the presence of Hünig's base in tetrahydrofuran at room temperature, b value of KK; 0.19 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), mass spectrum (E5I"): m/z - 488, 490 MANI; o (7). 4-(Z -chloro-4-fluorophenyl)amino|-6--1-(morpholin-4-yl)uacetyl|piperidin-4-yloxy)-7-methoxyquinazoline: the reaction is carried out in the presence of Hunig's base in tetrahydrofuran at room temperature, mass spectrum (E5I"): t/2 - 530, 532 MANI. "

Example 5

Dihydrochloride of 4-((3-chloro-4-fluorophenyl)amino)|-6-(5)-pyrrolidin-3-yloxy)-7-methoxyquinazoline in s Solution of 37Omg "with 4-(3-chloro-4-fluorophenyl) of amino1-6-((5)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yloxy|-7-methoxyquinazoline in bml of dioxane is mixed with 0.32 ml of concentrated hydrochloric acid and stirred overnight at room temperature. The precipitate that has formed , separated by vacuum filtration and washed with a large amount of dioxane.

The crude product is dissolved in a small amount of methanol and precipitated again by adding the same amount of ethyl acetate. The white solid obtained in this way is separated by vacuum filtration and dried.

Te) Yield: 200mg (5790 from theory), melting point: 2812C, e mass spectrum (E5I"): t/2 - 389, 391 MANI. 1 50 Similarly to example 5, the following compounds are obtained: sp (1) dihydrochloride 4 -|((3-chloro-4-fluorophenyl)amino)-6-(piperidine-3-yloxy)-7-methoxyquinazoline: melting point: 2635C, mass spectrum (ESI"): t/2 - 403, 505 | MANI"; (2) dihydrochloride 4-((3-chloro-4-fluorophenyl)amino1|-6-(1--2-aminoethyl)piperidin-4-yloxy|-7-methoxyquinazoline: melting point: 2772С,

F, mass spectrum (EBI"): t/2 - 446, 448 MANI"; co (3) dihydrochloride of 4-((3-chloro-4-fluorophenyl)amino)|-6-(3-aminocyclohexan-1-yloxy)-7-methoxyquinazoline: mass spectrum (E5I"): t/2 - 417 , 419 MANI"; 60 (4) dihydrochloride 4-|(3-chloro-4-fluorophenyl)amino)-6-(tetrahydropyran-4-yloxy)-7-(2-aminoethoxy)quinazoline: the reaction is carried out with an isopropanol solution of hydrochloric acid (5-6 -molar) in methylene chloride, LC value 0.58 (ready-made reverse-phase TLC plates (E. MegskK company), acetonitrile/water/trifluoroacetic acid in a ratio of 50:50:1), mass spectrum (E5I"): t/2 - 433, 435 MANI"; b5 (5) dihydrochloride 4-((3-chloro-4-fluorophenyl)amino)|-6-(tetrahydropyran-4-yloxy)-7-(33-aminopropyloxy)quinazoline: the reaction is carried out with an isopropanol solution of hydrochloric acid (5- 6-molar) in methylene chloride,

value of K,: 0.44 (ready-made plates for reverse-phase TLC (E. Megsk company), methanol/59Uo solution of sodium chloride in a ratio of 7:3), mass spectrum (E5I"): t/z - 447 , 449 NAMES"; (6) dihydrochloride 4-((3-chloro-4-fluorophenyl)amino1|-6-(1--2-aminoethyl)piperidin-4-yloxy)quinazoline: LC value 0.50 (ready plates for TLC with inverted phase (firm E. MegskK), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (EBI"): t/2 - 416, 418 NAMES"; (7) dihydrochloride 70. 4-KZ-chloro-4-fluorophenyl)amino|-6-(cis-4-methylaminocyclohexan-1-yloxy)-7-methoxyquinazoline: the reaction is carried out with an isopropanol solution of hydrochloric acid (5-6 molar ) in methylene chloride, LC value 0.35 (ready-made reverse-phase TLC plates (E. MegskK company), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (EBI"): t/ 2 - 431, 433 MANI"; (8) dihydrochloride of 4-((3-ethynylphenyl)amino|-6-(piperidin-4-yloxy)-7-methoxyquinazoline: the reaction is carried out with an isopropanol solution of hydrochloric acid (5-6-molar) in methylene chloride, the value of LC is 0 ,50 (ready-made plates for reversed-phase TLC (E. MegskK company), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (EBI"): t/2 - 375 |MANI"; ( 9) dihydrochloride 4-(3-chloro-4-fluorophenyl)amino)|-6-(trans-4-methylaminocyclohexan-1-yloxy)-7-methoxyquinazoline: melting point: 2512C, mass spectrum (EBI"): t /2 - 431, 433 MONEY.

Example 6 ch 29 4-(3-chloro-4-fluorophenyl)amino)|-6-(tetrahydropyran-4-yloxy)-7-hydroxyquinazoline He)

A mixture of 9.00 g of 4-(3-chloro-4-fluorophenyl)amino)|-6-(tetrahydropyran-4-yloxy)-7-benzyloxyquinazoline hydrochloride and 5 Oml of trifluoroacetic acid is heated to 1002 and kept at this temperature for 1.5 hours . Then the reaction mixture is concentrated and the residue is dissolved in 1 Oml of acetonitrile. This solution is added dropwise to 100 ml of a saturated solution of sodium bicarbonate with intensive stirring. At the end of 1.5 hours, the formed precipitate of IC o) is separated by vacuum filtration and washed several times with water. The crude product is mixed with diethyl ether, subjected to vacuum filtration and dried. h

Yield: 5.90 g (8790 from theory), Ge) value of K,: 0.21 (silica gel, ethyl acetate), m mass spectrum (E5I"): t/2 - 390, 392 MANI.

Similarly to example 6, the following compound is obtained: (1). 4-(3-chloro-4-fluorophenyl)amino)|-6-(5)-tetrahydrofuran-3-yloxy)-7-hydroxyquinazoline: K value: 0.44 (silica gel, ethyl acetate/methanol in a ratio of 9:1 ), "mass spectrum (ESI"): t/2 - 376, 378 MANI. -o s Example 7 . 4-(3-chloro-4-fluorophenyl)amino)-6-(tetrahydropyran-4-yloxy)- 7-IZ-"morpholin-4-yl)propyloxy|)quinazoline "" Mixture with ZOOmg of 4-(3-chloro-4-fluorophenyl)amino)|-6-(tetrahydropyran-4-yloxy)-7-hydroxyquinazoline, 130 mg

of 3-(morpholin-4-yl)upropyl chloride and 53 mg of potassium carbonate in bml of M,M-dimethylformamide are mixed for

Nights at 802C. For processing, the reaction mixture is diluted with 25 ml of water and extracted with ethyl acetate. The combined -I organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated.

The residue is mixed with diethyl ether, subjected to vacuum filtration and dried. o Yield: 25O0mg (63905 from theory), "" melting point: 2059С, sl mass spectrum (EBI"): t/2 - 517, 519 MANI".

Similarly to example 7, the following compounds are obtained: compound (1). 4-(3-chloro-4-fluorophenyl)amino)|-6-(tetrahydropyran-4-yloxy)-7-(2-(morpholin-4-yl)-ethoxy)quinazoline: Kk value 0.33 (silica gel, ethyl acetate/methanol/concentrated aqueous ammonia solution in the ratio 40:10:0.5), mass spectrum (E5I"): t/: - 503, 505 NAMES"; (2). 4-(3-chloro-4-fluorophenyl)amino|-6-(tetrahydropyran-4-yloxy)-7-ethoxyquinazoline:

GF! Kk value 0.76 (silica gel, ethyl acetate/methanol/concentrated aqueous ammonia solution in the ratio 90:10:1), mass spectrum (E5I"): m/z - 418, 420 NAMES"; about (3). 4-K(3-chloro-4-fluorophenyl)amino)|-6-(5)-tetrahydrofuran-3-yloxy)-7-3-(morpholin-4-yl)propyloxy)quinazoline: Kk value 0.20 ( silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), 60 mass spectrum (EVIU: t/2 - 501, 503 |M-NI; (4). 4-(3-chloro- 4-fluorophenyl)amino|-6-(5)-tetrahydrofuran-3-yloxy)-7-(2-(morpholin-4-yl)-ethoxy)quinazoline: Cook value 0.19 (silica gel, ethyl acetate/methanol/conc . aqueous solution of ammonia in the ratio 90:10:1), mass spectrum (E5I"): t/2 - 489, 491 MANI"; c5 (5). 4-K(3-chloro-4-fluorophenyl)amino)-6-(tetrahydropyran-4-yloxy)-7-(2-methoxyethoxy)quinazoline: K value: 0.57 (silica gel, methylene chloride/methanol in a ratio of 9 :1),

mass spectrum (E5I"): t/2 - 448, 450 MANI"; 4-((3-chloro-4-fluorophenyl)amino)-6-(tetrahydropyran-4-yloxy)-7-(2-(tert-butyloxycarbonylamino)ethoxy)quinazoline: K value, 0.64 (silica gel, ethyl acetate/ methanol/concentrated aqueous ammonia solution in the ratio 95:5:0.1), mass spectrum (E5I"): m/z - 533, 535 IMENI ; (7 4-(3-chloro-4-fluorophenyl)amino) |-6-(Tetrahydropyran-4-yloxy)-7-III-"tert-Butyloxycarbonylamino)propyloxy)quinazoline: 710 Ku value, 0.74 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in a ratio of 95:5 :0.1), mass spectrum (E5I"): t/2 - 547, 549 MANI".

Example 8 4-(3-chloro-4-fluorophenyl)amino)|-6-(piperidin-4-yloxy)quinazoline

A solution of 4.55 g of 4-|((3-chloro-4-fluorophenyl)amino)|-6-(1-trifluoroacetylpiperidin-4-yloxy)quinazoline hydrochloride in ZbBml of methanol is mixed with 1Zml of Zn. caustic sodium and stir for about half an hour at room temperature. For processing, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated.

The residue is mixed with diethyl ether, subjected to vacuum filtration and dried.

Yield: 3.0Og (89905 from theory), LC value 0.48 (ready-made reverse-phase TLC plates (E. MegskK company), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (EBI"): t/2 - 373, 375 MANI.

Similarly to example 8, the following compounds are obtained: (1). 4-KZ-chloro-4-fluorophenyl)amino|-6-(piperidin-4-yloxy)-7-ethoxyquinazoline: with a Kk value of 0.20 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution in a ratio of 90:10 :1), d) mass spectrum (E5I"): t/2 - 417, 419 MANI"; (2). 4-KZ-chloro-4-fluorophenyl)amino|-6-(piperidin-4-yloxy)-7-(2-methoxyethoxy)quinazoline: Ku value, 0.10 (silica gel, methylene chloride/methanol/conc. aqueous ammonia in the ratio 90:10:1), mass spectrum (EBI"): t/z - 447449 MANI". and

Example 9 IC o) 4-(3-chloro-4-fluorophenyl)amino!-6-41-(ethylamino)carbonyl|piperidin-4-yloxy)-7-methoxyquinazoline

The title compound is obtained by reacting 4-(3-chloro-4-fluorophenyl)amino)|-6-(piperidin-4-yloxy)-7-methoxyquinazoline with ethyl isocyanate in tetrahydrofuran F) at room temperature.

Value of K.: 0.53 (silica gel, ethyl acetate/methanol/concentrated aqueous solution of ammonia in the ratio 90:10:1), - mass spectrum (E5I"): t/2 - 474, 476 (MANI.

Similarly to example 9, the following compounds are obtained: (1). 4-(3-chloro-4-fluorophenyl)amino!|-6-71-K(isopropylamino)carbonyl|piperidin-4-yloxy)-7-methoxyquinazoline: « 20 melting point: 2362С, w-v s mass spectrum (ESPIU: t/:2 - 486, 488 M-NO; and (2) 4-3 -chloro-4-fluorophenyl)amino!-6-41-(phenylamino)carbonyl|piperidin-4-yloxy)-7- methoxyquinazoline: and? Kk value 0.70 (silica gel, ethyl acetate/methanol/concentrated aqueous solution of ammonia in the ratio 95:5:0.1), mass spectrum (EBI"): t/2 - 522, 524 MANI"; (3) - I 4-(3-chloro-4-fluorophenyl)amino!|-6-(cis-4--M-Ketylamino)carbonyl|-M-methylamino)cyclohexan-1-yloxy)-7-methoxyquinazoline : what is the value of K,: 0.38 (silica gel, methylene chloride/methanol in the ratio 9:1), t" mass spectrum (E5I"): t/2 - 502, 504 MANI". sl 50 Example 10 4-(3-chloro-4-fluorophenyl)amino|-6-41-(dimethylamino)carbonylmethyl|piperidin-4-yloxy)quinazoline sl The compound indicated in the title is obtained by the interaction of 4-(3-chloro-4- of fluorophenyl)amino)|-6-(piperidin-4-yloxy)quinazoline with 2-chloro-M,M-dimethylacetamide in the presence of potassium carbonate in M,M-dimethylformamide at room temp.

K value: 0.24 (silica gel, methylene chloride/methanol in a ratio of 9:1),

Gee! mass spectrum (E5I"): t/2 - 458, 460 (MANI.

Similarly to example 10, the following compounds are obtained: o (1). 4-(3-Chloro-4-fluorophenyl)amino|-6-41-Cmorpholin-4-yl)carbonylmethyl piperidin-4-yloxy)quinazoline: QC value 0.42 (ready-made reverse-phase TLC plates (firm E . MegskK), 60 acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), mass spectrum (E5I"): t/2 - 500, 502 MANI"; (2). 4-((3-chloro-4-fluorophenyl)amino|-6-(1-aminocarbonylmethylpiperidin-4-yloxy)-7-methoxyquinazoline: melting point: 2512C, mass spectrum (E5I"): t/2 - 460, 462 MANI"; 65 (3). 4-((3-chloro-4-fluorophenyl)amino!|-6-41-(dimethylamino)carbonylmethyl|piperidin-4-yloxy)-7-methoxyquinazoline:

melting point: 2339C, mass spectrum (E5I"): m/z - 488, 490 MANI; (4). 4-KZ-chloro-4-fluorophenyl)amino|-6-41-(morpholin-4-yl) /carbonylmethyl(Ipiperidin-4-yloxy)-7-methoxyquinazoline: melting point: 2459C, mass spectrum (E5I"): t/2 - 530, 532 MANI".

Example 11 4-(3-chloro-4-fluorophenyl)amino!|-6-71-(tetrahydropyran-4-yl)carbonyl|piperidin-4-yloxy)-7-methoxyquinazoline

To a mixture of 10 mg of dihydrochloride 10.4-(33-chloro-4-fluorophenyl)amino)|-6-(piperidin-4-yloxy)-7-methoxyquinazoline, 82 mg of tetrahydropyran-4-carboxylic acid and 0.54 ml of Hunig's base in 390 mg of 1-hydroxy-1H-benzotriazole and 250 mg of /2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate are added to 5 ml of M,M-dimethylformamide. Next, the reaction mixture is stirred overnight at room temperature. For processing, the mixture is mixed with 25 ml of ethyl acetate and washed with water, a 1095 solution of potassium carbonate and a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and concentrated. The residue is mixed with a small amount of ethyl acetate, subjected to vacuum filtration and dried.

Yield: 250 mg (7790 from theory), K value: 0.43 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), mass spectrum (EBI"): t/2 - 515 , 517 MANI".

Similarly to example 11, the following compounds are obtained: (0) 4-(3-chloro-4-fluorophenyl)amino|-6--trans-4-(tetrahydropyran-4-yl)ucarbonylamino|cyclohexane-1-yloxy)-7- methoxy inazoline: Kc value 0.44 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), c mass spectrum (EVI7): m/z2 - 529, 531 MANI"; o (2 ) 4-(3-chloro-4-fluorophenyl)amino|-in--ucis-4--M-(tetrahydropyran-4-yl)ucarbonyl|-M-methylamino)cyclohexan-1-yloxy)-7-methoxyquinazoline: K values: 0.31 (silica gel, ethyl acetate/methanol in a ratio of 9:1), o3o mass spectrum (EBI7): t/g - 543, 545

Example 12 4-(3-chloro-4-fluorophenyl)amino1-6-41-((1,oxazepan-4-yl)/carbonyl|piperidin-4-yloxy|-7-methoxyquinazoline h

F) dihydrochloride 4-((3-chloro-4-fluorophenyl)amino|-6 -(piperidin-4-yloxy)-7-methoxyquinazoline and 1.05 ml of triethylamine. m

The resulting yellowish suspension is stirred for about 24 hours at room temperature. For processing, the reaction mixture is mixed with 100 ml of methylene chloride and extracted with water and 1096 citric acid. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed on a silica gel column using a mixture of di methylene chloride/methanol/conc. ammonia. The target product is mixed with diethyl ether, subjected to vacuum filtration and dried. c Yield: 80Omg (8095 from theory), :z" K value, 0.30 (silica gel, methylene chloride/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), mass spectrum (E5I"): t/ 2 - 530, 532 MANI.

Similarly to example 12, the following compounds are obtained: -1 (1). 4-KZ-chloro-4-fluorophenyl)amino|-6-41-Kcis-2,6-dimethylmorpholin-4-yl)carbonyl piperidin-4-yloxy)-7-methoxyquinazoline: re) Kk value 0.41 (silica gel , ethyl acetate/methanol/concentrated aqueous ammonia solution in the ratio 90:10:1), mass spectrum (E5I"): t/2 - 544, 546 MANI"; (2) about 4-(3-chloro-4-fluorophenyl)amino|-6-41-(2-methylmorpholin-4-yl)carbonyl|Ipiperidin-4-yloxy)-7-methoxyquinazoline: with Kk value 0.50 (silica gel, ethyl acetate/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), mass spectrum (E5I"): t/2 - 530, 532 MANI.

Example 13 4-(3-chloro-4-fluorophenyl)amino|-6-(1-methylpiperidin-4-yloxy)-7-ethoxyquinazoline

To 175 mg of 4-((3-chloro-4-fluorophenyl)amino|-6-(piperidin-4-yloxy)-7-ethoxyquinazoline in ml of tetrahydrofuran, add Zbmcl of a 3795% aqueous formalin solution and 110 mg of sodium triacetoxyborohydride. The reaction mixture was stirred for about four hours at room temperature. For processing, bml of saturated sodium bicarbonate solution is added and the mixture is thoroughly mixed. After that, 20ml of 60 ethyl acetate is added and the aqueous phase is separated. The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is mixed with isopropyl ether, subjected to vacuum filtration and dried.

Yield: 144 mg (8095 from theory), K value, 0.80 (silica gel, methylene chloride/methanol/conc. aqueous ammonia solution in the ratio 60:10:1), 65 mass spectrum (EBI"): t/2 - 431 , 433 MANI".

Similarly to example 13, the following compounds are obtained:

(1) 4-(3-chloro-4-fluorophenyl)amino)|-6-(1-methylpiperidin-4-yloxy)-7(2-methoxyethoxy)quinazoline: K value, 0.85 (silica gel, methylene chloride/methanol /concentrated aqueous solution of ammonia in the ratio 60:10:1), mass spectrum (EBI"): t/2 - 461, 463 MANI"; (2) 4-((3-ethynylphenyl)amino|-6-(1-methylpiperidin-4-yloxy)-7-methoxyquinazoline hydrochloride: Ku value, 0.26 (silica gel, methylene chloride/methanol/conc. aqueous ammonia in ratios 90:10:1), mass spectrum (E5I"): t/2 - 389 ME"; (3). 4-K(3-chloro-4-fluorophenyl)amino)|-6-(trans-4 -dimethylaminocyclohexan-1-yloxy)-7-methoxyquinazoline: K value: 0.80 (aluminum oxide, methylene chloride/methanol in a ratio of 9:1), mass spectrum (ESI"): t/2 - 445, 447 MANI.

Example 14 4-(3-ethynylphenyl)amino)|-6-(1-(tert-butyloxycarbonyl)piperidin-4-yloxy|-7-methoxyquinazoline

A mixture of 3,b0Og 4-(3-ethynylphenyl)amino)-b-hydroxy-7-methoxyquinazoline, 4.50 g of 1-(tert-butyloxycarbonyl)-4-(p-toluenesulfonyloxy)piperidine and 0 2.90 g of potassium carbonates in ZOml

M, Mm-dimethylformamide is stirred for three days at 602C. For processing, the mixture is mixed with 200 ml of ethyl acetate and extracted with water. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is purified on a silica gel column using a mixture of methylene chloride/methanol/conc. ammonia.

Yield: 3.25 g (6790 from theory), Kk value 0.25 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution in the ratio 95:5:1), mass spectrum (E5I"): t/2 - 475 MANI".

Similarly to example 14, the following compound is obtained: (1). 4-KZ-ethynylphenyl)amino|-6-(tetrahydropyran-4-yloxy|-7-methoxyquinazoline: Ku value 0.40 (silica gel, methylene chloride/methanol/conc. aqueous ammonia solution in the ratio 90:10:1), p 29 mass spectrum (EVI7): t/2 - 376 MEI".

Example 15 4-(3-chloro-4-fluorophenyl)amino!|-6-41-(2-(tert-butyloxycarbonylamino)ethyl|piperidin-4-yloxy)-7-methoxyquinase olin

A mixture of 41 mg of 4-((3-chloro-4-fluorophenyl)amino|-6-(piperidin-4-yloxy)-7-methoxyquinazoline dihydrochloride, 2 mg of M-(tert-butyloxycarbonyl)-2-bromomethylamine and 3 mg of potassium carbonate in bml of M,M-dimethylformamide is stirred overnight at room temperature.Then again add

M-(tert-butyloxycarbonyl)-2-bromomethylamine in a portion of 8Omg and the reaction mixture is stirred for the next t four hours at room temperature. For processing, the mixture is diluted with water and extracted with He») ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed on a silica gel column using a mixture of ethyl acetate/methanol (in a ratio varying from 95:5 to 90:1) as an eluent.

Output: 37 Ohms (79905 from the theory), value of LC; 0.33 (ready-made reverse-phase TLC plates (E. MegskK company), "acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), -o 79 mass spectrum (EBI): t/2 - 544, 546 |M-NO. c Similarly to example 15, the following compound is obtained: :z" (1). 4-KZ-chloro-4-fluorophenyl)amino!|-6-41-(2-(tert-butyloxycarbonylamino)ethyl|piperidin-4-yloxy)quinazoline: LC value 0.38 (ready plates for reverse-phase TLC (firm E. MegskK), acetonitrile/water/trifluoroacetic acid in the ratio 50:50:1), -I mass spectrum (E5I"): t/2 - 516, 518 MANI.

Analogously to the examples discussed above and other methods known from the literature, the following compounds can also be obtained: sh» sl 50 sl

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Dragee with the active substance content of 75 mg

Composition based on 1 dragee core: - - (22) zv M « 1111111 ovoomis a s h Production: The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, -» hydroxypropyl methylcellulose and half of the specified amount of magnesium stearate. Pressed products with a diameter of approximately 1 mm are obtained from the obtained mixture on a tableting machine, which are rubbed on a suitable machine through a sieve with a cell size of 1.5 mm and mixed with another amount of magnesium stearate. Tablets of a given shape are pressed from this granulate on a tabletting machine. c Core mass: 23Omg,

Punch: Omm diameter, with a concave working surface. t. A film coating is applied to the dragee cores obtained in this way, which consists mainly of 50 ml of hydroxypropyl methylcellulose. Finished dragees with a film coating are polished with beeswax.

Dragee mass: 245 mg. sl Example 17

Tablets with the active substance content of 100 mg

Composition based on 1 tablet: 1111 grams

Preparation: The active substance is mixed with lactose and starch and evenly moistened with an aqueous solution of polyvinylpyrrolidone. After pressing the wet mass through a sieve (with a cell size of 2.00 mm) and drying in a 65 Lattice oven at 502C, the product is again sieved through a sieve (with a cell size of 1.5 mm) and a lubricant is mixed in. The mixture ready for pressing is processed into tablets.

Tablet weight: 220 mg.

Tablet diameter: 1 Ohm, biplane with a two-sided facet and a separate notch on one side.

Example 18

Tablets with the active substance content of 150 mg

Composition based on 1 tablet: I 1111 two-eyed and y. and

Preparation: A mixture of the active substance with lactose, corn starch and silicic acid is moistened with a 2090 aqueous solution of polyvinylpyrrolidone and pressed through a sieve with a cell size of 1.5 mm. The granulate dried at 4523 is once again rubbed through the same sieve and mixed with the specified amount of magnesium stearate. Tablets are pressed from this mixture.

Tablet mass: ZOOmg.

Punch: diameter 10 mm, with a flat working surface.

Example 19

Hard gelatin capsules containing 150 mg of active substance

Composition based on 1 capsule: 2 tbsp. 11111111 approx.

Preparation: The active substance is mixed with excipients, sifted through a sieve with a cell size of 0.75 mm and mixed to homogeneity in the appropriate apparatus. The resulting mixture is packaged in hard gelatin capsules of size 1. Ge)

The mass of the contents of the capsule: approximately 320 Ω.

Capsule shell: hard gelatin capsule size 1. -

Example 20

Suppositories with the active substance content of 150 mg

Composition based on 1 candle: "what is it made of" 1111111 droooyumo - Preparation: After melting the mass for suppositories, the active substance is homogeneously dispersed in it and

Gee! the molten mass is poured into pre-cooled forms.

Example 21 pi Suspension with an active substance content of 50 mg g 20 Composition based on 10 Oml of suspension: sl active substance 1.00 g

Carboxymethylcellulose oil O1og methyl ether of p-hydroxybenzoic acid 0.05g propyl ether of p-hydroxybenzoic acid 0.01g

F! cane sugar 10.00g glycerin B, sorbitol solution, 7095th 20.0g flavoring O, Zog 60 water, distilled to 10O0ml

Preparation: Distilled water is heated to 702C. Then methyl and propyl esters of p-hydroxybenzoic acid, as well as glycerin and sodium salt of carboxymethylcellulose are dissolved in it with stirring. The solution is cooled to room temperature, the active substance is added while stirring and dispersed until homogeneity. After adding and dissolving sugar, sorbitol solution, and flavoring, the suspension is vacuumed while stirring to remove air from it.

5 ml of suspension contains 5 mg of active substance.

Example 22

Ampoules with 10 mg of active ingredient

Composition: active substance 10,Omg

O, O01n. hydrochloric acid 4.5. double-distilled water up to 2.O0ml 70 Preparation: The active substance is dissolved in the required amount of 0.01n. NSI, the solution is rendered isotonic by adding table salt, after which it is sterilized by filtration and packaged in 2-milliliter ampoules.

Example 23

Ampoules containing 50 mg of active substance

Composition: active substance BO Omg

O, O1n. hydrochloric acid 4.5. twice distilled water up to 10.Oml

Preparation: The active substance is dissolved in the required amount of 0.01n. NSI, the solution is rendered isotonic by adding table salt, after which it is sterilized by filtration and packaged in 10-milliliter ampoules.

Example 24

Capsules for powder inhalation with the active substance content of 5 mg

Composition based on 1 capsule: c with (8) scraps

IF)

Preparation: The active substance is mixed with lactose for inhalation. The resulting mixture is packed into capsules (the weight of an empty capsule is about 5 mg) in a machine for filling capsules.

Capsule weight: 70.Omg. "AND

Capsule size: 3. F

Example 25

Inhalation solution, which contains 2.5 mg of the active substance, for a manual inhaler

The composition based on one portion, which is released with a single click on the head of the inhaler: active substance 2,500 mg " benzalkonium chloride 0,001 mg other. hydrochloric acid 9.5. shsh with ethanol/water (50:50) up to 15,000 mg

G.Y. . NO. . and Preparation: The active ingredient and benzalkonium chloride are dissolved in ethanol/water (50:50). The pH value of the solution is set to neutral by adding 1N. hydrochloric acid. The resulting solution is filtered and packaged in replaceable canisters (cartridges) intended for a manual inhaler. -I Weight of the contents of the can: 4.5 g. se)

Claims (1)

The invention formula of the Cheka" and o, . 1 1. Bicyclic heterocycles of the general formula спя во (), but Я: not юю ШЧИ in М in which KU means a hydrogen atom or a C. distant group, ВЕ? means a phenyl or 1-phenylethyl group, in each of which the phenyl nucleus is replaced by residues B 1-23, 65 where In and in? can have identical or different meanings and mean a hydrogen, fluorine, chlorine, bromine or iodine atom, C, a dalalkyl group, a hydroxy group, Si. daloxy group, C 0 alkenyl group, C 0 alkynyl group, aryl group, aryloxy group, arylmethyl group, arylmethoxy group, heteroaryl group, heteroaryloxy group, heteroarylmethyl group, heteroarylmethoxy group substituted with 1-3 fluorine atoms, methyl or methoxy group, or cyano-, nitro- or amino group, and BZ means a hydrogen, fluorine, chlorine or bromine atom, a methyl or trifluoromethyl group, KO means a cyclobutyl, cyclopentyl or cyclohexyl group, each of which is substituted by a 22-M-85 group, where B" means a hydrogen atom or a C. alkyl group, and means hydrogen atom, C alkyl group, aminocarbonyl-C alkyl group, C. alkylaminocarbonyl-C, alkyl group, di(Ci alkyl)aminocarbonyl-C 1 alkyl group, pyrrolidine-1-ylcarbonyl-C 4 alkyl group, piperidine-1-ylcarbonyl-C. alkyl group, homopiperidine-1-ylcarbonyl-C 4 alkyl group, morpholine-4-ylcarbonyl-C. alkyl group, homomorpholin-4-ylcarbonyl-C to alkyl group, piperazine-1-ylcarbonyl-C. alkaline group, 4-C. alkylpiperazine-1-ylcarbonyl-C / alkyl group, homopiperazine-1-ylcarbonyl-C alkyl group, 4-C. zalkylhomopiperazine-1-ylcarbonyl-C u. alkyl group, hydroxy-Co.alkyl group, Su.alkyloxy-Co alkyl GVUPU, Su dalalkyloxycarbonylamino-C»o alkyl group, amino-solalkyl group, C..alkylamino-C» alkyl group, di(C4 alkyl)amino-C » dalalkyl group, Su zalkylcarbonylamino-S o. alkyl group, aminocarbonylamino-C 5» alkyl group, C. alkylaminocarbonylamino-C » alkyl group, di(C. alkyl)aminocarbonylamino-C 5. alkyl group, pyrrolidine-1-ylcarbonylamino-C alkyl group, piperidine-1-ylcarbonylamino- C».alkyl group, morpholin-4-ylcarbonylamino-C» alkyl GROUP, sC C alkylsulfonyl-C» alkyl group, Su alkylsulfonylamino-C» alkyl group, (2-oxopyrrolidin-1-yl)-C » alkyl group, ( 2-oxopiperidin-1-yl)-C" alkyl group, and) (3-oxomorpholin-4-yl)-C" alkyl group, (2-oxoimidazolidin-1-yl)-C" alkyl group, (2-oxo -3-C 4 alkylimidazolidin-1-yl)-C alkyl group, (2-oxohexahydropyrimidin-1-yl)-C alkyl group, (2-oxo-3-C 4 alkylhexahydropyrimidin-1-yl)-C» alkyl group, Si dalalkylsulfonyl group, zo Xchloro-Ci-alkylsulfonyl group, bromo-Ci-alkylsulfonyl group, amino-C- dalkylsulfonyl group, Si alkylamino-C. alkylsulfonyl group, di(Cu alkyl)amino-C4 alkylsulfonyl group, o (pyrrolidin-1-yl)-C 4 dalalkylsulfonyl group, (piperidin-1-yl)-C alkylsulfonyl group, "h (homopiperidin-1-yl)- C 3 alkyl sulfonyl group, (morpholin-4-yl)-C- alkyl sulfonyl group, (homomorpholin-4-yl)-C 4 dal alkyl sulfonyl group, (piperazin-1-yl)-C 4 dal alkyl sulfonyl group, Me Zv (4-Si. alkylpiperazin-1-yl)-C 4 alkylsulfonyl group, (homopiperazin-1-yl)-C alkylsulfonyl group, r. (4-C; alkylhomopiperazin-1-yl)-C . alkylsulfonyl group, C.alkyloxycarbonyl group, formyl group, C.alkylcarbonyl group, C.alkyloxy-C-alkylcarbonyl group, tetrahydrofuranylcarbonyl group, tetrahydropyranylcarbonyl group, amino-C. lalkylcarbonyl group, Su alkylamino-C.i.dalkylcarbonyl group, di(Ci alkyl)amino-C..alkylcarbonyl group, "pyrrolidin-1-yl-C. lalkylcarbonyl group, piperidin-1-yl-C lalkylcarbonyl group, Z c (homopiperidin-1-yl)-C 1 lalkylcarbonyl group, morpholin-4-yl-C. lalkylcarbonyl group, . (homomorpholin-4-yl)-C and. alkylcarbonyl group, (piperazin-1-yl)-C alkylcarbonyl group, "" (4-C; alkylpiperazin-1-yl)-C and alkylcarbonyl group, (homopiperazin-1-yl)-C alkylcarbonyl group, (4-C Zalkylhomopiperazin-1-yl)-C. lalkylcarbonyl group, Sui.alkylsulfonyl-S. alkylcarbonyl group, Cyano group, aminocarbonyl group, C)u.alkylaminocarbonyl group, di(C-.alkyl)aminocarbonyl group, -I (Cu.alkyloxy-C» alkyl)aminocarbonyl group, M-(C.alkyl)-M-( C.1 alkyloxy-C" alkyl)aminocarbonyl group, arylaminocarbonyl group, pyrrolidin-1-ylcarbonyl group, piperidin-1-ylcarbonyl group, and, homopiperidin-1-ylcarbonyl group, morpholin-4-ylcarbonyl group, homomorpholin-4-ylcarbonyl group group, their 2-oxa-5-azabicyclo|2.2.1|)hept-b--ylcarbonyl group, 3-oxa-8-azabicyclo|3.2.1|oct-B-ylcarbonyl group, 8-oxa-3-azabicyclo |3.2.1|oct-Z-ylcarbonyl group, piperazin-1-ylcarbonyl group, o 4-C. alkylpiperazin-1-ylcarbonyl group, homopiperazin-1-ylcarbonyl group, sp 4-C. alkylhomopiperazin-1-ylcarbonyl group, aminosulfonyl group, C alkylaminosulfonyl group, di(C alkyl)aminosulfonyl group, pyrrolidin-1-ylsulfonyl group, piperidin-1-ylsulfonyl group, homopiperidin-1-ylsulfonyl group, morpholine-4- ylsulfonyl group, homomorpholin-4-ylsulfonyl group, two piperazin-1-ylsulfonyl group, 4-C. alkylpiperazin-1-ylsulfonyl group, homopiperazin-1-ylsulfonyl group or 4-C.; an alkylhomopiperazin-1-ylsulfonyl group, a cyclobutyl, cyclopentyl, or cyclohexyl group, each of which is substituted by a group B, where ) VU means a 2-oxopyrrolidin-1-yl group, a 2-oxopiperidin-1-yl group, a 3-oxomorpholin-4 -yl group, 2-oxoimidazolidin-1-yl group, 2-oxo-3-C1 alkylimidazolidin-1-yl group, or 2-oxohexahydropyrimidin-1-yl group or 2-oxo-3-C1 alkylhexahydropyrimidine-1- yl group, azetidine-Z-yl group, which in position 1 is replaced by residue B 7, where B? has the values indicated above, the pyrrolidine-Z-yl group, which in position 1 is replaced by the residue B 7, where KO has the values indicated above, the piperidine-Z-yl group, which in position 1 is substituted by the residue BK 7, where B? has the values indicated above, a piperidin-4-yl group, which in position 1 is replaced by a B Z residue, where BE? has the above values, or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, BZ means a hydrogen, fluorine, chlorine or bromine atom, a hydroxy group, a C dalalkyloxy group, a methoxy group substituted with 1-3 fluorine atoms, an ethyloxy group substituted with 1-5 fluorine atoms, Co. dalalkyloxy group, which is substituted by the residue 5 or B", where 9 25 has the above values, and B means a hydroxy group, C. alkyloxy group, C.sub.3-cycloalkyloxy group, amino group, C.sub.alkylamino group, di(C4.alkyl)amino group, bis(2-methoxyethyl) iamino group, pyrrolidin-1-yl group, piperidin-1-yl group, homopiperidin-1-yl group, morpholin-4-yl group, homomorpholin-4-yl group, 2-oxa-5-azabicyclo|2.2.1)hept -5-yl group, 3-oxa-8-azabicyclo!/3.2.oct-8-yl group, 8-oxa-3-azabicyclo|3.2.1|oct-3-yl group, piperazin-1-yl group, 4-C.3 alkylpiperazin-1-yl group, homopiperazin-1-yl group, C alkylhomopiperazin-1-yl group, formylamino group, C dalalkylcarbonylamino group, C. alkyloxy-C. alkylcarbonylamino group, C. dalyloxycarbonylamino group, aminocarbonylamino group, C. alkylaminocarbonylamino group, di(C. alkyl)aminocarbonylamino group, pyrrolidine-1-ylcarbonylamino group, piperidin-1-ylcarbonylamino group, piperazin-1-ylcarbonylamino group, 19 4-C. alkylpiperazin-1-ylcarbon ylamino group, morpholine-4-ylcarbonylamino group or C 1 alkylsulfonylamino group, C3-7cycloalkyloxy group, C3-7cycloalkyl-C3-alkyloxy group, tetrahydrofuran-3-yloxy group, tetrahydropyran-3-yloxy group, tetrahydropyran-4-yloxy group, tetrahydrofuranyl-C. dalalkyloxy group, tetrahydropyranyl-C 1 -alkyloxy group, C 1 daloxy group, which is substituted in position 1 by residue 28 with a pyrrolidinyl, piperidinyl or homopiperidinyl group, where BZ means a hydrogen atom or a C. alkyl group, or C. a daloxy group, which is substituted by a morpholinyl group substituted in position 4 by the residue B C, where KZ has the above values, and X means a methine group or a nitrogen atom substituted by a cyano group, with the aryl groups mentioned in the definitions of the above residues in each case refers to i) a phenyl group that is mono- or disubstituted by a P residue, where in the case of double substitution, the substituents can have identical or different values, and where BO means a hydrogen, fluorine, chlorine, bromine or iodine atom, a sisalalkyl group, a hydroxy group, C. a alkyloxy group, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, or a cyano group, the heteroaryl groups mentioned in the definitions of the above-mentioned residues mean a pyridyl, (Z) pyridazinyl, pyrimidinyl, or pyrazinyl group, and the above-mentioned heteroaryl groups are in each case the same - or disubstituted by a KU residue, where in the case of double substitution, the substituents can have identical or different values and where REZ has the above values, - each of the above pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups can be replaced by one or two C. alkyl groups, and the above alkyl groups, unless otherwise specified, may be straight or branched, " with the exception of 4-|(3-chloro-4-fluorophenyl)amino)|-6-(5)-tetrahydrofuran-3-yloxy)- 7-hydroxyquinazoline, their tautomers, their stereoisomers, their mixtures and their salts. c 2. Bicyclic heterocycles of the general formula I according to claim 1, in which "z" VU means a hydrogen atom, B? means a phenyl group substituted by K-2EZ residues, where B" means a hydrogen, fluorine, chlorine or bromine atom, a methyl group, a trifluoromethyl group, an ethynyl group, -I phenyloxy group or a phenylmethoxy group, where the phenyl fragment of the above groups is optionally substituted by a fluorine or chlorine atom , or a pyridyloxy or pyridinylmethoxy group, where the pyridinyl fragment of the above groups is optionally replaced by a methyl or trifluoromethyl group, "" B2 means a hydrogen, fluorine or chlorine atom or a methyl group and sl 50 BZ means a hydrogen atom, B: means a cyclopentyl group, which in the C position is replaced by the K7-M-VU group, where "B" means a hydrogen atom or C. alkyl group, and vo means a hydrogen atom, Su alkyl group, aminocarbonyl-C. alkaline group, C. alkylaminocarbonyl-C, alkyl group, di(Ci alkyl)aminocarbonyl-C 1 alkyl group, pyrrolidine-1-ylcarbonyl-C 4 alkyl group, piperidine-1-ylcarbonyl-C. an alkyl group, piperazine-HF) 1-ylcarbonyl-C into an alkyl group, 4-C. Alkylpiperazine-1-ylcarbonyl-C 4 alkyl group, 7 morpholine-4-ylcarbonyl-C 3 alkyl group, hydroxy-Soalkyl group, Sui.alkyloxy-Soalkyl group, C dalalkyloxycarbonylamino-Co alkyl group, amino-Soalkyl group, S.. alkylamino-Soalkyl group, di(C alkyl)amino-C" alkyl group, C. alkylcarbonylamino-C" alkyl group, because aminocarbonylamino-C" alkyl group, Su. alkylaminocarbonylamino-C» alkyl group, di(C4.alkyl)aminocarbonylamino-C» alkyl group, morpholin-4-ylcarbonylamino-C» alkyl group, Ci alkylsulfonyl-C» alkyl group, Su alkylsulfonylamino-C» alkyl group, (2- oxopyrrolidin-1-yl)-C » alkyl group, (2-oxopiperidin-1-yl)-C» dalalkyl group, (3-oxomorpholin-4-yl)-C » alkyl group, (2-oxoimidazolidin-1-yl )-C» alkyl group, because (2-oxo-3-methylimidazolidin-1-yl)-C» alkyl group, (2-oxohexahydropyrimidin-1-yl)-Co alkyl group, (2-oxo-3-methylhexahydropyrimidin-1-yl)-C» alkyl group, C 1 alkylsulfonyl group, chloro-C 10 alkylsulfonyl group, bromo-C 10 alkylsulfonyl group, amino-C 10 alkylsulfonyl group, C 1 alkylamino-C 10 alkylsulfonyl group, di(C alkyl)amino-C»o alkylsulfonyl group, (pyrrolidin-1-yl)-C2.alkylsulfonyl group, (piperidin-1-yl)-Co lalkylsulfonyl group, (morpholin-4-yl)-C» laalkylsulfonyl group , Su dalalkyloxycarbonyl group, formyl group, Si alkylcarbonyl group, C. alkyloxy-C.- alkylcarbonyl group, tetrahydrofuranylcarbonyl group, tetrahydropyranylcarbonyl group, amino-C. and alkylcarbonyl group, C.. alkylamino-C. alkylcarbonyl group, di(Ci.alkyl)amino-C 4 alkylcarbonyl group, pyrrolidin-1-yl-C alkylcarbonyl group, 70 piperidin-1-yl-C. alkylcarbonyl group, piperazin-1-yl-C. alkylcarbonyl group, 4-C. alkylpiperazin-1-yl-C alkylcarbonyl group, morpholin-4-yl-C. alkylcarbonyl group, C 1 alkylsulfonyl-C 3 alkylcarbonyl group, cyano group, aminocarbonyl group, C 1 alkylaminocarbonyl group, di(C-alkyl)aminocarbonyl group, (C 1 alkyloxy-C 10 alkyl)aminocarbonyl group, M-(C 4 alkyl) )-M-(C. zalkyloxy-Colalkyl)aminocarbonyl group, phenylaminocarbonyl group, pyrrolidin-1-ylcarbonyl group, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl group, C 1 alkylmorpholin-4-ylcarbonyl group, di(Si. alkyl)umorpholin-4-ylcarbonyl group, homomorpholin-4-ylcarbonyl group, 2-oxa-5-azabicyclo|2.2.1|)hept-5-ylcarbonyl group, 3-oxa-8-azabicyclo|3.2.1|oct- 8-ylcarbonyl group, 8-oxa-3-azabicyclo|3.2.1|oct-3-ylcarbonyl group, piperazin-1-ylcarbonyl group, 4-(C3.alkyl)/piperazin-1-ylcarbonyl group, aminosulfonyl group, Si -alkylaminosulfonyl group, di(C--alkyl)aminosulfonyl group, pyrrolidin-1-yl-sulfonyl group, piperidin-1-ylsulfonyl group or morpholin-4-ylsulfonyl group, cyclopentyl group , which in position C is replaced by a KU group, where U means 2-oxopyrrolidin-1-yl group, 2-oxopiperidin-1-yl group, 3-oxomorpholin-4-yl group, 2-oxoimidazolidin-1-yl group, 2- an oxo-3-methylimidazolidin-1-yl group, a 2-oxohexahydropyrimidin-1-yl SM group or a 2-oxo-3Z-methylhexahydropyrimidin-1-yl group, or a cyclohexyl group, which in position З or in position 4 is replaced by group B 7 -M-VE?, where B7 and B? have the above values, a cyclohexyl group, which in position C or in position 4 is substituted by a group B 2, where 9 has the above values, a pyrrolidine-Z-yl group, which in position 1 is substituted by a residue B C, where B? has the above values, a piperidin-3-yl group, which in position 1 is replaced by the residue B?, where K? has the specified and higher values, and a piperidin-4-yl group, which in position 1 is replaced by a B residue, where EE? has the above values, or "tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, VU means a hydrogen atom, a C--alkyloxy group, a methoxy group substituted by one to three fluorine atoms, b" 3z5 ethyloxy group, which in position 2 is replaced by residue 25 or VK", where KZ has the values indicated above, and rch- B/ means "hydroxy group, C alkyloxy group, amino group, C alkyl amino group, di(C alkyl)amino group, bis(2-methoxyethyl) amino group, pyrrolidin-1-yl group, piperidin-1-yl group, morpholin-4-yl group, homomorpholin-4-yl group, 2-oxa-5-azabicyclo|2.2.1)hept-5-yl group, " 3-oxa-8-azabicyclo|3.2.1|oct-d-yl group, 8-oxa-3-azabicyclo|3.2.1|oct-Z-yl group, piperazin-1-yl group, 4-C)3 zalkylpiperazin-1-yl group, formylamino group, C. dalalkylcarbonylamino group, - C. C. alkyloxy-C. 1 alkylcarbonylamino group, C. dalalkyloxycarbonylamino group, aminocarbonylamino group, h. C. alkylaminocarbonylamino group, di(C-.alkyl)uaminocarbonylamino group, pyrrolidine-1 - ylcarbonylamino group, piperidine-1-ylcarbonylamino group, piperazin-1-ylcarbonylamino group, 4-C. alkylpiperazine-1-ylcarbonylamino group, morpholine-4-ylcarbonylamino group or C dalalkylsulfonylamino group, propyloxy group, which in position C is substituted by the residue K 3 or B", devb and c have the above values, or butyloxy group, which in position 4 is substituted by the residue E5 or В", where З В Ге) have the values indicated above, and X means a nitrogen atom, while the alkyl groups indicated above, unless otherwise specified, can have a straight or branched chain, c 20 their tautomers, their stereoisomers, their mixtures and their salts. C. Bicyclic heterocycles of the general formula 1 according to claim 1, in which sl KU means a hydrogen atom, vo means a 3-ethynylphenyl group, 3-bromophenyl group, 3,4-difluorophenyl group, 3-chloro-4-fluorophenyl group, 3-chloro -4-benzyloxyphenyl group, 3-chloro-4-(3-fluorobenzyl)oxy|phenyl group, 4-(pyridin-3-yloxy)phenyl group, 4-(b-methylpyridin-3-yl)oxy|phenyl group, HF) 3-methyl-4-(pyridin-3-yloxy)phenyl group, 3-methyl-4-((b-methylpyridin-3-yl)oxy|phenyl group, 7 3-chloro-4-(pyridin-3 -yloxy)phenyl group or 3-chloro-4-((b-methylpyridin-3-yl)oxy|phenyl group, B? means a cyclohexyl group, which in position C or in position 4 is replaced by a group K7-M-B, where in B" means a hydrogen atom, a methyl group or an ethyl group, and B? means a hydrogen atom, a methyl group, an aminocarbonylmethyl group, a methylaminocarbonylmethyl group, a dimethylaminocarbonylmethyl group, a pyrrolidin-1-ylcarbonylmethyl group, a piperidin-1-ylcarbonylmethyl group, a piperazine-1- ylcarbonylmethyl group, 4-methylpiperazin-1-ylcarbo nylmethyl group, morpholin-4-ylcarbonylmethyl group, 2-(morpholin-4-ylcarbonyl)ethyl group, 3-(morpholin-4-ylcarbonyl)upropyl group, ethyl group, propyl 65 Group, 2-hydroxyethyl group, 3-hydroxypropyl group , 2-methoxyethyl group, 3-methoxypropyl group, 2-(butyloxycarbonylamino)ethyl group, 2-aminoethyl group, 3-aminopropyl group, 2--acetylamino)dethyl group, 3-(acetylamino)propyl group, 2-(ethylcarbonylamino) ethyl group, 3-(ethylcarbonylamino)propyl group, 2-(propylcarbonylamino)ethyl group, 3-(propylcarbonylamino)propyl group, 2-(ethylaminocarbonylamino)ethyl group, 3-(ethylaminocarbonylamino)propyl group, 2-(dimethylaminocarbonylamino)detyl group , 33-(dimethylaminocarbonylamino)propyl group, 2-(morpholin-4-ylcarbonylamino)dethyl group, 3-(morpholin-4-ylcarbonylamino)propyl group, 2-(methylsulfonyl)ethyl group, 3-(methylsulfonyl)propyl group, 2 -(methylsulfonylamino)ethyl group, C-(methylsulfonylamino)propyl group, 2-(2 -oxopyrrolidin-1-yl)ethyl group, 2-(2-oxopiperidin-1-yl)ethyl group, 2-(3-oxomorpholin-4-yl)ethyl group, 7/0. 2-(2-oxoimidazolidin-1-yl)ethyl group, 2-(2-oxo-3-methylimidazolidin-1-yl)ethyl group, 2-(2-oxohexahydropyrimidin-1-yl)ethyl group, 2-(2 -oxo-3-methylhexahydropyrimidin-1-yl)ethyl group, 3-(2-oxopyrrolidin-1-yl)upropyl group, 3-(2-oxopiperidin-1-yl)upropyl group, 3-(3-oxomorpholine-4 -yl)propyl group, 3-(2-oxoimidazolidin-1-yl)upropyl group, 3-(2-oxo-3-methylimidazolidin-1-yl)upropyl group, 3-(2-oxohexahydropyrimidin-1-yl)upropyl group group, 75 3-(2-oxo-3-methylhexahydropyrimidin-1-yl)propyl group, methylsulfonyl group, ethylsulfonyl group, 3-chloropropylsulfonyl group, 2-(morpholin-4-yl)"'ethylsulfonyl group, 3-(morpholine-4 -yl)upropylsulfonyl group, propyloxycarbonyl group, butyloxycarbonyl group, formyl group, acetyl group, ethylcarbonyl group, propylcarbonyl group, methoxyacetyl group, (2-methoxyethyl)carbonyl group, (3-methoxypropyl)carbonyl group, tetrahydrofuran-2-ylcarbonyl group, tetrahydropyran-4-ylcarbo nyl group, aminoacetyl group, methylaminoacetyl group, dimethylaminoacetyl group, morpholin-4-ylacetyl group, (|2-(morpholin-4-yl)ethylcarbonyl group, 3-(morpholin-4-yl)/propyl|carbonyl group, methylsulfonylacetyl group , cyano group, aminocarbonyl group, methylaminocarbonyl group, dimethylaminocarbonyl group, ethylaminocarbonyl group, diethylaminocarbonyl group, propylaminocarbonyl group, (2-methoxyethyl)aminocarbonyl group, ch M-methyl-M-(2-methoxyethyl)aminocarbonyl group, (3-methoxypropyl)aminocarbonyl group group, M-methyl-M-(3-methoxypropyl)aminocarbonyl group, phenylaminocarbonyl group, pyrrolidin-1-ylcarbonyl i) group, piperidin-1-ylcarbonyl group, morpholin-4-ylcarbonyl group, 2-methylmorpholin-4-ylcarbonyl group , 2,6-dimethylmorpholin-4-ylcarbonyl group, homomorpholin-4-ylcarbonyl group, 2-oxa-5-azabicyclo|2.2.1|)hept-b--ylcarbonyl group, 3-oxa-8-azabicyclo|3.2. 1|oct-B-ylcarbonyl group, juzo 8-oxa-3-azabicyclo|3.2.1|ok t-3-ylcarbonyl group, 4-methylpiperazin-1-ylcarbonyl group, aminosulfonyl group, methylaminosulfonyl group, dimethylaminosulfonyl group or omorpholin-4-ylsulfonyl group, "E cyclohexyl group, which in position C or in position 4 is substituted by group P, where 25 means 2-oxopyrrolidin-1-yl group, 2-oxopiperidin-1-yl group, 3-oxomorpholin-4-yl group, F 2-oxoimidazolidin-1-yl group, 2-oxo-3-methylimidazolidin-1- yl group, 2-oxohexahydropyrimidin-1-yl group or 2-oxo-33-methylhexahydropyrimidin-1-yl group, pyrrolidin-Z-yl group, which in position 1 is replaced by residue B 9, where KE? has the above values, a piperidine-Z-yl group, which in position 1 is replaced by the BC 7 residue, where B? has the values indicated above, "piperidin-4-yl group, which in position 1 is replaced by the B Z residue, where BE? has the values indicated above, or - t0 is a tetrahydrofuran-3-yl group, a tetrahydropyran-3Z-yl group or a tetrahydropyran-4-yl group, with BZ means a hydrogen atom, a methoxy group, a difluoromethoxy group, an ethyloxy group, an ethyloxy group which is in position 2:z» substituted by the residue 25 or in", where 25 has the above values, and B means a hydroxy group, a methoxy group, an ethoxy group, an amino group, a dimethylamino group, a diethylamino group, a bis(2-methoxyethyl)amino group, a pyrrolidin-1-yl group, a piperidin-1-yl group , morpholin-4-yl group, -I homomorpholin-4-yl group, 2-oxa-5-azabicyclo|2.2.1)hept-5-yl group, 3-oxa-8-azabicyclo|3.2.1|oct- d-yl group, 8-oxa-3-azabicyclo|3.2.1|oct-Z-yl group, piperazin-1-yl and, group, 4-methylpiperazin-1-yl group, 4-ethylpiperazin-1-yl group , acetylamino group, their ethylcarbonylamino group, propylcarbonylamino group, butylcarbonylamino group, methoxyacetylamino group, butyloxycarbonylamino group, ethylaminocarbonylamino group, dimethylaminocarbonylamino group, o pyrrolidin-1-yl rbonylamino group, piperidin-1-ylcarbonylamino group, morpholin-4-ylcarbonylamino group, sp methylsulfonylamino group, ethylsulfonylamino group or butylsulfonylamino group, propyloxy group, which in position C is substituted by residue 25 or B", where VK5 and KE" have the above values, or butyloxy group, which is in position C 4 is replaced by the residue 25 or B", where C and B have the above values and X represents a nitrogen atom, while the above alkyl groups, unless otherwise specified, may have a straight or branched chain, or their tautomers, their stereoisomers, their mixtures and their salts. ko 4. Bicyclic heterocycles of the general formula | according to claim 1, in which KU means a hydrogen atom, 60 V? means 3-bromophenyl group, 3,4-difluorophenyl group, 3-chloro-4-fluorophenyl group, 3-ethynylphenyl group, 3-chloro-4-benzyloxyphenyl group, 3-chloro-4-(33-fluorobenzyl)oxy|phenyl group, 4-(pyridin-3-yloxy)phenyl group, 4-(b-methylpyridin-3-yl)oxy|phenyl group, 3-methyl-4-(pyridin-3-yloxy)phenyl group, 3-methyl- 4-((b-methylpyridin-3-yl)oxy|phenyl group, 3-chloro-4-(pyridin-3-yloxy)phenyl group or 3-chloro-4-((b-methylpyridin-3-yl)oxy |phenyl group, because KS means a cyclohexyl group, which in position C is substituted by amino-, acetylamino-, tert-butyloxycarbonylamino- or methylsulfonylamino group, a cyclohexyl group substituted in position 4 by amino-, methylamino-, ethylamino-, dimethylamino-, aminocarbonylmethylamino-, methylaminocarbonylmethylamino-, dimethylaminocarbonylmethylamino-, morpholin-4-ylcarbonylmethylamino-, IZ-(morpholin-4- ylcarbonyl)propylamino-, |(2-(methylsulfonyl)ethylamino-, (3-(methylsulfonyl)propylamino- or (2-(methylsulfonylamino)ethylamino), a cyclohexyl group, which in position 4 is substituted by (2-(2- oxopyrrolidin-1-yl)ethyl|amino-, (2-(2-oxopiperidin-1-yl)ethylamino-, (2-(2-oxoimidazolidin-1-yl)ethyl|amino-, (2-(2-oxo -3-methylimidazolidin-1-yl)ethyl|amino-, (2-(2-oxohexahydropyrimidin-1-yl)ethyl|amino- or 70. I2-(2-oxo-3-methylhexahydropyrimidin-1-iluethyl|amino group, cyclohexyl group, which in position 4 is substituted by IZ-(2-oxopyrrolidin-1-yl)propyl|amino-, IZ-(2-oxopiperidine- 1-yl)propyl|amino-, 3-(2-oxoimidazolidin-1-yl)propyl|amino-, 3-(2-oxo-3-methylimidazolidin-1-yl)propyl)amino-, 3-(2- oxohexahydropyrimidin-1-yl)propyl|amino- or 3-(2-oxo-3-methylhexahydropyrimidin-1-yl)propyl with an amino group, a cyclohexyl group, which in position 4 is substituted by acetylamino-, M-(acetyl)methylamino-, aminomethylcarbonylamino- , methylaminomethylcarbonylamino-, dimethylaminomethylcarbonylamino-, morpholin-4-ylmethylcarbonylamino-, methoxyacetylamino-, M-(methoxyacetyl)methylamino-, tetrahydropyran-4-ylcarbonylamino-, M-(tetrahydropyran-4-ylcarbonyl)methylamino-, tert-butyloxycarbonylamino-, M -(tert-butyloxycarbonyl)methylamino-, aminocarbonylamino-, methylaminocarbonylamino-, M-(ethylaminocarbonyl)methylamino-, dimethylaminocarbonylamino-, M-(dimethylaminocarbonyl)methylamino-, M-(piperidin-1-ylcarbonyl)methylamine o-, morpholin-4-ylcarbonylamino-, M-(morpholin-4-ylcarbonyl)methylamino- or M-(4-methylpiperazin-1-ylcarbonyl)methylamino group, cyclohexyl group, which in position 4 is substituted by 2-oxopyrrolidin-1-yl , 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl, 2-oxoimidazolidin-1-yl, 2-oxo-3-methylimidazolidin-1-yl, 2-oxohexahydropyrimidin-1-yl or 2-oxo-3Z -methylhexahydropyrimidin-1-yl group, cyclohexyl group A group substituted in position 4 by methylsulfonylamino-, M-(methylsulfonyl)methylamino-, ethylsulfonylamino-, M-(ethylsulfonyl)methylamino-, dimethylaminosulfonylamino-, M-(dimethylaminosulfonyl)methylamino- , i) morpholin-4-ylsulfonylamino-, M-(morpholin-4-ylsulfonyl)methylamino-, 3-chloropropylsulfonylamino-, (2-(morpholin-4-yl)ethyl|isulfonylamino- or (|3-(morpholin-4 - yl)propyl|isosulfonylamino group, pyrrolidin-3Z-yl group, pyrrolidin-Z-yl group substituted in position 1 with methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarb bonyl or methylsulfonyl group, piperidin-3-yl group, piperidin-Z-yl group, which is substituted in position 1 by methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl group, piperidin-4-yl " E group substituted in position 1 with methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulfonyl)ethyl, 3-("methylsulfonyl)propyl, Me 2-(tert-butyloxycarbonylamino) )detyl, 2-aminoethyl, 2-(acetylamino)ethyl, M 2-(ethylcarbonylamino)detyl, 2-(propylcarbonylamino)ethyl, 2-(ethylaminocarbonylamino)detyl, 2-(dimethylaminocarbonylamino)detyl, 2-(morpholine-4- ylcarbonylamino)detyl, 3-(acetylamino)propyl, 3-(ethylcarbonylamino)propyl, 3-(propylcarbonylamino)propyl, 3-(ethylaminocarbonylamino)propyl, 3-(dimethylaminocarbonylamino)propyl, 3-(morpholin-4-ylcarbonylamino)propyl, " 2-(methylsulfonylamino)ethyl, C-(" methylsulfonylamino)propyl, (aminocarbonyl)methyl, pt) with (methylaminocarbonyl)methyl, (dimethylaminocarbonyl)methyl, (pyrrolidin-1-ylcarbonyl)umethyl, . (morpholin-4-ylcarbonyl)umethyl, 2-(morpholin-4-ylcarbonyl)ethyl or α3-(morpholin-4-ylcarbonyl)upropyl group, piperidin-4-yl group, which in position 1 is substituted by 2-(2- Oxopyrrolidin-1-yl)ethyl, 2-(2-oxopiperidin-1-yl)ethyl, 2-(33-oxomorpholin-4-yl)ethyl, 2-(2-oxoimidazolidin-1-yl)ethyl, 2-( 2-oxo-3-methylimidazolidin-1-yl)ethyl, -I 2-(2-oxohexahydropyrimidin-1-yl)ethyl or 2-(2-oxo-3-methylhexahydropyrimidin-1-yl)ethyl group, piperidine-4 -yl group, which in position 1 is substituted by 3-(2-oxopyrrolidin-1-yl)upropyl, and, 3-(2-oxopiperidin-1-yl)upropyl, 3-(33-oxomorpholin-4-yl)upropyl, 3-(2-oxoimidazolidin-1-yl)upropyl, their 3-(2-oxo-3-methylimidazolidin-1-yl)upropyl, 3-(2-oxohexahydropyrimidin-1-yl)upropyl or 3-(2-oxo -3-methylhexahydropyrimidin-1-yl)upropyl group, piperidin-4-yl group, which in position 1 o is substituted by formyl, acetyl, methoxyacetyl, (2-methoxyethyl)carbonyl, sp (3-methoxypropyl)/carbonyl, m ethylsulfonylacetyl, aminoacetyl, methylaminoacetyl, (dimethylamino)acetyl, (morpholin-4-yl acetyl, (2-(morpholin-4-yl)ethyl)carbonyl, 3-(morpholin-4-yl)/propylcarbonyl, tetrahydrofuran-2-ylcarbonyl or tetrahydropyran- 4-ylcarbonyl group, piperidin-4-yl group, which in position 7 is replaced by a cyano group, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, (2-methoxyethyl)aminocarbonyl, F) M-methyl-M-(2-methoxyethyl)aminocarbonyl, (Z -methoxypropyl)aminocarbonyl, ka M-methyl-M-(3-methoxypropyl)aminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholine-4-ylcarbonyl, 2-methylmorpholine- 4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-azabicyclo|2.2.1|)hept-5--ylcarbonyl, 3-oxa-8-azabicyclo|3.2. 1|oct-in-ylcarbonyl, 8-oxa-3-azabicyclo|3.2.1|oct-Z-y lcarbonyl, 4-methylpiperazin-1-ylcarbonyl, isopropyloxycarbonyl or tert-butyloxycarbonyl group, piperidin-4-yl group, which in position 1 is substituted b5 Methylsulfonyl, ethylsulfonyl, (2-(morpholin-4-yl)ethyl|isulfonyl, IZ- (morpholin-4-yl)/propyl|sulfonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl group, tetrahydrofuran-3-yl group, tetrahydropyran-3-yl group or tetrahydropyran-4-yl group, BZ means a hydrogen atom, methoxy group, difluoromethoxy group, ethyloxy group, 2-(morpholin-4-yl) ethyloxy group, C-(morpholin-4-yl)propyloxy group, 4-(morpholin-4-yl)butyloxy group, C-(dimethylamino)propyloxy group, C-(diethylamino)propyloxy group, C - Ibis(2-methoxyethyl)amino|propyloxy group, 3-(piperazin-1-yl)propyloxy group, 3-(4-methylpiperazin-1-yl)propyloxy group, 3-(4-ethylpiperazin-1-yl)upropyloxy group, 3-(homomorpholin-4-yl)propyloxy group, 3- (2-oxa-5-azabicyclo|2.2.1|hept-5-yl)propyloxy group, 70. 3-(3-oxa-8-azabicyclo|3.2.1|oct-8-yl)propyloxy group, 3-(8-oxa-3-azabicyclo|3.2.1|oct-3-yl)propyloxy group, 2- (2-oxopyrrolidin-1-yl)ethyloxy group, 2-(2-oxopiperidin-1-yl)ethyloxy group, 2-(3-oxomorpholin-4-yl)ethyloxy group, 2-(2-oxoimidazolidin-1-yl)ethyloxy group, 2-(2-oxo-3-methylimidazolidin-1-yl)ethyloxy group, 2-(2-oxohexahydropyrimidin-1-yl)ethyloxy group, 2-(2-oxo-3-methylhexahydropyrimidin-1-yl)ethyloxy group, 3-( 2-oxopyrrolidin-1-yl)upropyloxy group, 75. C-(2-oxopiperidin-1-yl)upropyloxy group, 3-(3-oxomorpholin-4-yl)upropyloxy group, 3-(2-oxoimidazolidin-1-yl)upropyloxy group, 3-(2-oxo-3- methylimidazolidin-1-yl)upropyloxy group, 3-(2-oxohexahydropyrimidin-1-yl)upropyloxy group, 3-(2-oxo-3-methylhexahydropyrimidin-1-yl)upropyloxy group, 2-(methoxy)ethyloxy group, 2-(tert- butyloxycarbonylamino)ethyloxy group, 2-(amino)dethyloxy group, 2-(acetylamino)ethyloxy group, 2-(ethylcarbonylamino)ethyloxy group, 2-(propylcarbonylamino)ethyloxy group, 2-(isobutylcarbonylamino)ethyloxy group, 2-(methoxyacetylamino)ethyloxy group, 2-(ethylaminocarbonylamino) )ethyloxy group, 2-(dimethylaminocarbonylamino)ethyloxy group, 2-(pyrrolidin-1-ylcarbonylamino)ethyloxy group, 2-(piperidin-1-ylcarbonylamino)ethyloxy group, 2-(morpholin-4-ylcarbonylamino)ethyloxy group, 2-(methylsulfonylamino)ethyloxy group, 2-ethylsulfonylamino)ethyloxy group, 2-(butylsulfonylamino)ethyloxy group, 3-(tert-butyloxycarbonylamino)propyloxy group, 3-(amino)propyloxy group, 3-(acetylamine o) a propyloxy group or a C-(methylsulfonylamino)propyloxy group, and i) X means a nitrogen atom, their tautomers, their stereoisomers, their mixtures and their salts. 5. Bicyclic heterocycles of the general formula I according to claim 1, in which Ю КУ means a hydrogen atom, ю В? means a 3-chloro-4-fluorophenyl group or a 3-ethynylphenyl group, KS means a cyclohexyl group, which is substituted in position C with an amino-, acetylamino-, "tert-butyloxycarbonylamino- or methylsulfonylamino group, a cyclohexyl group which is in position 4 Ge! substituted amino-, methylamino-, dimethylamino-, acetylamino-, M-(acetyl)methylamino-, methoxyacetylamino-, Zo M-(methoxyacetyl)methylamino-, tetrahydropyran-4-ylcarbonylamino-, y- M-(tetrahydropyran-4-ylcarbonyl )methylamino-, tert-butyloxycarbonylamino-, M-(tert-butyloxycarbonyl)methylamino-, M-(ethylaminocarbonyl)methylamino-, dimethylaminocarbonylamino-, M-(dimethylaminocarbonyl)methylamino-, M-(piperidin-1-ylcarbonyl)methylamino-, morpholin-4-ylcarbonylamino-, M-(morpholin-4-ylcarbonyl)methylamino-, M-(4-methylpiperazin-1-ylcarbonyl)methylamino-, methylsulfonylamino-, 49 M-(methylsulfonyl)methylamino-, ethylsulfonylamino-, M -(ethylsulfonyl)methylamino-, C c dimethylaminosulfonylamino-, M-(dimethylaminosulfonyl)methylamino-, morpholin-4-ylsulfonylamino-, "» M-(morpholin-4-ylsulfonyl)methylamino-, C-chloropropylsulfonylamino- or " IZ-( morpholin-4-yl)/propyl|sulfonylamino group, pyrrolidine-Z-yl group, pyrrolidine-Z-yl group, which in position 1 is substituted by tert-butyloxycarbonyl or methylsulfonyl group, piperidin-3-yl group, piperidin-33-yl group, which is substituted in position 1 by tert-butyloxycarbonyl or methylsulfonyl group, piperidin-4-yl group, piperidin-4-yl group, which is substituted in position 1 methyl, Ge) (aminocarbonyl)umethyl, (dimethylaminocarbonyl)methyl, (morpholin-4-ylcarbonyl)umethyl, 2-(tert-butyloxycarbonylamino)deethyl, 2-aminoethyl, 2-(acetylamino)ethyl, o 2-(methylsulfonylamino)ethyl group, cyano group, acetyl, methoxyacetyl, c 20 (dimethylamino)acetyl, (morpholin-4-yl acetyl, tetrahydropyran-4-ylcarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl, dimethylaminocarbonyl, sl diethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, picarbonperidin-1-yl , morpholin-4-ylcarbonyl, 2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl , 25 methylsulfonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl group, HF) tetrahydrofuran-3-yl group, tetrahydropyran-3Z-yl group or tetrahydropyran-4-yl group, c means a hydrogen atom, methoxy group, ethyloxy group, 2-(morpholine -4-yl)ethyloxy group, (morpholin-4-yl)propyloxy group, 4-(morpholin-4-yl)butyloxy group, 2-(3-methyl-2-oxohexahydropyrimidin-1-yl)ethyloxy group, 2-(methoxy)ethyloxy group , 60 2-(tert-butyloxycarbonylamino)ethyloxy group, 2-aminoethyloxy group, 2-(acetylamino)ethyloxy group, 2-(methylsulfonylamino)ethyloxy group, 3-(tert-butyloxycarbonylamino)propyloxy group, 3-aminopropyloxy group, 3-(acetylamino)propyloxy group or 3 -(methylsulfonylamino)propyloxy group, and X means a nitrogen atom, their tautomers, their stereoisomers, their mixtures and their salts. because 6. Compounds of the general formula | for claim 1 from the group that includes: (and). 4-(3-chloro-4-fluorophenyl)amino)|-6-(5)-tetrahydrofuran-3-yloxy)-7-methoxyquinazoline, (6). 4-((3-chloro-4-fluorophenyl)amino)|-6-(tetrahydropyran-4-yloxy)-7-methoxyquinazoline, (in). 4-KZ-chloro-4-fluorophenyl)amino|-6-(K)-tetrahydrofuran-3-yloxy)-7-methoxyquinazoline, (d). 4-KZ-chloro-4-fluorophenyl)amino|-6-(trans-4-aminocyclohexan-1-yloxy)-7-methoxyquinazoline, (d). 4-(3-chloro-4-fluorophenyl)amino)|-6-(trans-4-methanesulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline, (is). 4-KZ-chloro-4-fluorophenyl)amino|-6-(piperidin-4-yloxy)-7-methoxyquinazoline, (is). 4-(3-chloro-4-fluorophenyl)amino|-6-(1-methanesulfonylpiperidin-4-yloxy)-7-methoxyquinazoline, (w) 70. 8-KZ-chloro-4-fluorophenyl)amino)|-6-(cis-4-3-(morpholin-4-yl)propyl|sulfonylamino)cyclohexan-1-yloxy)-7-methoxy quinazoline, (with). 4-(3-chloro-4-fluorophenyl)amino)-6-(tetrahydropyran-3-yloxy)-7-methoxyquinazoline, (s) 4-(3-chloro-4-fluorophenyl)amino)|-6-(trans -4-4I3-("morpholin-4-yl)upropyl|Isulfonylamino)cyclohexan-1-yloxy)-7-metho xyquinazoline, () 4-KZ-chloro-4-fluorophenyl)amino)|-6-(1- methylpiperidin-4-yloxy)-7-methoxyquinazoline, (). 4-KZ-chloro-4-fluorophenyl)amino|-6-71-(morpholin-4-yl)carbonyl|Ipiperidin-4-yloxy)-7-methoxyquinazoline, (and). 4-(3-chloro-4-fluorophenyl)amino|-6-41-(methoxymethyl)carbonyl|piperidin-4-yloxy)-7-methoxyquinazoline, (ju. 4-(3-chloro-4-fluorophenyl)amino|-6-(1-cyanopiperidin-4-yloxy)-7-methoxyquinazoline, (l). 4-(3-chloro-4-fluorophenyl)amino|-6-41-(morpholin-4-yl)usulfonyl|piperidin-4-yloxy)-7-methoxyquinazoline, (m). 4-(3-chloro-4-fluorophenyl)amino)-6-(1-(-2-acetylaminoethyl)piperidin-4-yloxy|-7-methoxyquinazoline, (n) 4-(3-chloro-4-fluorophenyl) amino)|-6--trans-4-(dimethylamino)sulfonylamino|cyclohexan-1-yloxy)-7-methoxyquinazole IN, Ha (o) 4-(3-chloro-4-fluorophenyl)amino|-6--trans -4-(morpholin-4-yl)ucarbonylamino|cyclohexan-1-yloxy)-7-methoxyquinazole i) n, (n) 4-(3-chloro-4-fluorophenyl)amino|-6--trans-4- (morpholin-4-yl) usulfonylamino|cyclohexan-1-yloxy)-7-methoxyquinazoline, (p). 4-KZ-chloro-4-fluorophenyl)amino)-6-(tetrahydropyran-4-yloxy)-7-(2-acetylaminoethoxy)quinazoline, o (c) 4-(3-chloro-4-fluorophenyl)amino)| -6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonylaminoethoxy)quinazoline and "E (t) 4-(3-chloro-4-fluorophenyl)amino)|-6-(tetrahydropyran-4-yloxy)- 7-(2-methoxyethoxy)quinazoline, as well as their salts. 7. Compounds according to claim 1, which are physiologically compatible salts of compounds of the general formula | with Mez with inorganic or organic acids or bases. uh- 8. Medicinal product containing a compound according to any of claims 1-6 or a physiologically compatible salt according to claim 7 and optionally one or more inert carriers and/or diluents. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated "Microcircuits", 2007, M 9, 25.06.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. ;" -I se) sh» sl 50 sl F) ime) 60 b5