HK1079095B - 4-(n-phenylamino)-quinazolines/quinolines as tyrosine kinase inhibitors - Google Patents

Description

4- (N-phenylamino) -quinazolines/quinolines as tyrosine kinase inhibitors

Field of the invention

The invention relates to bicyclic heterocyclic compounds of the general formula

Their tautomers, their stereoisomers, their mixtures and their salts, especially the physiologically acceptable salts with inorganic or organic acids or bases having valuable pharmaceutical properties, especially an inhibitory effect on signal transduction mediated by tyrosine kinases, their use for the treatment of diseases, especially cancer, and Benign Prostatic Hyperplasia (BPH), lung and respiratory diseases, and their preparation.

In the above general formula I

R^aRepresents a hydrogen atom or C_1-4-an alkyl group,

R^brepresents phenyl or 1-phenylethyl, in which the phenyl nucleus is in each case substituted by R¹To R³Is substituted by a group of

R¹And R²Identical or different and in each case represents a hydrogen, fluorine, chlorine, bromine or iodine atom,

C_1-4-alkyl, hydroxy, C_1-4-alkoxy, C_2-3-alkenyl or C_2-3-an alkynyl group,

aryl, aryloxy, arylmethyl or arylmethoxy,

heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy,

methyl or methoxy substituted by 1 to 3 fluorine atoms, or

Cyano, nitro or amino, and

R³represents a hydrogen, fluorine, chlorine or bromine atom, or

A methyl group or a trifluoromethyl group, or a salt thereof,

R^crepresents cyclobutyl, cyclopentyl or cyclohexyl, which is substituted in each case by a radical R⁴-N-R⁵Is substituted in which

R⁴Represents a hydrogen atom or C_1-3-alkyl, and

R⁵represents a hydrogen atom or C_1-3-an alkyl group,

aminocarbonyl-C_1-3Alkyl radical, C_1-3-alkylaminocarbonyl-C_1-3Alkyl, di- (C)_1-3-alkyl) aminocarbonyl-C_1-3-alkyl, pyrrolidin-1-ylcarbonyl-C_1-3-alkyl, piperidin-1-ylcarbonyl-C_1-3-alkyl, homopiperidin-1-ylcarbonyl-C_1-3-alkyl, morpholin-4-ylcarbonyl-C_1-3-alkyl, homomorpholin-4-ylcarbonyl-C_1-3-alkyl, piperazin-1-ylcarbonyl-C_1-3-alkyl, 4-C_1-3-alkyl-piperazin-1-ylcarbonyl-C_1-3-alkyl, homopiperazin-1-ylcarbonyl-C_1-3-alkyl or 4-C_1-3-alkyl-homopiperazin-1-ylcarbonyl-C_1-3-an alkyl group,

hydroxy-C_2-4Alkyl radical, C_1-3-alkyloxy-C_2-4Alkyl radical, C_1-4-alkyloxy-carbonylamino-C_2-4Alkyl, amino-C_2-4Alkyl radical, C_1-3-alkylamino-C_2-4Alkyl, di- (C)_1-3-alkyl) amino-C_2-4-alkyl radical, C_1-3-alkylcarbonylamino-C_2-4Alkyl, aminocarbonylamino-C_2-4Alkyl radical, C_1-3-alkylaminocarbonylamino-C_2-4Alkyl, di- (C)_1-3-alkyl) amino-carbonylamino-C_2-4-alkyl, pyrrolidin-1-ylcarbonylamino-C_2-4-alkyl, piperidin-1-ylcarbonylamino-C_2-4-alkyl, morpholin-4-ylcarbonylamino-C_2-4Alkyl radical, C_1-3-alkylsulfonyl-C_2-4-alkyl or C_1-3-alkylsulfonylamino-C_2-4-an alkyl group,

(2-oxo-pyrrolidin-1-yl) -C_2-4Alkyl, (2-oxopiperidin-1-yl) -C_2-4Alkyl, (3-oxo-morpholin-4-yl) -C_2-4Alkyl, (2-oxo-imidazolidin-1-yl) -C_2-4Alkyl, (2-oxo-3-C)_1-3-alkyl-imidazolidin-1-yl) -C_2-4Alkyl, (2-oxo-hexahydropyrimidin-1-yl) -C_2-4-alkyl, or (2-oxo-3-C_1-3-alkyl-hexahydropyrimidin-1-yl) -C_2-4-an alkyl group,

C_1-4-alkylsulfonyl, chloro-C_1-4-alkylsulfonyl, bromo-C_1-4-alkylsulfonyl, amino-C_1-4-alkylsulfonyl, C_1-3-alkylamino-C_1-4-alkylsulfonyl, di- (C)_1-3-alkyl) amino-C_1-4-alkylsulfonyl, (pyrrolidin-1-yl) -C_1-4-alkylsulfonyl, (piperidin-1-yl) -C_1-4-alkylsulfonyl, (homopiperidin-1-yl) -C_1-4-alkylsulfonyl, (morpholin-4-yl) -C_1-4-alkylsulfonyl, (homomorpholin-4-yl) -C_1-4-alkylsulfonyl, (piperazin-1-yl) -C_1-4-alkylsulfonyl, (4-C)_1-3-alkyl-piperazin-1-yl) -C_1-4-alkylsulfonyl, (homopiperazin-1-yl) -C_1-4-alkylsulfonyl or (4-C)_1-3-alkyl-homopiperazin-1-yl) -C_1-4-an alkylsulfonyl group,

C_1-4-an alkyloxycarbonyl group,

formyl radical, C_1-4-alkyl-carbonyl, C_1-3-alkoxy-C_1-4-alkyl-carbonyl, tetrahydrofurylcarbonyl, tetrahydropyrylcarbonyl, amino-C_1-4-alkyl-carbonyl, C_1-3-alkylamino-C_1-4-alkyl-carbonyl, di- (C)_1-3-alkyl) amino-C_1-4-alkyl-carbonyl, pyrrolidin-1-yl-C_1-4-alkyl-carbonyl, piperidin-1-yl-C_1-4-alkyl-carbonyl, (homopiperidin-1-yl) -C_1-4-alkyl-carbonyl, morpholin-4-yl-C_1-4-alkyl-carbonyl, (homomorpholin-4-yl) -C_1-4-alkyl-carbonyl, (piperazin-1-yl) -C_1-4-alkyl-carbonyl, (4-C)_1-3-alkyl-piperazin-1-yl) -C_1-4-alkyl-carbonyl, (homopiperazin-1-yl) -C_1-4-alkyl-carbonyl, (4-C)_1-3-alkyl-homopiperazin-1-yl) -C_1-4-alkyl-carbonyl or C_1-3-alkylsulfonyl-C_1-4-an alkyl-carbonyl group,

cyano, aminocarbonyl, C_1-3-alkyl-aminocarbonyl, di- (C)_1-3-alkyl) aminocarbonyl, (C)_1-3-alkoxy-C_2-4-alkyl) aminocarbonyl, N- (C)_1-3-alkyl) -N- (C_1-3alkyloxy-C_2-4Alkyl) aminocarbonyl, arylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-yl-Alkylcarbonyl, homopiperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo [3.2.1]Octan-8-ylcarbonyl, 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-ylcarbonyl, piperazin-1-ylcarbonyl, 4-C_1-3-alkyl-piperazin-1-ylcarbonyl, homopiperazin-1-ylcarbonyl, 4-C_1-3-alkyl-homopiperazin-1-ylcarbonyl, aminosulfonyl, C_1-3-alkyl-aminosulfonyl, di- (C)_1-3-alkyl) amino-sulfonyl, pyrrolidin-1-yl-sulfonyl, piperidin-1-ylsulfonyl, homopiperidin-1-ylsulfonyl, morpholin-4-ylsulfonyl, homomorpholin-4-ylsulfonyl, piperazin-1-ylsulfonyl, 4-C_1-3-alkyl-piperazin-1-ylsulfonyl, homopiperazin-1-ylsulfonyl or 4-C_1-3-alkyl-homopiperazin-1-ylsulfonyl,

cyclobutyl, cyclopentyl or cyclohexyl, which is substituted in each case by a radical R⁶Is substituted in which

R⁶Represents 2-oxo-pyrrolidin-1-yl, 2-oxopiperazin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3-C_1-3-alkyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or 2-oxo-3-C_1-3-alkyl-hexahydropyrimidin-1-yl,

azetidin-3-yl substituted at the 1-position with a group R⁵Is substituted in which R⁵The definition of (A) is as defined above,

pyrrolidin-3-yl radical which is substituted in the 1-position by a radical R⁵Is substituted in which R⁵The definition of the radicals is as defined above,

piperidin-3-yl which is substituted in position 1 by a radical R⁵Is substituted in which R⁵The definition of the radicals is as defined above,

piperidin-4-yl which is substituted in position 1 by a radical R⁵Is substituted in which R⁵The definition of the radicals is as defined above,

or tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl,

R^drepresents a hydrogen atom or a fluorine, chlorine or bromine atom,

a hydroxyl group(s),

C_1-4-an alkoxy group,

methoxy substituted by 1 to 3 fluorine atoms,

Ethoxy substituted by 1 to 5 fluorine atoms,

by the group R⁶Or R⁷Substituted C_2-4An alkoxy group, wherein

R⁶Is as defined above, and

R⁷represents hydroxy, C_1-3-alkyloxy, C_3-6-cycloalkyloxy, amino, C_1-3Alkylamino, di- (C)_1-3-alkyl) amino, bis- (2-methoxyethyl) -amino, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homoporpholin-4-yl, 2-oxa-5-aza-bicyclo [2, 2, 1]Hept-5-yl, 3-oxa-8-aza-bicyclo [3, 2, 1]]Oct-8-yl, 8-oxa-3-aza-bicyclo [3, 2, 1]Oct-3-yl, piperazin-1-yl, 4-C_1-3-alkyl-piperazin-1-yl, homopiperazin-1-yl or C_1-3-alkyl-homopiperazin-1-yl, or

Formylamino group, C_1-4-alkylcarbonylamino, C_1-3-alkyloxy-C_1-3-alkylcarbonylamino, C_1-4-alkyloxycarbonylamino, aminocarbonylamino, C_1-3-alkylaminocarbonylamino, di- (C)_1-3-alkyl) aminocarbonylamino, pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, 4-C_1-3-alkyl-piperazin-1-ylcarbonylamino, morpholin-4-ylcarbonylamino or C_1-4-an alkylsulfonylamino group,

C_3-7-cycloalkyloxy or C_3-7-cycloalkyl-C_1-4-an alkoxy group,

tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy,

tetrahydrofuryl-C_1-4-alkyloxy or tetrahydropyranyl-C_1-4-an alkoxy group,

C_1-4-alkoxy, which is substituted in the 1-position by R⁸Substituted by pyrrolidinyl, piperidinyl or homopiperidinyl groups, in which

R⁸Represents a hydrogen atom or C_1-3-an alkyl group,

or C_1-4-alkoxy, which is substituted in the 4-position by R⁸A morpholinyl group substituted with a substituent(s),

wherein R is⁸Is as defined above, and

x represents a methine group substituted with a cyano group or a nitrogen atom, an

The aryl radicals mentioned in the above definitions of the radicals mean in each case R⁹A mono-or di-substituted phenyl group,

and the substituents are the same or different, and

R⁹represents a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, or C_1-3-alkyl, hydroxy, C_1-3-alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano,

heteroaryl mentioned in the definition of the abovementioned radicals means in each case pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, where each of the abovementioned heteroaryl radicals is substituted by a radical R⁹Mono-or disubstituted, and the substituents are identical or different, and R⁹Is as defined above, and

the pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl radicals mentioned above may in each case be substituted by one or two C_1-3-alkyl is substituted, and

unless otherwise indicated, the above alkyl groups may be straight or branched,

with the proviso that the compound 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline is not included.

Preferred compounds of the above formula I are those wherein

R^aRepresents a hydrogen atom, and is represented by,

R^brepresents a group R¹To R³Substituted phenyl, wherein

R¹Represents a hydrogen, fluorine, chlorine or bromine atom,

a methyl group, a trifluoromethyl group or an ethynyl group,

a phenyloxy or phenylmethoxy group, in which the phenyl part of the above radicals is optionally substituted by fluorine or chlorine atoms, or

Pyridyloxy or pyridylmethoxy, wherein the pyridyl moiety of the above groups is optionally substituted with methyl or trifluoromethyl,

R²represents a hydrogen, fluorine or chlorine atom or a methyl group, and

R³represents a hydrogen atom, and is represented by,

R^crepresents in the 3 position by a group R⁴-N-R⁵Substituted cyclopentyl, wherein

R⁴Represents a hydrogen atom or C_1-3-alkyl, and

R⁵represents a hydrogen atom or C_1-3-an alkyl group,

aminocarbonyl-C_1-3Alkyl radical, C_1-3-alkylaminocarbonyl-C_1-3Alkyl, di- (C)_1-3-alkyl) aminocarbonyl-C_1-3-alkyl, pyrrolidin-1-ylcarbonyl-C_1-3-alkyl, piperidin-1-ylcarbonyl-C_1-3-alkyl, piperazin-1-ylcarbonyl-C_1-3-alkyl, 4-C_1-3-alkyl-piperazin-1-ylcarbonyl-C_1-3-alkyl or morpholin-4-ylcarbonyl-C_1-3-an alkyl group,

hydroxy-C_2-4Alkyl radical, C_1-3-alkyloxy-C_2-4Alkyl radical, C_1-4-alkyloxycarbonylamino-C_2-4Alkyl, amino-C_2-4Alkyl radical, C_1-3-alkylamino-C_2-4Alkyl, di- (C)_1-3-alkyl) amino-C_2-4-alkyl radical, C_1-3-alkylcarbonylamino-C_2-4Alkyl, aminocarbonylamino-C_2-4Alkyl radical, C_1-3-alkylaminocarbonylamino-C_2-4Alkyl, di- (C)_1-3-alkyl) amino-carbonylamino-C_2-4-alkyl, morpholin-4-ylcarbonylamino-C_2-4Alkyl radical, C_1-3-alkylsulfonyl-C_2-4-alkyl or C_1-3-alkylsulfonylamino-C_2-4-an alkyl group,

(2-oxo-pyrrolidin-1-yl) -C_2-4Alkyl, (2-oxopiperidin-1-yl) -C_2-4Alkyl, (3-oxo-morpholin-4-yl) -C_2-4Alkyl, (2-oxo-imidazolidin-1-yl) -C_2-4Alkyl, (2-oxo-3-methyl-imidazolidin-1-yl) -C_2-4Alkyl, (2-oxo-hexahydropyrimidin-1-yl) -C_2-4-alkyl or (2-oxo-3-methyl-hexahydropyrimidin-1-yl) -C_2-4-an alkyl group,

C_1-3-alkylsulfonyl, chloro-C_2-4-alkylsulfonyl, bromo-C_2-4-alkylsulfonyl, amino-C_2-4-alkylsulfonyl, C_1-3-alkylamino-C_2-4-alkylsulfonyl, di- (C)_1-3-alkyl) amino-C_2-4-alkylsulfonyl, (pyrrolidin-1-yl) -C_2-4-alkylsulfonyl, (piperidin-1-yl) -C_2-4-alkylsulfonyl or (morpholin-4-yl) -C_2-4-an alkylsulfonyl group,

C_1-4-an alkyloxy-carbonyl group,

formyl radical, C_1-3-alkyl-carbonyl, C_1-3-alkoxy-C_1-3-alkyl-carbonyl, tetrahydrofurylcarbonyl, tetrahydropyrylcarbonyl, amino-C_1-3-alkyl-carbonyl, C_1-3-alkylamino-C_1-3-alkyl-carbonyl, di- (C)_1-3-alkyl) amino-C_1-3-alkyl-carbonyl, pyrrolidin-1-yl-C_1-3-alkyl-carbonyl, piperidin-1-yl-C_1-3-alkyl-carbonyl, piperazin-1-yl-C_1-3-alkyl-carbonyl, 4-C_1-3-alkylpiperazin-1-yl-C_1-3Alkyl-carbonyl, morpholin-4-yl-C_1-3-alkyl-carbonyl or C_1-3-alkylsulfonyl-C_1-4-an alkyl-carbonyl group,

cyano, aminocarbonyl, C_1-3-alkyl-aminocarbonyl, di- (C)_1-3-alkyl) aminocarbonyl, (C)_1-3-alkoxy-C_2-4-alkyl) aminocarbonyl, N- (C)_1-3-alkyl) -N- (C_1-3alkyloxy-C_2-4-alkyl) aminocarbonyl, phenylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, C_1-3-alkyl-morpholin-4-ylcarbonyl, di- (C)_1-3-alkyl) morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo [3.2.1]Octan-8-ylcarbonyl, 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C)_1-3-alkyl) piperazin-1-ylcarbonyl, aminosulfonyl, C_1-3-alkyl-aminosulfonyl, di- (C)_1-3-alkyl) amino-sulfonyl, pyrrolidin-1-yl-sulfonyl, piperidin-1-ylsulfonyl or morpholin-4-ylsulfonyl, or

Cyclopentyl which is substituted at the 3-position by a radical R⁶Is substituted in which

R⁶Represents 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3-methyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or 2-oxo-3-methyl-hexahydropyrimidin-1-yl,

cyclohexyl which is substituted in the 3-or 4-position by a radical R⁴-N-R⁵Is substituted in which R⁴And R⁵The definitions of (A) and (B) are as above,

cyclohexyl which may be in the 3-or 4-positionIs substituted by a group R⁶Is substituted in which R⁶The definition of (A) is as defined above,

pyrrolidin-3-yl radical which is substituted in the 1-position by a radical R⁵Is substituted in which R⁵The definition of (A) is as defined above,

piperidin-3-yl which is substituted in position 1 by a radical R⁵Is substituted in which R⁵The definition of (A) is as defined above,

piperidin-4-yl which is substituted in position 1 by a radical R⁵Is substituted in which R⁵The definition of (A) is as defined above,

tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl,

R^drepresents a hydrogen atom, and is represented by,

C_1-3-an alkoxy group,

methoxy substituted by one to three fluorine atoms,

At the 2-position by a group R⁶Or R⁷Substituted ethoxy, wherein R⁶Is as defined above, and

R⁷represents hydroxy, C_1-3-alkyloxy, amino, C_1-3Alkylamino, di- (C)_1-3-alkyl) amino, bis- (2-methoxyethyl) -amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl, 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl, 8-oxa-3-aza-bicyclo [3, 2.1]]Oct-3-yl, piperazin-1-yl or 4-C_1-3-alkyl-piperazin-1-yl, or

Formylamino group, C_1-4-alkylcarbonylamino, C_1-3-alkyloxy-C_1-3-alkylcarbonylamino, C_1-4-alkyloxycarbonylamino, aminocarbonylamino, C_1-3-alkylaminocarbonylamino, di- (C)_1-3-alkyl) aminocarbonylamino, pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, 4-C_1-3-alkyl-Piperazin-1-ylcarbonylamino, morpholin-4-ylcarbonylamino or C_1-4-an alkylsulfonylamino group,

at the 3-position by a group R⁶Or R⁷Substituted propoxy groups wherein R⁶And R⁷Is as defined above, or

At the 4-position by a group R⁶Or R⁷Substituted butoxy wherein R⁶And R⁷The definition of (A) is as defined above,

x represents a nitrogen atom, and X represents a nitrogen atom,

wherein, unless otherwise stated, the above alkyl groups are straight or branched,

its tautomers, its stereoisomers, its mixtures and its salts.

The most preferred compounds of the above formula I are

R^aRepresents a hydrogen atom

R^bRepresents 3-ethynylphenyl, 3-bromophenyl, 3, 4-difluorophenyl or 3-chloro-4-fluoro-phenyl,

3-chloro-4-benzyloxy-phenyl, 3-chloro-4- [ (3-fluoro-benzyl) oxy ] -phenyl, 4- (pyridin-3-yloxy) -phenyl, 4- [ (6-methyl-pyridin-3-yl) oxy ] -phenyl, 3-methyl-4- (pyridin-3-yloxy) -phenyl, 3-methyl-4- [ (6-methyl-pyridin-3-yl) oxy ] -phenyl, 3-chloro-4- (pyridin-3-yloxy) -phenyl, or 3-chloro-4- [ (6-methyl-pyridin-3-yl) oxy ] -phenyl,

R^crepresents a radical R in the 3-position or in the 4-position⁴-N-R⁵A substituted cyclohexyl radical, wherein

R⁴Represents a hydrogen atom, a methyl group or an ethyl group, and

R⁵represents 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 piperazin-1-ylcarbonylmethyl group, a 4-Methylpiperazin-1-ylcarbonylmethyl, morpholin-4-ylcarbonylmethyl, 2- (morpholin-4-yl-carbonyl) ethyl or 3- (morpholin-4-yl-carbonyl) propyl,

ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (butoxycarbonylamino) -ethyl, 2-aminoethyl, 3-aminopropyl, 2- (acetylamino) ethyl, 3- (acetylamino) propyl, 2- (ethylcarbonylamino) ethyl, 3- (ethylcarbonylamino) propyl, 2- (propylcarbonylamino) ethyl, 3- (propylcarbonylamino) propyl, 2- (ethylaminocarbonylamino) ethyl, 3- (ethylaminocarbonylamino) propyl, 2- (dimethylaminocarbonylamino) ethyl, 3- (dimethylaminocarbonylamino) propyl, 2- (morpholin-4-ylcarbonylamino) ethyl, methyl-ethyl, ethyl-propyl, propyl-ethyl, propyl-propyl, propyl-ethyl-amino, propyl-ethyl-carbonylamino, propyl-ethyl, propyl-amino, propyl-ethyl, propyl, 3- (morpholin-4-ylcarbonylaminopropyl), 2- (methylsulfonyl) ethyl, 3- (methylsulfonyl) propyl, 2- (methylsulfonylamino) ethyl or 3- (methylsulfonylamino) propyl,

2- (2-oxo-pyrrolidin-1-yl) -ethyl, 2- (2-oxopiperidin-1-yl) ethyl, 2- (3-oxo-morpholin-4-yl) ethyl, 2- (2-oxo-imidazolidin-1-yl) ethyl, 2- (2-oxo-3-methyl-imidazolidin-1-yl) ethyl, 2- (2-oxo-hexahydropyrimidin-1-yl) ethyl or 2- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) ethyl,

3- (2-oxo-pyrrolidin-1-yl) propyl, 3- (2-oxopiperidin-1-yl) propyl, 3- (3-oxo-morpholin-4-yl) propyl, 3- (2-oxo-imidazolidin-1-yl) propyl, 3- (2-oxo-3-methyl-imidazolidin-1-yl) propyl, 3- (2-oxo-hexahydropyrimidin-1-yl) propyl or 3- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) propyl,

methylsulfonyl, ethylsulfonyl, 3-chloropropylsulfonyl, 2- (morpholin-4-yl) -ethylsulfonyl or 3- (morpholin-4-yl) -propylsulfonyl,

a propyloxycarbonyl group or a butyloxycarbonyl group,

formyl, acetyl, ethylcarbonyl, propylcarbonyl, methoxyacetyl, (2-methoxyethyl) carbonyl, (3-methoxypropyl) carbonyl, tetrahydrofuran-2-ylcarbonyl, tetrahydropyran-4-ylcarbonyl, aminoacetyl, methylaminoacetyl, dimethylaminoacetyl, morpholin-4-ylacetyl, [2- (morpholin-4-yl) ethyl ] carbonyl, [3- (morpholin-4-yl) propyl ] carbonyl or methylsulfonylacetyl,

cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, (2-methoxyethyl) aminocarbonyl, N-methyl-N- (2-methoxyethyl) aminocarbonyl, (3-methoxypropyl) aminocarbonyl, N-methyl-N- (3-methoxypropyl) -aminocarbonyl, phenylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 2-methylmorpholin-4-ylcarbonyl, 2, 6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-ylcarbonyl, di-ethylaminocarbonyl, N-methyl-N- (3-methoxypropyl) -aminocarbonyl, N-methyl-N- (4-methoxypropyl) -aminocarbonyl, p-henylaminocarbonyl, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-ylcarbonyl, 8-oxa-3-aza-bicyclo [3.2.1] oct-3-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl,

cyclohexyl which is substituted in the 3-or 4-position by a radical R⁶Is substituted in which

R⁶Represents 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3-methyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or 2-oxo-3-methylhexahydropyrimidin-1-yl,

pyrrolidin-3-yl radical which is substituted in the 1-position by a radical R⁵Is substituted in which R⁵The definition of (A) is as defined above,

piperidin-3-yl which is substituted in position 1 by a radical R⁵Is substituted in which R⁵The definition of (A) is as defined above,

piperidin-4-yl which is substituted in position 1 by a radical R⁵Is substituted in which R⁵The definition of (A) is as defined above,

tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl,

R^drepresents a hydrogen atom, and is represented by,

a methoxy group, a difluoromethoxy group or an ethyloxy group,

ethoxy by a radical R in the 2-position⁶Or R⁷Is substituted in which R⁶The definition of (A) is as defined above,

R⁷represents hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis- (2-methoxyethyl) -amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl, 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl, 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl, piperazin-1-yl, 4-methylpiperazin-1-yl or 4-ethyl-piperazin-1-yl, or

Acetylamino, ethylcarbonylamino, propylcarbonylamino, butylcarbonylamino, methoxyacetylamino, butoxycarbonylamino, ethylaminocarbonylamino, dimethylaminocarbonylamino, pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino, morpholin-4-ylcarbonylamino, methylsulfonylamino, ethylsulfonylamino or butylsulfonylamino,

at the 3-position by a group R⁶Or R⁷Substituted propoxy groups wherein R⁶And R⁷Is as defined above, or

At the 4-position by a group R⁶Or R⁷Substituted butoxy wherein R⁶And R⁷Is as defined above, and

x represents a nitrogen atom, and X represents a nitrogen atom,

and, unless otherwise specified, the above alkyl groups are straight or branched,

its tautomers, its stereoisomers, its mixtures and its salts.

The most preferred compounds of the formula I are

R^aRepresents a hydrogen atomIn the case of a hybrid vehicle,

R^brepresents 3-bromophenyl, 3, 4-difluorophenyl, 3-chloro-4-fluoro-phenyl or 3-ethynylphenyl, or 3-chloro-4-benzyloxy-phenyl, 3-chloro-4- [ (3-fluorobenzyl) oxy]-phenyl, 4- (pyridin-3-yloxy) -phenyl, 4- [ (6-methyl-pyridin-3-yl) oxy]-phenyl, 3-methyl-4- (pyridin-3-yloxy) -phenyl, 3-methyl-4- [ (6-methyl-pyridin-3-yl) oxy]-phenyl, 3-chloro-4- (pyridin-3-yloxy) -phenyl or 3-chloro-4- [ (6-methyl-pyridin-3-yl) oxy]-a phenyl group,

R^crepresents cyclohexyl which is substituted in the 3-position by amino, acetylamino, tert-butyloxycarbonylamino or methylsulfonylamino,

cyclohexyl substituted at the 4-position with amino, methylamino, ethylamino, dimethylamino, aminocarbonylmethylamino, methylaminocarbonylmethylamino, dimethylaminocarbonylmethylamino, morpholin-4-ylcarbonylmethylamino, [3- (morpholin-4-ylcarbonyl) propyl ] amino, [2- (methylsulfonyl) ethyl ] amino, [3- (methylsulfonyl) propyl ] amino or [2- (methylsulfonylamino) ethyl ] amino,

cyclohexyl substituted at the 4-position with [2- (2-oxo-pyrrolidin-1-yl) ethyl ] amino, [2- (2-oxopiperidin-1-yl) ethyl ] amino, [2- (2-oxo-imidazolidin-1-yl) ethyl ] amino, [2- (2-oxo-3-methyl-imidazolidin-1-yl) ethyl ] amino, [2- (2-oxo-hexahydropyrimidin-1-yl) ethyl ] amino or [2- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) ethyl ] amino,

cyclohexyl substituted at the 4-position with [3- (2-oxo-pyrrolidin-1-yl) propyl ] amino, [3- (2-oxopiperidin-1-yl) propyl ] amino, [3- (2-oxo-imidazolidin-1-yl) propyl ] amino, [3- (2-oxo-3-methyl-imidazolidin-1-yl) propyl ] amino, [3- (2-oxo-hexahydropyrimidin-1-yl) propyl ] amino or [3- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) propyl ] amino,

cyclohexyl which is substituted in the 4-position with acetylamino, N- (acetyl) -methylamino, aminomethylcarbonylamino, methylaminomethylcarbonylamino, dimethylaminomethylcarbonylamino, morpholin-4-ylmethylcarbonylamino, methoxyacetylamino, N- (methoxyacetyl) -methylamino, tetrahydropyran-4-ylcarbonylamino, N- (tetrahydropyran-4-ylcarbonyl) -methylamino, tert-butyloxycarbonylamino, N- (tert-butyloxycarbonyl) -methylamino, aminocarbonylamino, methylaminocarbonylamino, N- (ethylaminocarbonyl) -methylamino, dimethylaminocarbonylamino, N- (dimethylaminocarbonyl) -methylamino, N- (piperidin-1-ylcarbonyl) -methylamino, methyl amino, N- (N-tert-butyloxycarbonyl) -methylamino, N- (methylaminocarbonyl) -methylamino, N- (dimethylaminocarbonyl) -methylamino, N- (piperidin-1-ylcarbonyl) -methylamino, methyl amino, N- (N-, Morpholin-4-ylcarbonylamino, N- (morpholin-4-ylcarbonyl) -methylamino or N- (4-methylpiperazin-1-ylcarbonyl) -methylamino,

cyclohexyl which is substituted in the 4-position by 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3-methyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or 2-oxo-3-methyl-hexahydropyrimidin-1-yl,

cyclohexyl substituted at the 4-position with methylsulfonylamino, N- (methylsulfonyl) methylamino, ethylsulfonylamino, N- (ethylsulfonyl) -methylamino, dimethylaminosulfonylamino, N- (dimethylaminosulfonyl) -methylamino, morpholin-4-ylsulfonylamino, N- (morpholin-4-ylsulfonyl) -methylamino, 3-chloropropylsulfonylamino, [2- (morpholin-4-yl) -ethyl ] sulfonylamino or [3- (morpholin-4-yl) -propyl ] sulfonylamino,

a pyrrolidin-3-yl group which is,

pyrrolidin-3-yl substituted at the 1-position with methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl,

a piperidin-3-yl group, a pharmaceutically acceptable salt thereof,

piperidin-3-yl substituted at the 1-position with methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl,

piperidin-4-yl which is substituted at the 1-position with methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulfonyl) ethyl, 3- (methylsulfonyl) -propyl, 2- (tert-butyloxycarbonylamino) -ethyl, 2-aminoethyl, 2- (acetylamino) -ethyl, 2- (ethylcarbonylamino) -ethyl, 2- (propylcarbonylamino) -ethyl, 2- (ethylaminocarbonylamino) -ethyl, 2- (dimethylaminocarbonylamino) -ethyl, 2- (morpholin-4-ylcarbonylamino) -ethyl, 3- (acetylamino) -propyl, methyl, ethyl, propyl, isopropyl, 2- (tert-butyloxycarbonylamino) -ethyl, 2-aminoethyl, 2- (acetylamino) -ethyl, 2- (propylcarbonylamino) -ethyl, 2- (ethylcarbonylamino) -ethyl, 2- (, 3- (ethylcarbonylamino) -propyl, 3- (propylcarbonylamino) -propyl, 3- (ethylaminocarbonylamino) -propyl, 3- (dimethylaminocarbonylamino) -propyl, 3- (morpholin-4-ylcarbonylamino) -propyl, 2- (methylsulfonylamino) -ethyl, 3- (methylsulfonylamino) -propyl, (aminocarbonyl) methyl, (methylaminocarbonyl) methyl, (dimethylaminocarbonyl) methyl, (pyrrolidin-1-ylcarbonyl) methyl, (morpholin-4-ylcarbonyl) methyl, 2- (morpholin-4-ylcarbonyl) ethyl or 3- (morpholin-4-ylcarbonyl) -propyl,

piperidin-4-yl substituted at the 1-position with 2- (2-oxo-pyrrolidin-1-yl) -ethyl, 2- (2-oxopiperidin-1-yl) -ethyl, 2- (3-oxomorpholin-4-yl) -ethyl, 2- (2-oxo-imidazolidin-1-yl) -ethyl, 2- (2-oxo-3-methyl-imidazolidin-1-yl) -ethyl, 2- (2-oxo-hexahydropyrimidin-1-yl) -ethyl or 2- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) -ethyl,

piperidin-4-yl substituted at the 1-position with 3- (2-oxo-pyrrolidin-1-yl) -propyl, 3- (2-oxopiperidin-1-yl) -propyl, 3- (3-oxomorpholin-4-yl) -propyl, 3- (2-oxo-imidazolidin-1-yl) -propyl, 3- (2-oxo-3-methyl-imidazolidin-1-yl) -propyl, 3- (2-oxo-hexahydropyrimidin-1-yl) -propyl or 3- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) -propyl,

piperidin-4-yl substituted at the 1-position with formyl, acetyl, methoxyacetyl, (2-methoxyethyl) carbonyl, (3-methoxypropyl) carbonyl, methylsulfonylacetyl, aminoacetyl, methylaminoacetyl, (dimethylamino) acetyl, (morpholin-4-yl) acetyl, [2- (morpholin-4-yl) -ethyl ] carbonyl, [3- (morpholin-4-yl) propyl ] carbonyl, tetrahydrofuran-2-ylcarbonyl or tetrahydropyran-4-ylcarbonyl,

piperidin-4-yl which is substituted at the 1-position with cyano, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, (2-methoxyethyl) aminocarbonyl, N-methyl-N- (2-methoxyethyl) -aminocarbonyl, (3-methoxypropyl) aminocarbonyl, N-methyl-N- (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, aminocarbonyl, methyl-aminocarbonyl, N-methyl-N- (3-methoxypropyl), 2-oxa-5-aza-bicyclo [2.2.1] hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-ylcarbonyl, 8-oxa-3-aza-bicyclo [3.2.1] oct-3-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, isopropyloxycarbonyl or tert-butyloxycarbonyl,

piperidin-4-yl substituted at the 1-position with methylsulfonyl, ethylsulfonyl, [2- (morpholin-4-yl) -ethyl ] sulfonyl, [3- (morpholin-4-yl) -propyl ] sulfonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl, or

Tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl,

R^drepresents a hydrogen atom, and is represented by,

a methoxy group, a difluoromethoxy group or an ethyloxy group,

2- (morpholin-4-yl) ethyloxy, 3- (morpholin-4-yl) propyloxy or 4- (morpholin-4-yl) butyloxy, 3- (dimethylamino) propyloxy, 3- (diethylamino) propyloxy, 3- [ bis- (2-methoxyethyl) -amino ] propyloxy, 3- (piperazin-1-yl) propyloxy, 3- (4-methylpiperazin-1-yl) propyloxy or 3- (4-ethylpiperazin-1-yl) propyloxy,

3- (homomorpholin-4-yl) -propyloxy, 3- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -propyloxy, 3- (3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl) -propyloxy or 3- (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -propyloxy,

2- (2-oxo-pyrrolidin-1-yl) -ethyloxy, 2- (2-oxopiperidin-1-yl) -ethyloxy, 2- (3-oxomorpholin-4-yl) -ethyloxy, 2- (2-oxo-imidazolidin-1-yl) -ethyloxy, 2- (2-oxo-3-methyl-imidazolidin-1-yl) -ethyloxy, 2- (2-oxo-hexahydropyrimidin-1-yl) -ethyloxy or 2- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) -ethyloxy,

3- (2-oxo-pyrrolidin-1-yl) -propyloxy, 3- (2-oxopiperidin-1-yl) -propyloxy, 3- (3-oxomorpholin-4-yl) -propyloxy, 3- (2-oxo-imidazolidin-1-yl) -propyloxy, 3- (2-oxo-3-methyl-imidazolidin-1-yl) -propyloxy, 3- (2-oxo-hexahydropyrimidin-1-yl) -propyloxy or 3- (2-oxo-3-methyl-hexahydropyrimidin-1-yl) -propyloxy,

2- (methoxy) -ethyloxy, 2- (tert-butyloxycarbonylamino) -ethyloxy, 2- (amino) -ethyloxy, 2- (acetylamino) -ethyloxy, 2- (ethylcarbonylamino) -ethyloxy, 2- (propylcarbonylamino) -ethyloxy, 2- (isobutylcarbonylamino) -ethyloxy, 2- (methoxyacetylamino) -ethyloxy, 2- (ethylaminocarbonylamino) -ethyloxy, 2- (dimethylaminocarbonylamino) -ethyloxy, 2- (pyrrolidin-1-ylcarbonylamino) -ethyloxy, 2- (piperidin-1-ylcarbonylamino) -ethyloxy, 2- (morpholin-4-ylcarbonylamino) -ethyloxy, 2- (methylsulfonylamino) -ethyloxy, 2- (ethylsulfonylamino) -ethyloxy or 2- (butylsulfonylamino) -ethyloxy, or

3- (tert-butyloxycarbonylamino) -propyloxy, 3- (amino) -propyloxy, 3- (acetylamino) -propyloxy or 3- (methylsulfonylamino) -propyloxy,

and is

X represents a nitrogen atom, and X represents a nitrogen atom,

its tautomers, its stereoisomers, its mixtures and its salts.

The most preferred compounds of the formula I are

R^aRepresents a hydrogen atom,

R^bPreferably represents 3-chloro-4-fluoro-phenyl or 3-ethynylphenyl,

R^crepresents cyclohexyl which is substituted in the 3-position by amino, acetylamino, tert-butyloxycarbonylamino or methylsulfonylamino,

cyclohexyl substituted at the 4-position with amino, methylamino, dimethylamino, acetylamino, N- (acetyl) -methylamino, methoxyacetylamino, N- (methoxyacetyl) -methylamino, tetrahydropyran-4-ylcarbonylamino, N- (tetrahydropyran-4-ylcarbonyl) -methylamino, tert-butyloxycarbonylamino, N- (tert-butyloxycarbonyl) -methylamino, N- (ethylaminocarbonyl) -methylamino, dimethylaminocarbonylamino, N- (dimethylaminocarbonyl) -methylamino, N- (piperidin-1-ylcarbonyl) -methylamino, morpholin-4-ylcarbonylamino, N- (morpholin-4-ylcarbonyl) -methylamino, N, N- (4-methylpiperazin-1-ylcarbonyl) -methylamino, methylsulfonylamino, N- (methylsulfonyl) -methylamino, ethylsulfonylamino, N- (ethylsulfonyl) -methylamino, dimethylaminosulfonylamino, N- (dimethylaminosulfonyl) -methylamino, morpholin-4-ylsulfonylamino, N- (morpholin-4-ylsulfonyl) -methylamino, 3-chloropropylsulfonylamino or [3- (morpholin-4-yl) -propyl ] sulfonylamino,

a pyrrolidin-3-yl group which is,

pyrrolidin-3-yl substituted at the 1-position with tert-butyloxycarbonyl or methylsulfonyl,

a piperidin-3-yl group, a pharmaceutically acceptable salt thereof,

piperidin-3-yl substituted at the 1-position with tert-butylcarbonyl or methylsulfonyl,

a piperidin-4-yl group, a pharmaceutically acceptable salt thereof,

piperidin-4-yl which is substituted at the 1-position with methyl, (aminocarbonyl) methyl, (dimethylaminocarbonyl) methyl, (morpholin-4-ylcarbonyl) methyl, 2- (tert-butyloxycarbonylamino) ethyl, 2-aminoethyl, 2- (acetylamino) ethyl, 2- (methylsulfonylamino) ethyl, cyano, acetyl, methoxyacetyl, (dimethylamino) acetyl, (morpholin-4-yl) acetyl, tetrahydropyran-4-ylcarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 2-methylmorpholin-4-ylcarbonyl, methyl-4-methyl-morpholin-4-ylcarbonyl, methyl-4-methyl-sulfonylamino-ethyl, 2, 6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, methylsulfonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl, or

Tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl,

R^drepresents a hydrogen atom, and is represented by,

a methoxy group or an ethyl-oxy group,

2- (morpholin-4-yl) ethyloxy, 3- (morpholin-4-yl) propyloxy or 4- (morpholin-4-yl) butyloxy, 2- (3-methyl-2-oxo-hexahydropyrimidin-1-yl) -ethyloxy,

2- (methoxy) -ethyloxy, 2- (tert-butyloxycarbonylamino) -ethyloxy, 2-amino-ethyloxy, 2- (acetylamino) -ethyloxy or 2- (methylsulfonylamino) -ethyloxy, or

3- (tert-butyloxycarbonylamino) -propyloxy, 3-amino-propyloxy, 3- (acetylamino) -propyloxy or 3- (methylsulfonylamino) -propyloxy,

and is

X represents a nitrogen atom, and X represents a nitrogen atom,

its tautomers, its stereoisomers, its mixtures and its salts.

Bicyclic heterocyclic radicals of the above-mentioned formula I, and the subunits designated as preferred, particularly preferred, most preferred and particularly preferred, are particularly preferred for the compounds in which

(a)R^cRepresents a cyclohexyl group substituted in the 4 position,

(b)R^crepresents pyrrolidin-3-yl optionally substituted in position 1,

(c)R^crepresents piperidin-3-yl optionally substituted in position 1,

(d)R^crepresents piperidin-4-yl optionally substituted in position 1,

(e)R^crepresents a tetrahydrofuran-3-yl group, or a salt thereof,

(f)R^crepresents tetrahydropyran-3-yl, or

(g)R^cRepresents a tetrahydropyran-4-yl group,

wherein R is^a、R^b、R^dAnd X is as defined above in each case.

The following are mentioned as the best compounds of the formula I

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) tetrahydrofuran-3-yloxy) -7-methoxy-quinazoline

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline

(3)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((R) tetrahydrofuran-3-yloxy) -7-methoxy-quinazoline

(4)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

(5)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

(6)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline

(7)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

(8)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { [3- (morpholin-4-yl) -propyl ] sulfonylamino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

(9)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline

(10)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4- { [3- (morpholin-4-yl) -propyl ] sulfonylamino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

(11)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline

(12)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

(13)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (methoxymethyl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

(14)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline

(15)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) sulfonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

(16)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline

(17)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (dimethylamino) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

(18)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

(19)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholin-4-yl) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

(20)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline

(21)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylaminoethoxy) -quinazoline, and

(22)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline,

and salts thereof.

The compounds of the general formula I can be prepared, for example, in the following manner:

(a) reacting a compound of the formula with a compound of the formula (III)

In the formula (II)

R^a、R^b、R^dAnd X are as defined above, and the definition of X,

Z¹-R^c (III)

in the formula (III)

R^cIs as defined above, and Z¹Represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulfonyloxy group such as a methanesulfonyloxy group, or a p-toluenesulfonyloxy group or a hydroxyl group.

To the Z in¹Compounds of the formula III which represent hydroxy groups, in the presence of dehydrating agents, preferably phosphines and azodicarboxylic acid derivatives such as triphenylphosphine/diethyl azodicarboxylate, are suitableIn a solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dioxane, toluene or ethylene glycol diethyl ether at a temperature of-50 ℃ to 150 ℃, preferably at a temperature of-20 ℃ to 80 ℃.

(b) To prepare wherein R^dA compound of formula I representing one of the optionally substituted alkyloxy groups described hereinbefore:

reacting a compound of the formula

(wherein R is^a、R^b、R^cAnd X is as defined above) with a compound of the following general formula (V)

Z²-R^d′(V)

Wherein R is^d' represents C_1-4Alkyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, by the radical R⁶Or R⁷(wherein R is⁶And R⁷Radical as defined above) substituted C_2-4-alkyl, substituted in the 1-position by R⁸C substituted by pyrrolidinyl, piperidinyl or homopiperidinyl groups_1-4-alkyl, or by R in the 4 position⁸C substituted by morpholinyl_1-4Alkyl, where in each case a radical R⁸Is as defined above, and

Z²represents a leaving group such as a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group or a hydroxyl group.

If the leaving group is a halogen atom, such as a chlorine, bromine or iodine atom, or an alkylsulfonyloxy or arylsulfonyloxy group, such as a methylsulfonyloxy or p-toluenesulfonyloxy group, the reaction is preferably carried out in the presence of an organic or inorganic base, such as potassium carbonate, sodium hydride or N-ethyl-diisopropylamine. If the leaving group is a hydroxyl group, the reaction is preferably carried out in the presence of a dehydrating agent, and preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine/diethyl azodicarboxylate.

(c) To prepare wherein R^dA compound of the general formula I which represents one of the abovementioned alkyloxy groups substituted by optionally substituted amino, alkylamino or dialkylamino groups or by an optionally substituted heterocyclic radical bonded via the imino nitrogen atom:

reacting a compound of the general formula with ammonia, a corresponding optionally substituted alkylamine, dialkylamine or imino compound or a suitable salt or derivative thereof, for example morpholine.

R in the formula (VI)^a、R^b、R^cAnd X are as defined above, Z³Represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, or a sulfonyloxy group such as a methanesulfonyloxy group or a p-toluenesulfonyloxy group,

(d) to prepare wherein R^dA compound of formula I representing hydroxy:

cleaving the protecting group from a compound of the formula

Wherein R is^a、R^b、R^cAnd X are as defined above, and R^d"represents a group convertible to a hydroxyl group, such as an optionally substituted benzyloxy, trimethylsilyloxy, acetyloxy, benzoyloxy, methoxy, ethoxy, tert-butoxy or trityloxy group.

The cleavage of the protecting group is carried out by hydrolysis in an aqueous solvent, e.g. 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 aprotic, e.g. in the presence of trimethyliodosilane, at a temperature of 0 to 120 ℃, preferably at a temperature of 10 to 100 ℃.

However, the cleavage of benzyl or methoxybenzyl is carried out, for example, by hydrogenolysis with hydrogen in the presence of a catalyst such as palladium on carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at an ambient temperature of between 0 and 100 ℃, preferably between 20 and 60 ℃, and a hydrogen pressure of between 1 and 7 bar, preferably between 3 and 5 bar. However, the 2, 4-dimethoxybenzyl group is preferably carried out in trifluoroacetic acid in the presence of anisole.

Cleavage of the tert-butyl or benzyl group is carried out, for example, by treatment with an acid, such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid, or with trimethyliodosilane, and optionally using a solvent, such as dichloromethane, dioxane, methanol or diethyl ether.

(e) To prepare wherein R^cA compound of formula I containing an-NH-group:

cleaving the protecting group from a compound of the formula

Wherein R is^a、R^b、R^cAnd X are as defined above, and R^cThe meaning of' is the same as R mentioned above^cSame, with the proviso that R^cContaining a protected nitrogen atom.

Customary protecting groups for amino, alkylamino or imino are, for example, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2, 4-dimethoxybenzyl, but in the case of amino, furthermore phthaloyl is possible.

The cleavage of the protecting group is carried out by hydrolysis in an aqueous solvent, for example 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 aprotic, such as trimethyliodosilane, at a temperature of 0 to 120 ℃, preferably at a temperature of 10 to 100 ℃.

However, the cleavage of benzyl, methoxybenzyl or benzyloxycarbonyl is carried out, for example, by hydrogenolysis with hydrogen in the presence of a catalyst such as palladium on carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at an ambient temperature of between 0 and 100 ℃ but preferably between 20 and 60 ℃ and a hydrogen pressure of between 1 and 7 bar, preferably between 3 and 5 bar. However, the 2, 4-dimethoxybenzyl group is preferably carried out in trifluoroacetic acid in the presence of anisole.

Cleavage of the tert-butyl or tert-butyloxycarbonyl group is preferably carried out, for example, by treatment with an acid, such as trifluoroacetic acid or hydrochloric acid, or with trimethyliodosilane, and optionally using a solvent, such as dichloromethane, dioxane, methanol or diethyl ether.

The cleavage of the trifluoroacetyl group is preferably carried out by treatment with an acid, such as hydrochloric acid, optionally in the presence of a solvent, such as acetic acid, at a temperature of between 50 and 120 ℃ or by treatment with a sodium hydroxide solution, optionally in the presence of a solvent, such as tetrahydrofuran, at a temperature of between 0 and 50 ℃.

The cleavage of the phthaloyl group is preferably carried out 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 temperatures of from 20 to 50 ℃. (f) To prepare R therein^cCompounds of the general formula I containing alkyl substituted by optionally substituted amino, alkylamino or dialkylamino or by optionally substituted heterocyclyl bound via a nitrogen atom:

reacting a compound of the general formula with ammonia, a corresponding optionally substituted alkylamine, dialkylamine or imino compound or a suitable salt or derivative thereof, for example morpholine.

R in the formula (IX)^a、R^b、R^cAnd X are as defined above, Z³Represents a leaving group such as a halogen atom, e.g. a chlorine or bromine atom, or a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group, and R^c"has the meaning of R mentioned above^cProvided that the hydrogen atom bonded to the aliphatic carbon is Z³And (4) substituting the group.

According to the invention, the compounds of the formula I are amino-, alkylamino-or imino-containing compounds which can be converted by means of an activator such as N, N '-carbonyldiimidazole, N, N' -dicyclohexylcarbonyldiimine or O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium-tetrafluoroborate, by acylation, cyanation or sulfonylation into the corresponding acyl, cyano or sulfonyl compounds of the formula I, such as isocyanates, carbamoyl chlorides, carboxylic acid halides, carboxylic acid anhydrides and carboxylic acids as acylating agents, sulfonyl halides and cyanogen chloride or bromide as cyanating agents, and/or

If the compounds of the formula I contain amino, alkylamino or imino groups, they can be converted into the corresponding alkyl compounds of the formula I by alkylation or reductive alkylation and/or

If the compounds of the formula I contain chlorine-C_1-4-alkylsulfonyl or bromo-C_1-4An alkylsulfonyl group, which can be converted into the corresponding amino-C by reaction with an amine_1-4-an alkylsulfonyl compound, and/or

If the compounds of the formula I contain tert-butyloxycarbonylamino, N-alkyl-N- (tert-butyloxycarbonyl) amino or N-tert-butyloxycarbonylimino, they can be converted into the corresponding amino, alkylamino or imino compounds of the formula I by treatment with an acid, such as hydrochloric acid or trifluoroacetic acid.

In the preceding reactions, any reactive groups present, such as hydroxyl, amino, alkylamino or imino, can, if desired, be protected during the reaction with customary protecting groups and cleaved after the reaction.

For example, the protecting group for a hydroxyl group may be a trimethylsilyl group, an acetyl group, a trityl group, a benzyl group or a tetrahydropyranyl group.

As the protecting group of the amino group, alkylamino group or imino group, there may be mentioned, for example, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2, 4-dimethoxybenzyl group.

Any protecting group used is optionally cleavable, 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, hydrochloric acid or sulfuric acid, or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, or aprotic, e.g., trimethyliodosilane, at a temperature of 0 to 120 ℃, preferably at a temperature of 10 to 100 ℃.

However, benzyl, methoxybenzyl or benzyloxycarbonyl is cleaved by hydrogenolysis with hydrogen, for example in the presence of a catalyst such as palladium on carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at a temperature of between 0 and 100 ℃, preferably at an ambient temperature of between 20 and 60 ℃ and a hydrogen pressure of between 1 and 7 bar, preferably between 3 and 5 bar. However, the 2, 4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.

The tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved by treatment, for example, with an acid, such as trifluoroacetic acid or hydrochloric acid, or with trimethyliodosilane, and optionally using a solvent, such as dichloromethane, dioxane, methanol or diethyl ether.

The cleavage of the trifluoroacetyl group is preferably carried out by treatment with an acid, such as hydrochloric acid, optionally in a solvent, such as acetic acid, at a temperature between 50 and 120 ℃ or by treatment with a sodium hydroxide solution, optionally in the presence of a solvent, such as tetrahydrofuran or methanol, at a temperature between 0 and 50 ℃.

Furthermore, the resulting compounds of the general formula I can be resolved into their enantiomers and/or diastereomers as already described. Thus, for example, cis/trans mixtures can be separated into their cis and trans isomers, and compounds having at least one optically active carbon atom can be separated into their enantiomers.

Thus, for example, the resulting cis/trans mixture can be separated into its cis and trans isomers by chromatography, the resulting compounds of the formula I present as racemates can be separated into their optical enantiomers by known methods (for example Allinger N.L. and Eliel E.L.in "Topics in stereoschemistry", Vol.6, Wiley Interscience, 1971) and the compounds of the formula I having at least 2 diastereomeric carbon atoms can be separated into their diastereomers on the basis of their physico-chemical differences by known methods, for example by chromatography and/or partial crystallization, and subsequently resolved into the abovementioned enantiomers if these compounds are prepared in racemic form.

The enantiomeric separations are preferably carried out by column separation on a chiral phase or recrystallization from optically active solvents or by reaction with an optically active substance formed with a racemic compound salt or derivative, such as an ester or amide, especially an acid and its active derivative or its alcohol, and, depending on the difference in solubility, the diastereoisomeric mixture of the salt or derivative thus obtained is separated, while the free enantiomer can be liberated from the pure, diastereoisomeric salt or derivative by action of suitable preparations. The optically active acids generally used are, for example, tartaric acid or dibenzyltartaric acid in the D-or L-form, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid, or quinic acid. The optically active alcohol may be, for example, an optically active acyl group in (+) or (-) -alcohols and amides, and may be, for example, (+) -or (-) -oxycarbonyl.

In addition, the compounds of the formula I can be converted into their salts, in particular for pharmaceutical use and inorganic or organic acids into physiologically acceptable salts. Examples of acids which may be mentioned are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The compounds of the formulae II to IX used as starting materials are partly obtainable from the literature or can be prepared by methods known from the literature (e.g.examples I to XXII) or the methods mentioned above, and optionally protective groups (e.g.compounds of the formulae IV or VII and VIII) can additionally be used.

As already mentioned above, the compounds of the general formula I according to the invention and their physiologically acceptable salts have valuable pharmaceutical properties, in particular an inhibitory effect on the signal transduction via the Epidermal Growth Factor receptor (EGF-R), which can be achieved, for example, by inhibiting ligand binding, receptor dimerization or tyrosine kinase itself. The transmission of signals to the underlying components may also be blocked.

The biological properties of the novel compounds were investigated as follows:

inhibition of human EGF-receptor kinase was determined using the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186, successively published according to Nature309(1984), 418). Therefore, this protein was expressed in Sf9 insect cells as a GST fusion protein using a Baculovirus (baculovir) expression system.

Enzyme activity is measured in the presence or absence of serial dilutions of the test compound. Polymer pEY (4: 1) from SIGMA was used as the substrate. Biotinylated pEY (bio-pEY) was added as tracer. 100 microliters of reaction solution contained 10 microliters of a 50% DMSO solution of inhibitor, 20 microliters of a matrix solution (200mM HEPES pH7.4, 50mM magnesium acetate, 2.5 mg/ml poly (EY), 5 micrograms/ml bio-pEY), and 20 microliters of enzyme preparation. The enzymatic reaction was started by dissolving 50. mu.l of 100. mu. MATP in 10mM magnesium chloride. The dilution of the enzyme preparation was adjusted so that the phosphate added in bio-pEY was linearized with respect to time and amount of enzyme. The enzyme preparation was diluted in 20mM HEPES pH7.4, 1mM EDTA, 130mM salt, 0.05% Triton X-100, 1mM DTT and 10% glycerol.

The enzyme assay was performed at ambient temperature over 30 minutes and was stopped by the addition of 50. mu.l of stop solution (250 mM EDTA in 20mM HEPES pH7.4). 100 microliters were placed on a streptavidin-coated microtiter plate and incubated at ambient temperature for 60 minutes. The plate was washed with 200. mu.l of a washing solution (50mM Tris, 0.05% Tween 20). 100 microliters of HRPO-labeled Anti-PY antibody (PY20H Anti-PTyt: HRP manufactured by Transduction Laboratories, 250ng/ml) was added and the preparation was incubated for 60 minutes. The microtiter plate was then washed three times with 200 microliters of wash solution. The sample was then combined with 100 microliters of TMB-peroxidase solution (A: B1: 1, Kirkegaard Perry Laboratories). After 10 minutes, the reaction was terminated. At OD_450nmThe extinction was measured with an ELISA reader. All results were measured in triplicate.

Data were calculated iteratively by using the analysis program of a sigmoidal curve (Graph Pad prism version 3.0) with variable Hill intervals (Steigung). The correction factor for all the replicates generated exceeded 0.9 and the upper and lower values of the curve showed a distribution factor of at least 5. At 50% (IC)₅₀) The concentration of active substance inhibiting the activity of the EGF receptor kinase is derived from the curve.

The following results were obtained:

compound (example No.)	Inhibition of EGF-receptor kinase IC[nM]
		1	0.13
1(1)	0.12
		1(2)	2
1(3)	1.1
		1(4)	0.6
1(5)	0.6
		1(6)	0.69

Compound (example No.)	Inhibition of EGF-receptor kinase IC[nM]
		1(7)	1.6
2	4.5
		2(1)	0.16
2(2)	0.22
		3	0.9
3(1)	0.14
		3(2)	0.22
3(7)	0.7
		3(8)	0.6
3(9)	0.2
		3(11)	0.1
3(15)	1
		3(16)	1
3(17)	0.3
		3(18)	0.4
3(20)	1
		3(21)	0.4
4	0.41
		4(1)	0.16
7(5)	1

The compounds of general formula I according to the invention can therefore inhibit the transduction of signals by tyrosine kinases, as demonstrated in the examples of human EGF receptors, and can therefore be used for the treatment of pathophysiological processes which are caused by an excessive function of tyrosine kinases, these including, for example, benign or malignant tumors, in particular of epithelial and neuroepithelial origin, the metastasis of vascular endothelial cells (neovascularization) and abnormal hyperplasia.

The compounds of the present invention are also useful for the prevention and treatment of airway and pulmonary diseases caused by increased or altered mucus production due to tyrosine kinase stimulation, for example inflammatory diseases of the airways, such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic and non-allergic rhinitis or sinusitis, cystic fibrosis, alpha 1-antitrypsin deficiency or cough, emphysema, pulmonary fibrosis and hyper-reactive airways.

The compounds are also useful in the treatment of diseases of the gastrointestinal tract and bile ducts and gallbladder involving disruption of tyrosine kinase activity, such as seen in chronic inflammatory changes, e.g., cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract, or gastrointestinal diseases associated with increased endocrine secretion, such as Menetter's disease, tumors of secretory glands and protein loss.

In addition, the compounds of the general formula I and their physiologically acceptable salts can be used for the treatment of other diseases which are caused by abnormal functions of tyrosine kinases, such as epidermal hyperplasia (psoriasis), Benign Prostatic Hyperplasia (BPH), inflammatory processes, diseases of the immune system, proliferation of hematopoietic cells, treatment of nasal polyps, etc.

Based on their physiological properties, the compounds of the invention can therefore be used alone or in combination with other pharmaceutically active compounds, for example in tumor therapy, alone or in combination with other antitumor therapeutic agents, for example in combination with topoisomerase inhibitors, for example etoposide, mitotic inhibitors, for example vinblastine (vinblastine), compounds which interact with nucleic acids, for example cisplatin (platin), cyclophosphamide, adriamycin (adriamycin), hormone antagonists, for example tamoxifen, inhibitors of metabolic processes, for example 5-FU etc., cytokines, for example interferons, antibodies etc. For the treatment of respiratory diseases, these compounds can be used alone or in combination with other therapeutic agents for the airways, such as with secretory agents (e.g. ambroxol, N-acetylcysteine), bronchogenic agents (e.g. tiotropium or ipratropium or fenoterol), salmeterol, salbutamol or salbutamol and/or anti-inflammatory activity (e.g. theophylline or glucocorticoids).

These compounds can be administered by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal routes, alone or in combination with other active substances. By inhalation or transdermal or oral administration, whereas aerosol formulations are particularly suitable for administration by inhalation.

For pharmaceutical use, the compounds of the invention are generally administered to warm-blooded animals, especially humans, at a dose of 0.01 to 100 mg/kg body weight, preferably 0.1 to 15 mg/kg. For administration, they are also formulated with one or more customary inert carriers and/or diluents, for example corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances, such as hard fat, or suitable mixtures thereof, and in general formulations such as tablets or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.

Detailed description of the preferred embodiments

The following examples will illustrate the invention in detail, but do not limit it:

preparation of the starting compound:

example I

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (tetrahydropyran-4-yloxy) -7-benzyloxy-quinazoline-hydrochloride

A mixture of 10.84 g of 4-chloro-6- (tetrahydropyran-4-yloxy) -7-benzyloxy-quinazoline and 4.50 g of 3-chloro-4-fluoroaniline in 300 ml of isopropanol was heated under reflux for four hours, followed by standing at ambient temperature overnight. The precipitate formed was aspirated, washed with isopropanol and stirred with 150 ml of methanol. The suspension was stirred at ambient temperature for a further half an hour and then filtered with suction. The filter cake was washed repeatedly with methanol and dried.

Yield: 9.07 g (60% of theory).

R_fThe value: 0.29 (silica gel, cyclohexane/ethyl acetate 1: 1)

Mass spectrometry (ESI)^-)：m/z＝478，480[M-H]^-

The following compounds were prepared as in example I:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy) -7-benzyloxy-quinazoline-hydrochloride

R_fThe value: 0.34 (silica gel, cyclohexane/ethyl acetate 1: 1)

Mass spectrometry (ESI)⁺)：m/z＝466，468[M+H]⁺

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-trifluoroacetyl-piperidin-4-yloxy) -quinazoline-hydrochloride

R_fThe value: 0.17 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝469，471[M+H]⁺

(3)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-trifluoroacetyl-piperidin-4-yloxy) -7-acetoxy-quinazoline-hydrochloride

R_fThe value: 0.70 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝527，529[M+H]⁺

(4)4- [ (3-ethynyl-phenyl) amino ] -6-acetoxy-7-methoxy-quinazoline

R_fThe value: 0.59 (silica gel, ethyl acetate)

Mass spectrometry (ESI)⁺)：m/z＝334[M+H]⁺

Example II

4-chloro-6- (tetrahydropyran-4-yloxy) -7-benzyloxy-quinazoline

Prepared by reacting 6- (tetrahydropyran-4-yloxy) -7-benzyloxy-3H-quinazolin-4-one with thionyl chloride in acetonitrile in the presence of N, N-dimethylformamide at reflux temperature.

R_fThe value: 0.90 (silica gel, ethyl acetate/methanol ═ 9: 1)

The following compounds were prepared as in example II:

(1) 4-chloro-6- ((S) -tetrahydrofuran-3-yloxy) -7-benzyloxy-quinazoline

R_fThe value: 0.85 (silica gel, ethyl acetate/methanol ═ 9: 1)

(2) 4-chloro-6- (1-trifluoroacetyl-piperidin-4-yloxy) -quinazoline

R_fThe value: 0.92 (silica gel, ethyl acetate)

(3) 4-chloro-6- (1-trifluoroacetyl-piperidin-4-yloxy) -7-acetoxy-quinazoline

Example III

6- (tetrahydropyran-4-yloxy) -7-benzyloxy-3H-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 heated at reflux overnight. The cooled reaction mixture was combined with 250 ml of water. The precipitate formed is filtered off with suction and dried in a drying cabinet at 70 ℃.

Yield: 10.00 g (65% of theory).

R_fThe value: 0.40 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝353[M+H]⁺

The following compounds were prepared as in example III:

(1)6- ((S) -tetrahydrofuran-3-yloxy) -7-benzyloxy-3H-quinazolin-4-one

R_fThe value: 0.60 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝339[M+H]⁺

(2)6- [1- (tert-Butyloxycarbonyl) -piperidin-4-yloxy ] -3H-quinazolin-4-one

R_fThe value: 0.48 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝346[M+H]⁺

(3)6- [1- (tert-Butyloxycarbonyl) -piperidin-4-yloxy) -7-hydroxy-3H-quinazolin-4-one

R_fThe value: 0.35 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝362[M+H]⁺

Example IV

2-amino-4-benzyloxy-5- (tetrahydropyran-4-yloxy) -benzoic acid

16.40 g of 2-nitro-4-benzyloxy-5- (tetrahydropyran-4-yloxy) -benzoic acid are hydrogenated in the presence of 1.64 g of Raney nickel in 800 ml of methanol at 55 ℃ until the calculated amount of hydrogen is consumed. The catalyst is filtered off and the filtrate is evaporated, at which point the desired product crystallizes.

Yield: 15.08 g (100% of theory).

R_fThe value: 0.60 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

The following compounds were prepared as in example IV:

(1) 2-amino-4-benzyloxy-5- ((S) -tetrahydrofuran-3-yloxy) -benzyl benzoate

R_fThe value: 0.70 (silica gel, cyclohexane/ethyl acetate 1: 1)

Mass spectrometry (ESI)⁺)：m/z＝420[M+H]⁺

(2) 2-amino-5- [1- (tert-butoxycarbonyl) -piperidin-4-yloxy ] -benzoic acid

R_fThe value: 0.43 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝337[M+H]⁺

(3) 2-amino-4-hydroxy-5- [1- (tert-butoxycarbonyl) -piperidin-4-yloxy ] -benzoic acid

R_fThe value: 0.23 (silica gel, dichloromethane/methanol/acetic acid 90: 10: 1)

Example V

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

Prepared by saponification of 2-nitro-4-benzyloxy-5- (tetrahydropyran-4-yloxy) -benzyl benzoate with 1N sodium hydroxide solution in methanol at ambient temperature.

R_fThe value: 0.20 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝374[M+H]⁺

Example VI

2-Nitro-4-benzyloxy-5- (tetrahydropyran-4-yloxy) -benzyl benzoate

42.60 g of potassium tert-butoxide are added to 38 ml of tetrahydropyran-4-ol in 228 ml of N, N-dimethylformamide under ice-bath cooling, the mixture is stirred at ambient temperature for one hour, 22.90 g of 6-nitro-benzo [1, 3] dioxolanyl-5-carboxylic acid are added, after 1.5 hours, the reaction is complete according to thin-layer chromatography, 28.94 ml of bromobenzyl are added dropwise under ice-bath cooling, the reaction mixture is stirred at ambient temperature overnight, mixed with 100 ml of 10% citric acid and stirred at ambient temperature for a further day, the reaction mixture is evaporated in vacuo at 60 ℃ and added to 800 ml of ice-water, the aqueous phase is extracted with ethyl acetate, the extracts are washed with water and saturated sodium chloride solution, dehydrated over magnesium sulfate and evaporated.

The residue was stirred with diethyl ether and 2-nitro-4-benzyloxy-5- (tetrahydropyran-4-yloxy) -benzoic acid was crystallized as a by-product. It was filtered off and the filtrate was evaporated. The main product remaining was 2-nitro-4-benzyloxy-5- (tetrahydropyran-4-yloxy) -benzyl benzoate, which was saponified to the carboxylic acid without further purification (see example V).

The following compounds were prepared as in example VI:

(1) 2-Nitro-4-benzyloxy-5- ((S) -tetrahydrofuran-3-yloxy) -benzyl benzoate

R_fThe value: 0.75 (silica gel, cyclohexane/ethyl acetate 1: 1)

Mass spectrometry (ESI)⁺)：m/z＝450[M+H]⁺

(2) 2-Nitro-4-hydroxy-5- [1- (tert-butyloxycarbonyl) piperidin-4-yloxy) -benzoic acid was not reacted with benzyl bromide.

R_fThe value: 0.40 (silica gel, dichloromethane/methanol/acetic acid 90: 10: 1)

Mass spectrometry (ESI)^-)：m/z＝381[M-H]^-

Example VII

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- {1- [2- (tert-butyloxycarbonylamino) -ethyl]-piperidin-4-yloxy Phenyl } -7-methoxy-quinazolines

A mixture of 410 mg of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline-dihydrochloride, 240 mg of N- (tert-butyloxycarbonylamino) -2-bromo-ethylamine and 360 mg of potassium carbonate in 5 ml of N, N-dimethylformamide was stirred at ambient temperature overnight. Then another 80 mg of N- (tert-butyloxycarbonyl) -2-bromo-ethylamine were added and the reaction mixture was stirred at ambient temperature for a further four hours. The reaction was quenched by dilution with water and extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium hydrogen chloride solution, dehydrated over magnesium sulfate and evaporated. The residue was passed through a silica gel column. Chromatography was carried out with ethyl acetate/methanol (95: 5 to 90: 1) as eluent.

Yield: 370 mg (79% of theory).

R_fThe value: 0.33 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)^-)：m/z＝544，546[M-H]^-

The following compounds were prepared as in example VII:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [2- (tert-butyloxycarbonylamino) -ethyl ] -piperidin-4-yloxy } -quinazoline

R_fThe value: 0.38 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝516，518[M+H]⁺

Example VIII

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (piperidin-4-yloxy) -7-methoxy-quinazoline-dihydrochloride

Prepared by treating 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline with concentrated hydrochloric acid in dioxane at ambient temperature.

R_fThe value: 0.53 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝403，405[M+H]⁺

The following compounds were prepared as in example VIII:

(1)6- (piperidin-4-yloxy) -3H-quinazolin-4-one x 2 trifluoroacetic acid

In dichloromethane with trifluoroacetic acid.

Mass spectrometry (ESI)⁺)：m/z＝246[M+H]⁺

(2)6- (piperidin-4-yloxy) -7-hydroxy-3H-quinazolin-4-one

In dichloromethane with trifluoroacetic acid.

R_fThe value: 0.60 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝262[M+H]⁺

Example IX

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy]-7-methoxy- Quinazoline

A solution of 7.80 ml of diethyl azodicarboxylate in 100 ml of dichloromethane is added dropwise at ambient temperature to a mixture of 10.00 g of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6-hydroxy-7-methoxy-quinazoline and 9.40 g of 1- (tert-butyloxycarbonyl) -4-hydroxy-piperidine and 12.40 g of triphenylphosphine in 400 ml of dichloromethane. The suspension was stirred at ambient temperature for three days and then filtered under suction. The filtrate was evaporated and chromatographed on a silica gel column with dichloromethane/methanol (98: 2 to 95: 5) as eluent. The resulting crude product was combined with diisopropyl ether, stirred overnight, filtered off with suction and dried.

Yield: 5.34 g (34% of theory)

R_fThe value: 0.46 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝503，505[M+H]⁺

Example X

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (tetrahydropyran-4-yloxy)]-7- (4-bromo-butyloxy) -quinazoline

A mixture of 500 mg of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy ] -7-hydroxy-quinazoline, 165 μ l of 1-bromo-4-chloro-propane and 360 mg of potassium carbonate in 5 ml of N, N-dimethylformamide was stirred at 80 ℃ overnight, the reaction mixture was diluted with water to terminate the reaction, and extracted with ethyl acetate.

Yield: 650 mg (97% of theory)

The following compounds were prepared as in example X:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy ] -7- (4-bromo-butyloxy) -quinazoline

R_fThe value: 0.84 (silica gel, ethyl acetate/methanol ═ 9: 1)

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-trifluoroacetyl-piperidin-4-yloxy ] -7-ethoxy) -quinazoline

Mass spectrometry (ESI)⁺)：m/z＝513，515[M+H]⁺

(3)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-trifluoroacetyl-piperidin-4-yloxy ] -7- (2-methoxy-ethoxy) -quinazoline

R_fThe value: 0.38 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝543，545[M+H]⁺

Example XI

1- (2-hydroxy-ethyl) -3-methyl-tetrahydropyrimidin-2-one

Prepared by hydrogenolysis cleavage of 1- (2-benzyloxy-ethyl) -3-methyl-tetrahydropyrimidin-2-one in methanol in the presence of palladium on activated carbon at ambient temperature.

R_fThe value: 0.23 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝159[M+H]⁺

Example XII

1- (2-benzyloxy-ethyl) -3-methyl-tetrahydropyrimidin-2-one

Prepared by reacting 1- (2-benzyloxy-ethyl) -tetrahydropyrimidin-2-one with methyl iodide in N, N-dimethylformamide at ambient temperature.

R_fThe value: 0.62 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝249[M+H]⁺

Example XIII

1- (2-benzyloxy-ethyl) -tetrahydropyrimidin-2-one

Prepared by treating 1- (2-benzyloxy-ethyl) -3- (3-chloro-propyl) -urea with potassium tert-butoxide at ambient temperature in N, N-dimethylformamide.

R_fThe value: 0.42 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝235[M+H]⁺

Example XIV

1- (2-benzyloxy-ethyl) -tetrahydropyrimidin-2-one

2-benzyloxy-ethylamine is reacted with 3-chloro-propyl-isopropyl-isocyanate in tetrahydrofuran.

R_fThe value: 0.73 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝271，273[M+H]⁺

Example XV

3- (tert-butyloxycarbonylamino) -cyclohexanols

Prepared by reacting 3-amino-cyclohexanol with di-tert-butyl pyrocarbonate in a mixture of dioxane/water (2: 1) and in the presence of triethylamine at 50 ℃.

R_fThe value: 0.34 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)^-)：m/z＝214[M-H]^-

The following compounds were prepared as in example XV:

(1) cis-4- [ N- (tert-butyloxycarbonyl) -N-methyl-amino ] -cyclohexanol

The reaction was carried out in methanol.

R_fThe value: 0.70 (silica gel, ethyl acetate)

Mass spectrometry (ESI)⁺)：m/z＝230[M+H]⁺

Example XVI

6- (1-trifluoroacetyl-piperidin-4-yloxy) -3H-quinazolQuinoline-4-ones

Prepared by reacting 6- (piperidin-4-yloxy) -3H-quinazolin-4-one x 2 trifluoroacetic acid with trifluoroacetic anhydride in tetrahydrofuran in the presence of triethylamine.

R_fThe value: 0.48 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝342[M+H]⁺

The following compounds were prepared as in example XVI:

(1)6- (1-trifluoroacetyl-piperidin-4-yloxy) -7-hydroxy-3H-quinazolin-4-one

In methanol and in the presence of Hunig's base.

R_fThe value: 0.80 (silica gel, dichloromethane/methanol 4: 1)

Mass spectrometry (ESI)⁺)：m/z＝358[M+H]⁺

Example XVII

2-nitro-5- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy]-benzoic acid

21.00 g of potassium tert-butoxide are added in portions to 120 ml of N, N-dimethylformamide containing 25.14 g of 1- (tert-butyloxycarbonyl) -piperidin-4-ol cooled in an ice bath, while the temperature is maintained below 10 ℃. The mixture was stirred for 30 minutes under cooling in an ice bath, followed by the addition of 11.60 g of 5-fluoro-2-nitro-benzoic acid. After three hours, the reaction mixture was poured into water, adjusted to pH 1 with concentrated hydrochloric acid, and extracted with ethyl acetate. The combined organic phases were washed with diluted citric acid solution, dehydrated over magnesium sulphate and evaporated. The residue was triturated with ether, filtered off with suction and dried. After a period of standing more product crystallized from the filtrate and was likewise filtered off with suction and dried.

Yield: 9.58 g (42% of theory)

R_fThe value: 0.43 (silica gel, dichloromethane/methanol/acetic acid 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝367[M+H]⁺

Example XVIII

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (1-bromoacetyl-piperidin-4-yloxy) -quinazoline and 4- [ (3-chloro-4-yl) -quinazoline -4-fluoro-phenyl) amino]-6- (1-chloroacetyl-piperidin-4-yloxy) -quinazoline

Prepared by reacting 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -quinazoline with bromoacetyl chloride in tetrahydrofuran and in the presence of Hunig's base at ambient temperature. A mixture of bromine and chlorine compounds is obtained.

R_fThe value: 0.43 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝493，495，497[M1+H]⁺And 449, 451, 453[ M2+ H ]]⁺

The following compounds were prepared as in example XVIII:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-chloroacetyl-piperidin-4-yloxy) -7-methoxy) -quinazoline

The reaction is carried out in chloroacetyl chloride.

R_fThe value: 0.59 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)^-)：m/z＝477，479，481[M-H]^-

Example XIX

1-methyl-3- [ ([1, 4)]Oxazepan (oxazepan) -4-yl) carbonyl]-3H-imidazol-1-ium-iodide

3- [ ([1, 4] oxazepan-4-yl) carbonyl ] -3H-imidazole is reacted with methyl iodide in acetonitrile at ambient temperature. The crude product was reacted further without any further purification.

The following compounds were prepared as in example XIX:

(1) 1-methyl-3- [ (cis-2, 6-dimethyl-morpholin-4-yl) carbonyl ] -3H-imidazol-1-ium-iodide

R_fThe value: 0.12 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

(2) 1-methyl-3- [ (2-methyl-morpholin-4-yl) carbonyl ] -3H-imidazol-1-ium-iodide

R_fThe value: 0.02 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Example XX

3- [ ([1, 4] oxazepan-4-yl) carbonyl ] -3H-imidazole

By reacting [1, 4] oxazepane with N, N' -carbonyldiimidazole in the presence of triethylamine in tetrahydrofuran at ambient temperature.

R_fThe value: 0.30 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝196[M+H]⁺

The following compounds were prepared as in example XX:

(1)3- [ (cis-2, 6-dimethyl-morpholin-4-yl) carbonyl ] -3H-imidazole

R_fThe value: 0.46 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

(2)3- [ (2-methyl-morpholin-4-yl) carbonyl ] -3H-imidazole

R_fThe value: 0.43 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Example XXI

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (1-trifluoroacetyl-piperidin-4-yloxy) -7-hydroxy-quinazoline

4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-trifluoroacetyl-piperidin-4-yloxy) -7-acetoxy-quinazoline-hydrochloride is treated with a saturated solution of sodium bicarbonate in methanol at ambient temperature. In addition to the desired product, some 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7-hydroxy-quinazoline was isolated as a by-product.

R_fThe value: 0.20 (silica gel, dichloromethane/methanol 20: 1)

Mass spectrometry (ESI)^-)：m/z＝483，485[M-H]^-

The following compounds are prepared as in example XXI:

(1)4- [ (3-ethynyl-phenyl) amino ] -6-hydroxy-7-methoxy-quinazoline

With 40% sodium hydroxide solution in ethanol.

R_fThe value: 0.32 (silica gel, ethyl acetate)

Mass spectrometry (ESI)⁺)：m/z＝292[M+H]⁺

Example XXII

6- (1-trifluoroacetyl-piperidin-4-yloxy) -7-acetylhydro-3H-quinazolin-4-one

Prepared by reacting 6- (1-trifluoroacetyl-piperidin-4-yloxy) -7-hydroxy-3H-quinazolin-4-one with acetic anhydride in pyridine at 80 ℃.

R_fThe value: 0.60 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝400[M+H]⁺

Preparation of the final compound:

example 1

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- ((S) -tetrahydrofuran-3-yloxy) -7-methoxy-quinazoline

300 mg of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6-hydroxy-7-methoxy-quinazoline were mixed with 114. mu.l of (R) -3-hydroxy-tetrahydrofuran and 370 mg of triphenylphosphine in 6 ml of acetonitrile. 234 microliters of diethyl azodicarboxylate were then added, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered to terminate the reaction and the filtrate was evaporated in vacuo. The crude product was purified by chromatography on a silica gel column with ethyl acetate/methanol (95: 5) as eluent.

Yield: 53 mg (15% of theory)

Melting point: 178 deg.C

Mass spectrometry (ESI)⁺)：m/z＝390，392[M+H]⁺

The following compounds were prepared as in example 1:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.54 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝404，406[M+H]⁺

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (tert-butyloxycarbonylamino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

R_fThe value: 0.70 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝517，519[M+H]⁺

(3)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((R) -tetrahydrofuran-3-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.64 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝390，392[M+H]⁺

(4)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ trans-4- (tert-butyloxycarbonylamino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

R_fThe value: 0.65 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝517，519[M+H]⁺

(5)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline

Melting point: 184 ℃ C

Mass spectrometry (ESI)⁺)：m/z＝503，505[M+H]⁺

(6)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.52 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝404，406[M+H]⁺

(7)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline

Melting point: 218 deg.C

Mass spectrometry (ESI)⁺)：m/z＝417，419[M+H]⁺

(8)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ (S) -1- (tert-butyloxycarbonyl) -pyrrolidin-3-yloxy ] -7-methoxy-quinazoline

The reaction is carried out in dichloromethane with diisopropyl azodicarboxylate.

R_fThe value: 0.51 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry(ESI⁺)：m/z＝489，491[M+H]⁺

(9)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (tert-butyloxycarbonyl) -piperidin-3-yloxy) -7-methoxy-quinazoline

The reaction is carried out in dichloromethane with diisopropyl azodicarboxylate.

R_fThe value: 0.56 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)^-)：m/z＝501，503[M-H]^-

(10)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy) -7- [2- (3-methyl-2-oxo-hexahydropyrimidin-1-yl) -ethoxy ] -quinazoline

In dichloromethane with diisopropyl azodicarboxylate.

Melting point: 235 deg.C

Mass spectrometry (ESI)⁺)：m/z＝516，518[M+H]⁺

(11)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [3- (tert-butyloxycarbonylamino) -cyclohexan-1-yloxy) -7-methoxy-quinazoline

In dichloromethane with diisopropyl azodicarboxylate.

R_fThe value: 0.68 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)^-)：m/z＝515，517[M-H]^-

(12)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ N- (tert-butyloxycarbonyl) -N-methyl-amino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

In dichloromethane with diisopropyl azodicarboxylate.

R_fThe value: 0.37 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝531，533[M+H]⁺

(13)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ N- (tert-butyloxycarbonyl) -N-methyl-amino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

In dichloromethane with diisopropyl azodicarboxylate.

Melting point: 231 ℃ C

Mass spectrometry (ESI)⁺)：m/z＝531，533[M+H]⁺

Example 2

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (cis-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline X trifluoroacetic acid

Prepared by treating 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (tert-butyloxycarbonyl) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline with trifluoroacetic acid in dichloromethane at ambient temperature.

Melting point: 221 deg.C

Mass spectrometry (ESI)⁺)：m/z＝417，419[M+H]⁺

The following compounds were prepared as in example 2:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

Mass spectrometry (ESI)⁺)：m/z＝417，419[M+H]⁺

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazolin-x-trifluoroacetic acid

Melting point: 232 ℃ C

Mass spectrometry (ESI)⁺)：m/z＝403，405[M+H]⁺

Example 3

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (cis-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy Phenyl-quinazolines

Prepared by reacting 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline x-trifluoroacetic acid with methanesulfonic acid chloride in the presence of Hunig's base at ambient temperature and in tetrahydrofuran.

R_fThe value: 0.77 (silica gel, ethyl acetate/methanol/concentrated ammonia 40: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝495，497[M+H]⁺

The following compounds were prepared as in example 3:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.20 (silica gel, ethyl acetate)

Mass spectrometry (ESI)⁺)：m/z＝495，497[M+H]⁺

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.59 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝481，483[M+H]⁺

(3)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4- [ (3-chloro-propyl) sulfonylamino ] -cyclohexan-1-yloxy) -7-methoxy-quinazoline

The reaction is carried out with 3-chloropropane sulfonyl chloride.

R_fThe value: 0.79 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)^-)：m/z＝555，557，559[M-H]^-

(4)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (3-chloro-propyl) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

The reaction was carried out with 3-chloropropanesulfonyl chloride.

R_fThe value: 0.42 (silica gel, ethyl acetate)

Mass spectrometry (ESI)⁺)：m/z＝557，559，561[M+H]⁺

(5)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methylcarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

The reaction is carried out with acetic anhydride.

Melting point: 216 deg.C

Mass spectrometry (ESI)⁺)：m/z＝445，447[M+H]⁺

(6)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (dimethylamino) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

The reaction is carried out with N, N-dimethylcarbamoyl chloride.

R_fThe value: 0.28 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝474，476[M+H]⁺

(7)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

The reaction was carried out with (morpholin-4-yl) carbonyl chloride in acetonitrile.

R_fThe value: 0.37 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝516，518[M+H]⁺

(8)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (methoxymethyl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

The reaction was carried out as methoxyacetyl chloride.

R_fThe value: 0.80 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝475，477[M+H]⁺

(9)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline

The reaction is carried out in dichloromethane with cyanogen bromide.

R_fThe value: 0.40 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝428，430[M+H]⁺

(10)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (dimethylamino) sulfonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

The reaction was carried out in acetonitrile with N, N-dimethylaminosulfonyl chloride.

R_fThe value: 0.24 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝510，512[M+H]⁺

(11)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) sulfonyl ] -piperidin-4-yloxy) -7-methoxy-quinazoline

The reaction was carried out with (morpholin-4-yl) sulfonyl chloride in acetonitrile.

R_fThe value: 0.29 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝552，554[M+H]⁺

(12)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-3-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.33 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝481，483[M+H]⁺

(13)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -1-methanesulfonyl-pyrrolidin-3-yloxy) -7-methoxy-quinazoline

Melting point: 249 deg.C

Mass spectrometry (ESI)⁺)：m/z＝467，469[M+H]⁺

(14)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-methanesulfonylamino-ethyl) -piperidin-4-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.49 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝524，526[M+H]⁺

(15)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline

The reaction is carried out in acetic anhydride.

R_fThe value: 0.51 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝488，490[M+H]⁺

(16)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (dimethylamino) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

The reaction was carried out in acetonitrile with N, N-dimethylaminosulfonyl chloride.

R_fThe value: 0.69 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝524，526[M+H]⁺

(17)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

The reaction was carried out with (morpholin-4-yl) carbonyl chloride in acetonitrile.

R_fThe value: 0.38 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝530，532[M+H]⁺

(18)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholin-4-yl) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

The reaction was carried out with (morpholin-4-yl) sulfonyl chloride in acetonitrile.

Melting point: 237 deg.C

Mass spectrometry (ESI)^-)：m/z＝564，566[M-H]^-

(19)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (3-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.66 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)^-)：m/z＝493，495[M-H]^-

(20)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline

The reaction was carried out in acetonitrile as acetyl chloride.

Melting point: 224 deg.C

Mass spectrometry (ESI)⁺)：m/z＝475，477[M+H]⁺

(21)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline

Melting point: 227 deg.C

Mass spectrometry (ESI)⁺)：m/z＝511，513[M+H]⁺

(22)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-3-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

The reaction was carried out in acetonitrile as acetyl chloride. The cis and trans isomers were separated by chromatography on a silica gel column.

R_fThe value: 0.43 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝459，461[M+H]⁺

(23)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-3-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

The reaction was carried out in acetonitrile as acetyl chloride. The cis and trans isomers were separated by chromatography on a silica gel column.

R_fThe value: 0.49 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝459，46 1[M+H]⁺

(24)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (3-acetylamino-propoxy) -quinazoline

The reaction was carried out with acetyl chloride.

Melting point: 225 deg.C

Mass spectrometry (ESI)⁺)：m/z＝489，491[M+H]⁺

(25)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (3-methanesulfonylamino-propyloxy) -quinazoline

Melting point: 222 deg.C

Mass spectrometry (ESI)⁺)：m/z＝525，527[M+H]⁺

(26)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -quinazoline

R_fThe value: 0.44 (silica gel, dichloromethane)Alkane/methanol 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝45 1，453[M+H]⁺

(27)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } quinazoline

The reaction was carried out with (morpholin-4-yl) carbonyl chloride in acetonitrile.

R_fThe value: 0.40 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝486，488[M+H]⁺

(28)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-acetyl-piperidin-4-yloxy) -quinazoline

The reaction is carried out with acetic anhydride.

R_fThe value: 0.50 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝415，417[M+H]⁺

(29)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (dimethylamino) carbonyl ] -piperidin-4-yloxy } -quinazoline

The reaction is carried out with N, N-dimethylcarbamoyl chloride.

R_fThe value: 0.47 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝444，446[M+H]⁺

(30)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4-acetylamino-cyclohexan-1-yloxy } -7-methoxy-quinazoline

The reaction is carried out with acetic anhydride.

R_fThe value: 0.50 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝459，461[M+H]⁺

(31)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (dimethylamino) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

The reaction is carried out with N, N-dimethylcarbamoyl chloride.

R_fThe value: 0-40 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝488，490[M+H]⁺

(32)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ trans-4- (2-methoxy-acetylamino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

The reaction was carried out as methoxyacetyl chloride.

R_fThe value: 0.35 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝489，491[M+H]⁺

(33)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy ] -quinazoline

The reaction was carried out as methoxyacetyl chloride.

R_fThe value: 0.41 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝445，447[M+H]⁺

(34)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

The reaction is carried out with isopropyl chloride.

R_fThe value: 0.67 (silica gel, ethyl acetate/methanol/concentrated ammonia 98: 2: 1)

Mass spectrometry (ESI)⁺)：m/z＝489，491[M+H]⁺

(35)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-cyano-piperidin-4-yloxy) -quinazoline

The reaction is carried out in dichloromethane with cyanogen bromide.

R_fThe value: 0.49 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)^-)：m/z＝396，398[M-H]^-

(36)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (dimethylamino) sulfonyl ] -piperidin-4-yloxy } -quinazoline

The reaction was carried out in acetonitrile with N, N-dimethylsulfamoyl chloride.

R_fThe value: 0.34 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝480，482[M+H]⁺

(37)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) sulfonyl ] -piperidin-4-yloxy } -quinazoline

The reaction was carried out with (morpholin-4-yl) sulfonyl chloride in acetonitrile.

R_fThe value: 0.15 (silica gel, cyclohexane/ethyl acetate 1: 1)

Mass spectrometry (ESI)⁺)：m/z＝522，524[M+H]⁺

(38)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy ] -quinazoline

The reaction was carried out in acetonitrile with acetic anhydride.

Melting Point 221 deg.C

Mass spectrometry (ESI)⁺)：m/z＝458，460[M+H]⁺

(39)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (diethylamino) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

The reaction was carried out with N, N-diethylcarbamyl chloride.

R_fThe value: 0.40 (silica gel, ethyl acetate/methanol/concentrated ammonia 95: 5: 1)

Mass spectrometry (ESI)⁺)：m/z＝502，504[M+H]⁺

(40)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (piperidin-1-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

The reaction was carried out with (piperidin-1-yl) carbonyl chloride.

R_fThe value: 0.51 (silica gel, ethyl acetate/methanol/concentrated ammonia 95: 5: 1)

Mass spectrometry (ESI)^-)：m/z＝512，514[M-H]^-

(41)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (pyrrolidin-1-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

The reaction is carried out with (pyrrolidin-1-yl) carbonyl chloride.

Melting point: 237 deg.C

Mass spectrometry (ESI)⁺)：m/z＝500，502[M+H]⁺

(42)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (4-methyl-piperazin-1-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

The reaction was carried out with (4-methyl-piperazin-1-yl) carbonyl chloride.

R_fThe value: 0.28 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)^-)：m/z＝527，529[M-H]^-

(43)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

The reaction was carried out in dichloromethane.

R_fThe value: 0.71 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝509，511[M+H]⁺

(44)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-acetyl-N-methyl-amino-) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

The reaction is carried out with acetic anhydride.

Melting point: 234 deg.C

Mass spectrometry (ESI)⁺)：m/z＝473，475[M+H]⁺

(45)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ N- (2-methoxy-acetyl) -N-methyl-amino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

The reaction was carried out as methoxyacetyl chloride.

R_fThe value: 0.40 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝503，505[M+H]⁺

(46)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- [ N-dimethylaminocarbonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

The reaction is carried out with N, N-dimethylcarbamoyl chloride.

R_fThe value: 0.51 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝502，504[M+H]⁺

(47)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

The reaction was carried out with (morpholin-4-yl) carbonyl chloride.

R_fThe value: 0.50 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝544，546[M+H]⁺

(48)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (morpholin-4-yl) sulfonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

The reaction was carried out with (morpholin-4-yl) sulfonyl in acetonitrile.

R_fThe value: 0.24 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝580，582[M+H]⁺

(49)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-dimethylsulfamoyl-N-methyl-amino) -cyclohexan-1-yloxy } -7-methoxy-quinazoline

The reaction was carried out in acetonitrile with N, N-dimethylsulfamoyl chloride.

R_fThe value: 0.53 (silica gel, ethyl acetate)

Mass spectrometry (ESI)⁺)：m/z＝538，540[M+H]⁺

(50)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

The reaction was carried out in dichloromethane with ethane sulfonic acid chloride.

R_fThe value: 0.41 (silica gel, ethyl acetate)

Mass spectrometry (ESI)⁺)：m/z＝509，511[M+H]⁺

(51)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-ethoxy-quinazoline

The reaction was carried out with (morpholin-4-yl) carbonyl chloride.

R_fThe value: 0.48 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝530，532[M+H]⁺

(52)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline

R_fThe value: 0.50 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝495，497[M+H]⁺

(53)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy ] -7-ethoxy-quinazoline

The reaction was carried out as methoxyacetyl chloride.

R_fThe value: 0.40 (silica gel, dichloromethane/methanol 20: 1)

Mass spectrometry (ESI)⁺)：m/z＝489，491[M+H]⁺

(54)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline

R_fThe value: 0.47 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝525，527[M+H]⁺

(55)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7- (2-methoxy-ethoxy) -quinazoline

The reaction was carried out with (morpholin-4-yl) carbonyl chloride.

R_fThe value: 0.48 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝560，562[M+H]⁺

(56)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy ] -7- (2-methoxy-ethoxy) -quinazoline

The reaction was carried out as methoxyacetyl chloride.

R_fThe value: 0.48 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝519，521[M+H]⁺

(57)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

The reaction is carried out with acetic anhydride.

Melting point: 281 deg.C

Mass spectrometry (ESI)⁺)：m/z＝459，461[M+H]⁺

(58)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (2-methoxy-acetylamino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

The reaction was carried out as methoxyacetyl chloride.

Melting point: 264 deg.C

Mass spectrometry (ESI)⁺)：m/z＝489，491[M+H]⁺

(59)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (piperidin-1-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

The reaction was carried out with (piperidin-1-yl) carbonyl chloride.

Melting point: 253 deg.C

Mass spectrometry (ESI)⁺)：m/z＝542，544[M+H]⁺

(60)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (4-methyl-piperazin-1-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

The reaction was carried out with (4-methyl-piperazin-1-yl) carbonyl chloride-hydrochloride.

Melting point: 262 deg.C

Mass spectrometry (ESI)⁺)：m/z＝557，559[M+H]⁺

(61)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-ethanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

The reaction was carried out with ethanesulfonyl chloride in dichloromethane.

R_fThe value: 0.19 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝523，525[M+H]⁺

(62)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

The reaction was carried out with (morpholin-4-yl) carbonyl chloride.

R_fThe value: 0.33 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝530，532[M+H]⁺

(63)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ (morpholin-4-yl) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

The reaction was carried out with (morpholin-4-yl) carbonyl chloride in acetonitrile.

R_fThe value: 0.81 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝566，568[M+H]⁺

(64)4- [ (3-ethynyl-phenyl) amino ] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline was reacted with acetic anhydride.

R_fThe value: 0.30 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝417[M+H]⁺

(65)4- [ (3-ethynyl-phenyl) amino ] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline

The reaction was carried out as methoxyacetyl chloride.

R_fThe value: 0.37 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝447[M+H]⁺

(66)4- [ (3-ethynyl-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.59 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝453[M+H]⁺

(67)4- [ (3-ethynyl-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

The reaction was carried out with (morpholin-4-yl) carbonyl chloride.

R_fThe value: 0.43 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝488[M+H]⁺

(68)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

R_fThe value: 0.50 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝509，511[M+H]⁺

(69)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

The reaction was carried out with (morpholin-4-yl) carbonyl chloride.

R_fThe value: 0.54 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝544，546[M+H]⁺

Example 4

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (cis-4- { [ (3- (morpholin-4-yl) propyl)]Sulfonylamino } -cyclohexanes Alk-1-yloxy) -7-methoxy-quinazolines

23 microliters of morpholine were added to 60 mg of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ (3-chloro-propyl) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline in 2 ml of acetonitrile, and the reaction mixture was heated at reflux overnight. To terminate the reaction, the mixture was taken up in ethyl acetate and washed with water. The organic phase was dehydrated over magnesium sulfate and evaporated. The crude product was purified by column chromatography over silica gel using dichloromethane/methanol (9: 1) as eluent.

Yield: 18 mg (27% of theory)

R_fThe value: 0.36 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝608，610[M+H]⁺

The following compounds were prepared as in example 4:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4- { [3- (morpholin-4-yl) propyl ] sulfonylamino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.16 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝608，610[M+H]⁺

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- [4- (morpholin-4-yl) butyloxy ] -quinazoline

At 100 ℃ in N-methylpyrrolidone in the presence of sodium carbonate and sodium iodide.

R_fThe value: 0.18 (silica gel, ethyl acetate/methanol/concentrated ammonia 40: 10: 0.5)

Mass spectrometry (ESI)⁺)：m/z＝531，533[M+H]⁺

(3)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy) -7- [4- (morpholin-4-yl) butyloxy ] -quinazoline

At 100 ℃ in N-methylpyrrolidone in the presence of sodium carbonate and sodium iodide.

R_fThe value: 0.32 (silica gel, ethyl acetate/methanol/concentrated ammonia 80: 20: 1)

Mass spectrometry (ESI)⁺)：m/z＝517，519[M+H]⁺

(4)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) -acetyl ] -piperidin-4-yloxy } -quinazoline

In tetrahydrofuran in the presence of Hunig's base at ambient temperature.

R_fThe value: 0.30 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝500，502[M+H]⁺

(5)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-dimethylaminoacetyl-piperidin-4-yloxy) -quinazoline

In tetrahydrofuran in the presence of Hunig's base at ambient temperature.

R_fThe value: 0.11 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝458，460[M+H]⁺

(6)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-dimethylaminoacetyl-piperidin-4-yloxy) -7-methoxy-quinazoline

In tetrahydrofuran in the presence of Hunig's base at ambient temperature.

R_fThe value: 0.19 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝488，490[M+H]⁺

(7)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) -acetyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

In tetrahydrofuran in the presence of Hunig's base at ambient temperature.

Mass spectrometry (ESI)⁺)：m/z＝530，532[M+H]⁺

Example 5

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- ((S) -pyrrolidin-3-ylOxy) -7-methoxy-quinazoline-dihydrochloride Salt (salt)

A solution of 370 mg of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ (S) -1- (tert-butyloxy-carbonyl) -pyrrolidin-3-yloxy ] -7-methoxy-quinazoline in 5 ml of dioxane was mixed with 0.32 ml of concentrated hydrochloric acid and stirred at ambient temperature overnight. The precipitate formed was filtered off with suction and washed with copious amounts of dioxane. The crude product was dissolved in a small amount of methanol and reprecipitated by adding the same amount of ethyl acetate. The white solid thus obtained was filtered off with suction and dried.

Yield: 200 mg (57% of theory)

Melting point: 281 deg.C

Mass spectrometry (ESI)⁺)：m/z＝389，391[M+H]⁺

The following compounds were prepared as in example 5:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline-dihydrochloride melting point: 263 deg.C

Mass spectrometry (ESI)⁺)：m/z＝403，405[M+H]⁺

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-amino-ethyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline-dihydrochloride

Melting point: 277 ℃ C

Mass spectrometry (ESI)⁺)：m/z＝446，448[M+H]⁺

(3)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (3-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline-dihydrochloride

Mass spectrometry (ESI)⁺)：m/z＝417，419[M+H]⁺

(4)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-aminoethoxy) -quinazoline-dihydrochloride

In dichloromethane with isopropanol-acidified hydrochloric acid (5-6M).

R_fThe value: 0.58 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝433，435[M+H]⁺

(5)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (3-amino-propyloxy) -quinazoline-dihydrochloride

In dichloromethane with isopropanol-acidified hydrochloric acid (5-6M).

R_fThe value: 0.44 (prepared reverse phase DC plate (E.Merck), methanol/5% aqueous sodium chloride solution 7: 3)

Mass spectrometry (ESI)⁺)：m/z＝447，449[M+H]⁺

(6)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-amino-ethyl) -piperidin-4-yloxy ] -quinazoline-dihydrochloride

R_fThe value: 0.50 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝416，418[M+H]⁺

(7)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline-dihydrochloride

In dichloromethane with isopropanol-acidified hydrochloric acid (5-6M).

R_fThe value: 0.35 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝431，433[M+H]⁺

(8) The 4- [ (3-ethynyl-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline-dihydrochloride phase was carried out in dichloromethane with isopropanol-ated hydrochloric acid (5-6M).

R_fThe value: 0.50 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝375[M+H]⁺

(9)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline-dihydrochloride

Melting point: 251 deg.C

Mass spectrometry (ESI)⁺)：m/z＝431，433[M+H]⁺

Example 6

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (tetrahydropyran-4-yloxy) -7-hydroxy-quinazoline

A mixture of 9.00 g of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-benzyloxy-quinazoline-hydrochloride and 50 ml of trifluoroacetic acid is heated at 100 ℃ for 1.5 hours. The reaction mixture was then evaporated and the residue was taken up in 10 ml of acetonitrile. The solution was stirred vigorously and added dropwise to 100 ml of saturated sodium bicarbonate solution. After 1.5 hours, the precipitate formed is filtered off with suction and washed several times with water. The crude product is stirred with diethyl ether, filtered off with suction and dried.

Yield: 5.90 g (87% of theory)

R_fThe value: 0.21 (silica gel, ethyl acetate)

Mass spectrometry (ESI)⁺)：m/z＝390，392[M+H]⁺

The following compounds were prepared as in example 6:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline

R_fThe value: 0.44 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝376，378[M+H]⁺

Example 7

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (tetrahydropyran-4-yloxy) -7- [3- (morpholin-4-yl) -propyloxy Base of]-quinazolines

A mixture of 300 mg of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-hydroxy-quinazoline, 130 mg of 3- (morpholin-4-yl) -propyl chloride and 530 mg of potassium carbonate in 5 ml of N, N-dimethylformamide was stirred at 80 ℃ overnight. To terminate the reaction, the reaction mixture was diluted with 25 ml of water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dehydrated over magnesium sulfate and evaporated. The residue was stirred with ether, filtered off with suction and dried.

Yield: 250 mg (63% of theory)

Melting point: 205 deg.C

Mass spectrometry (ESI)⁺)：m/z＝517，519[M+H]⁺

The following compounds were prepared as in example 7:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- [2- (morpholin-4-yl) -ethoxy ] -quinazoline

R_fThe value: 0.33 (silica gel, ethyl acetate/methanol/concentrated ammonia 40: 10: 0.5)

Mass spectrometry (ESI)⁺)：m/z＝503，505[M+H]⁺

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline

R_fThe value: 0.76 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝418，420[M+H]⁺

(3)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy) -7- [3- (morpholin-4-yl) -propyloxy ] -quinazoline

R_fThe value: 0.20 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)^-)：m/z＝501，503[M-H]^-

(4)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy) -7- [2- (morpholin-4-yl) -ethoxy ] -quinazoline

R_fThe value: 0.19 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝489，491[M+H]⁺

(5)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline

R_fThe value: 0.57 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝448，450[M+H]⁺

(6)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- [2- (tert-butyloxycarbonylamino) -ethoxy ] -quinazoline

R_fThe value: 0.64 (silica gel, ethyl acetate/methanol/concentrated ammonia 95: 5: 0.1)

Mass spectrometry (ESI)⁺)：m/z＝533，535[M+H]⁺

(7)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- [3- (tert-butyloxycarbonylamino) -propyloxy ] -quinazoline

R_fThe value: 0.74 (silica gel, ethyl acetate/methanol/concentrated ammonia 95: 5: 0.1)

Mass spectrometry (ESI)⁺)：m/z＝547，549[M+H]⁺

Example 8

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (piperidin-4-yloxy) -quinazolines

A solution of 4.55 g of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-trifluoroacetyl-piperidin-4-yloxy) -quinazoline-hydrochloride in 35 ml of methanol was mixed with 13 ml of (3N) sodium hydroxide solution and stirred at ambient temperature for half an hour. To terminate the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dehydrated over magnesium sulphate and evaporated. The residue was stirred with ether, filtered off with suction and dried.

Yield: 3.00 g (89% of theory)

R_fThe value: 0.48 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝373，375[M+H]⁺

The following compounds were prepared as in example 8:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.20 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝417，419[M+H]⁺

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline

R_fThe value: 0.10 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝447，449[M+H]⁺

Example 9

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- {1- [ (ethylamino) carbonyl]-piperidin-4-yloxy } -7-methoxy- Quinazoline

Prepared by reacting 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline with ethyl isocyanate in tetrahydrofuran at ambient temperature.

R_fThe value: 0.53 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝474，476[M+H]⁺

The following compounds were prepared as in example 9:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (isopropylamino) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

Melting point: 236 deg.C

Mass spectrometry (ESI)^-)：m/z＝486，488[M-H]^-

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (phenylamino) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

R_fThe value: 0.70 (silica gel, ethyl acetate/methanol/concentrated ammonia 95: 5: 0.1)

Mass spectrometry (ESI)⁺)：m/z＝522，524[M+H]⁺

(3)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (ethylamino) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.38 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝502，504[M+H]⁺

Example 10

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- {1- [ (dimethylamino) carbonylmethyl group]-piperidin-4-yloxy } -quine Azoline

Prepared by reacting 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -quinazoline with 2-chloro-N, N-dimethylacetamide in N, N-dimethylformamide and in the presence of potassium carbonate at ambient temperature.

R_fThe value: 0.24 (silica gel, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝458，460[M+H]⁺

The following compounds were prepared as in example 10:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonylmethyl ] -piperidin-4-yloxy } -quinazoline

R_fThe value: 0.42 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝500，502[M+H]⁺

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline

Melting point: 251 deg.C

Mass spectrometry (ESI)⁺)：m/z＝460，462[M+H]⁺

(3)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (dimethylamino) carbonylmethyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

Melting point: 233 deg.C

Mass spectrometry (ESI)⁺)：m/z＝488，490[M+H]⁺

(4)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonylmethyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

Melting point: 245 DEG C

Mass spectrometry (ESI)⁺)：m/z＝530，532[M+H]⁺

Example 11

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- {1- [ (tetrahydropyran-4-yl) carbonyl]-piperidin-4-yloxy } -7-carboxylic acid methyl ester Oxy-quinazolines

90 mg of 1-hydroxy-1H-benzotriazole and 250 mg of 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium-tetrafluoroborate are added to a mixture of 300 mg of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline-dihydrochloride, 82 mg of tetrahydropyran-4-carboxylic acid and 0.54 ml of Hunig's base in 5 ml of N, N-dimethylformamide. The reaction mixture was allowed to stir at ambient temperature overnight. To terminate the reaction, it was mixed with 25 ml of ethyl acetate and washed with water 10% sodium carbonate solution and saturated sodium chloride solution. The organic phase was dehydrated over magnesium sulfate and evaporated. The residue is stirred with a little ethyl acetate, filtered off with suction and dried.

Yield: 250 mg (77% of theory)

R_fThe value: 0.43 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝515，517[M+H]⁺

The following compounds were prepared as in example 11:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (tetrahydropyran-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

R_fThe value: 0.44 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝529，531[M+H]⁺

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (tetrahydropyran-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.31 (silica gel, ethyl acetate/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝543，545[M+H]⁺

Example 12

4- [ (3-chloro-4-fluoro-phenyl) amino]-6-{1-[([1，4]Oxazepan-4-yl) carbonyl]-piperidin-4-yl Oxy } -7-methoxy-quinazoline

4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline-dihydrochloride and 1.05 ml triethylamine were added to 900 mg of 1-methyl-3- [ ([1, 4] oxazepan-4-yl) carbonyl ] -3H-imidazol-1-ium-iodide in 10 ml of dichloromethane. The yellow suspension was allowed to stir at ambient temperature for about 24 hours. To terminate the reaction, the reaction mixture was mixed with 50 ml of dichloromethane and extracted with water and 10% citric acid hydroxide. The organic phase was washed with saturated sodium chloride solution, dehydrated over magnesium sulphate and evaporated. The residue was chromatographed over a silica gel column with dichloromethane/methanol/concentrated aqueous ammonia as eluent. The product obtained is stirred with diethyl ether, filtered off with suction and dried.

Yield: 800 mg (80% of theory)

R_fThe value: 0.30 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝530，532[M+H]⁺

The following compounds were prepared as in example 12:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (cis-2, 6-dimethyl-morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

R_fThe value: 0.41 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝544，546[M+H]⁺

(2)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (2-methyl-morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

R_fThe value: 0.50 (silica gel, ethyl acetate/methanol/concentrated ammonia water ═ 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝530，532[M+H]⁺

Example 13

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- (1-methyl-piperidin-4-yloxy) -7-ethoxy-quinazoline

35 microliters of 37% formalin and 110 mg sodium triacetoxyborohydride are added to 175 mg of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7-ethoxy-quinazoline in 1 ml tetrahydrofuran. The reaction mixture was allowed to stir at ambient temperature for about four hours. To terminate the reaction, 5 ml of saturated sodium bicarbonate solution was added and the mixture was stirred well. Then 20 ml of ethyl acetate were added and the aqueous phase was separated. The organic phase was washed with water and saturated sodium chloride solution, dehydrated over magnesium sulfate and evaporated. The residue is stirred with diisopropyl ether, filtered off with suction and dried.

Yield: 144 mg (80% of theory)

R_fThe value: 0.80 (silica gel, dichloromethane/methanol/concentrated ammonia 60: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝431，433[M+H]⁺

The following compounds were prepared as in example 13:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline

R_fThe value: 0.85 (silica gel, dichloromethane/methanol/concentrated ammonia 60: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝461，463[M+H]⁺

(2)4- [ (3-ethynyl-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline-hydrochloride

R_fThe value: 0.26 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝389[M+H]⁺

(3)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

R_fThe value: 0.80 (aluminum oxide, dichloromethane/methanol ═ 9: 1)

Mass spectrometry (ESI)⁺)：m/z＝445，447[M+H]⁺

Example 14

4- [ (3-ethynyl-phenyl) amino]-6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy]-7-methoxy- Quinazoline

A mixture of 3.00 g of 4- [ (3-ethynyl-phenyl) amino ] -6-hydroxy-7-methoxy-quinazoline, 4.50 g of 1- (tert-butyloxycarbonyl) -4- (p-toluenesulfonyloxy) -piperidine and 2.90 g of potassium carbonate in 30 ml of N, N-dimethylformamide is stirred at 60 ℃ for two days.

Yield: 3.25 g (67% of theory)

R_fThe value: 0.25 (silica gel, 95: 5: 1 ratio of dichloromethane/methanol/concentrated ammonia)

Mass spectrometry (ESI)⁺)：m/z＝475[M+H]⁺

The following compounds were prepared as in example 14:

(1)4- [ (3-ethynyl-phenyl) amino]-6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline R_fThe value: 0.40 (silica gel, dichloromethane/methanol/concentrated ammonia 90: 10: 1)

Mass spectrometry (ESI)⁺)：m/z＝376[M+H]⁺

Example 15

4- [ (3-chloro-4-fluoro-phenyl) amino]-6- {1- [2- (tert-butyloxycarbonylamino) -ethyl]-piperidin-4-yloxy Phenyl } -7-methoxy-quinazolines

A mixture of 410 mg of 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline-dihydrochloride, 240 mg of N- (tert-butyloxycarbonyl) -2-bromo-ethylamine and 360 mg of potassium carbonate in 5 ml of N, N-dimethylformamide was stirred at ambient temperature overnight. Then 80 mg of N- (tert-butyloxycarbonyl) -2-bromo-ethylamine were added and the reaction mixture was stirred at ambient temperature for a further four hours. To stop the reaction, it was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dehydrated over magnesium sulphate and evaporated. The residue was chromatographed on a silica gel column with ethyl acetate/methanol (95: 5 to 90: 1).

Yield: 370 mg (79% of theory)

R_fThe value: 0.33 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)^-)：m/z＝544，546[M-H]^-

The following compounds were prepared as in example 15:

(1)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [2- (tert-butyloxycarbonylamino) -ethyl ] -piperidin-4-yloxy } -quinazoline

R_fThe value: 0.38 (prepared reverse phase DC plate (E.Merck), acetonitrile/water/trifluoroacetic acid 50: 1)

Mass spectrometry (ESI)⁺)：m/z＝516，518[M+H]⁺

The following compounds can also be prepared by other methods known from the examples and literature:

example 16

Coated tablet containing 75 mg of active substance

Consists of the following components:

1 tablet core content:

75.0 mg of active substance

Calcium phosphate 93.0 mg

Corn starch 35.5 mg

Polyvinylpyrrolidone 10.0 mg

Hydroxypropyl methylcellulose 15.0 mg

Magnesium stearate1.50 mg

230.0 mg

Preparation:

the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half a given amount of magnesium stearate, compressed tablets having a diameter of about 13 mm are made in a tablet maker and ground in a sieve of 1.5 mm mesh in a suitable machine and mixed with the remaining magnesium stearate, the granules are pressed in a tabletting machine to tablets of the desired shape.

Core weight: 230 mg of

Die: 9 mm convexity

The tablet cores thus prepared are coated with a film consisting essentially of hydroxypropylmethylcellulose. The final coated tablets were polished with beeswax.

Weight of coated tablet: 245 mg of

Example 17

Tablet containing 100 mg of active substance

Consists of the following components:

1 tablet contains:

active substance 100.0 mg

Lactose 80.0 mg

Corn starch 34.0 mg

Polyvinylpyrrolidone 4.0 mg

Magnesium stearate2.0 mg

220.0 mg

The preparation method comprises the following steps:

the active substance, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. The wetted composition was sieved (2.0 mm mesh) and dried in a rack dryer at 50 ℃, then sieved again (1.5 mm mesh) and lubricant was added. The final mixture is compressed to form tablets.

Weight of the tablet: 220 mg of

Diameter: 10mm, biplane, faceted on both sides and grooved on one side.

Example 18

Tablet containing 150 mg of active substance

Consists of the following components:

1 tablet contains:

active substance 50.0 mg

Powdered lactose 89.0 mg

Corn starch 40.0 mg

Colloidal silicic acid 10.0 mg

Polyvinylpyrrolidone 10.0 mg

Magnesium stearate1.0 mg

300.0 mg

Preparation:

the active substance, mixed with lactose, corn starch and silicic acid, was moistened with a 20% aqueous solution of polyvinylpyrrolidone and passed through a sieve of 1.5 mm mesh. The granules dried at 45 ℃ were passed again through the same sieve and mixed with the given amount of magnesium stearate. Tablets were compressed from the mixture.

Tablet weight: 300 mg of

A die nozzle: 10mm, plane sheet

Example 19

Hard gelatin capsules containing 150 mg of active substance

Consists of the following components:

1 the capsule contains:

active substance 50.0 mg

Corn starch (dry) about 80.0 mg

Lactose (as powder) about 87.0 mg

Magnesium stearate3.0 mg

About 420.0 mg

Preparation:

the active substance is mixed with the excipients, passed through a sieve of 0.75 mm mesh and mixed homogeneously using a suitable device. The final mixture was filled into size 1 hard gelatin capsules.

And (3) filling capsules: about 320 mg

Capsule shell: hard gelatin capsule size 1

Example 20

Suppository containing 150 mg of active substance

Consists of the following components:

1 suppository contains:

150.0 mg of active substance

1500550.0 mg of polyethylene glycol

6000460.0 mg of polyethylene glycol

Polyoxyethylene sorbitan monostearate840.0 mg

2000.0 mg

Preparation:

after the suppository material is dissolved, the active material is uniformly dispersed therein, and the melt is poured into a cooled mold.

Example 21

Suspension containing 50 mg of active substance

Consists of the following components:

100 ml of suspension contained:

active substance 1.00 g

Carboxymethyl cellulose-Na-salt 0.10 g

0.05 g of methyl p-hydroxybenzoate

Propyl p-hydroxybenzoate 0.01 g

Glucose 10.00 g

Glycerol 5.00 g

20.00 g of 70% sorbitol solution

0.30 g of flavoring agent

Distilled water is added to 100 ml

Preparation:

distilled water was heated to 70 ℃. Methyl and propyl p-hydroxybenzoate and glycerol and sodium carboxymethyl cellulose were dissolved with stirring. The solution was cooled to ambient temperature and the active was added with stirring and dispersed homogeneously. After addition and dissolution of the sugar, sorbitol solution and odorant, the suspension was evacuated under stirring to remove air.

5 ml of the suspension contain 50 mg of active substance.

Example 22

Ampoules containing 10 mg of active substance

Consists of the following components:

active substance 10.0 mg

0.01N hydrochloric acid (in appropriate amount)

Twice distilled water is added to 2.0 ml

Preparation:

the active substance is dissolved in the desired amount of 0.01N HCl, made isotonic with common salt, sterile-filtered and transferred into 2 ml ampoules.

Example 23

Ampoule containing 50 mg of active substance

Consists of the following components:

active substance 50.0 mg

0.01N hydrochloric acid (in appropriate amount)

Adding distilled water twice to 10.0 ml

Preparation:

the active substance is dissolved in the desired amount of 0.01N HCl, made isotonic with common salt, sterile-filtered and transferred into 10 ml ampoules.

Example 24

Capsule for powder inhalation containing 5 mg of active substance

1 the capsule contains:

active substance 5.0 mg

Lactose for inhalation15.0 mg

20.0 mg

Preparation:

the active substance is mixed with lactose for inhalation. The mixture was filled into capsules in a capsule machine (weight of empty capsules about 50 mg).

The weight of the capsule is as follows: 70.0 mg

The size of the capsule is as follows: 3

Example 25

Inhalable solutions for hand-held nebulisers containing 2.5 mg of active substance

1 time of spraying agent comprises:

active substance 2.500 mg

Benzalkonium chloride 0.001 mg

1N hydrochloric acid (in appropriate amount)

Ethanol/water (50/50) to 15.000 mg

Preparation:

the active substance and benzalkonium chloride were dissolved in ethanol/water (50/50), and the pH of the solution was adjusted with 1N hydrochloric acid. The resulting solution was filtered and filled into the appropriate container of a hand-held sprayer.

Contents of the container: 4.5 g

Claims (13)

1. Bicyclic heterocyclic compounds of the formula

Wherein

R^aRepresents a hydrogen atom, and is represented by,

R^brepresents phenyl, wherein phenyl may be substituted by R¹To R³Is substituted by a group of

R¹And R²Identical or different and in each case represents a hydrogen, fluorine, chlorine, bromine or iodine atom,

R³represents a hydrogen, fluorine or chlorine atom,

R^crepresents cyclopentyl or cyclohexyl, which is substituted in each case by a radical R⁴-N-R⁵Are substituted and wherein

R⁴Represents a hydrogen atom or C_1-3-alkyl, and

R⁵represents a hydrogen atom or C_1-3-an alkyl group,

C_1-4-alkylsulfonyl, (morpholin-4-yl) -C_1-4-an alkylsulfonyl group,

C_1-4-an alkyloxycarbonyl group,

C_1-3-alkoxy-C_1-4-an alkyl-carbonyl group,

cyano, morpholin-4-ylcarbonyl, di- (C)_1-3-alkyl) amino-sulfonyl, morpholin-4-ylsulfonyl,

piperidin-4-yl radical, which is substituted by R in the 1-position⁵Is substituted by radicals in which R⁵The definition of the radicals is as defined above,

or tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl,

R^drepresents C_1-4-an alkoxy group,

by the group R⁷Substituted C_2-4An alkoxy group, wherein

R⁷Represents C_1-3-alkyloxy, formylamino, C_1-4-alkylcarbonylamino or C_1-4-an alkylsulfonylamino group,

x represents a nitrogen atom, an

The piperidinyl and morpholinyl radicals mentioned are in each case unsubstituted or substituted by one or two C_1-3-alkyl is substituted, and

unless otherwise indicated, the above alkyl groups are straight or branched chain,

with the proviso that the compound 4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline is not included,

its tautomers, its stereoisomers, its mixtures or its salts.

2. Bicyclic heterocyclic compounds of the general formula I according to claim 1, wherein

R^aRepresents a hydrogen atom, and is represented by,

R^bis represented by R¹To R³Phenyl substituted by the group of (a), and

R¹represents a hydrogen, fluorine, chlorine or bromine atom,

R²represents a hydrogen, fluorine or chlorine atom, and

R³represents a hydrogen atom, and is represented by,

R^crepresents in the 3 position by a group R⁴-N-R⁵Substituted cyclopentyl, wherein

R⁴Represents a hydrogen atom or C_1-3-alkyl, and

R⁵represents a hydrogen atom or C_1-3-an alkyl group,

C_1-3-alkylsulfonyl or (morpholin-4-yl) -C_2-4-an alkylsulfonyl group,

C_1-4-an alkyloxy-carbonyl group,

C_1-3-alkoxy-C_1-3-alkyl-carbonyl, cyano, morpholin-4-ylcarbonyl, or morpholin-4-ylsulfonyl, or

Piperidin-4-yl which is substituted in position 1 by a radical R⁵Is substituted in which R⁵The definition of (A) is as defined above,

tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl,

R^drepresents C_1-3-an alkoxy group,

at the 2-position by a group R⁷Substituted ethoxy, and

R⁷represents C_1-3-alkyloxy, formylamino, C_1-4-alkylcarbonylamino or C_1-4-an alkylsulfonylamino group,

x represents a nitrogen atom, and X represents a nitrogen atom,

and, unless otherwise specified, the above alkyl groups are straight or branched,

its tautomers, its stereoisomers, its mixtures or its salts.

3. Bicyclic heterocyclic compounds of the general formula I according to claim 1, wherein

R^aRepresents a hydrogen atom, and is represented by,

R^brepresents 3, 4-difluorophenyl or 3-chloro-4-fluoro-phenyl,

R^crepresents a radical R in the 3-position or in the 4-position⁴-N-R⁵A substituted cyclohexyl radical, wherein

R⁴Represents a hydrogen atom or a methyl group, and

R⁵represents

Methylsulfonyl, ethylsulfonyl, 2- (morpholin-4-yl) -ethylsulfonyl or 3- (morpholin-4-yl) -propylsulfonyl,

a propyloxycarbonyl group or a butyloxycarbonyl group,

cyano, morpholin-4-ylcarbonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl,

piperidin-4-yl which is substituted in position 1 by a radical R⁵Is substituted in which R⁵The definition of (A) is as defined above,

tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl,

R^drepresents a hydrogen atom, and is represented by,

a methoxy group or an ethoxy group, and a carboxyl group,

ethyloxy which is substituted in the 2-position by a radical R⁷Is substituted and

R⁷represents methoxy, ethoxy, ethylcarbonylamino, propylcarbonylamino, butylcarbonylamino, methylsulfonylamino, ethylsulfonylamino or butylsulfonylamino,

x represents a nitrogen atom, and X represents a nitrogen atom,

and, unless otherwise specified, the above alkyl groups are straight or branched,

its tautomers, its stereoisomers, its mixtures or its salts.

4. The following compounds of the general formula I according to claim 1:

(a)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) tetrahydrofuran-3-yloxy) -7-methoxy-quinazoline

(b)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline

(c)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((R) tetrahydrofuran-3-yloxy) -7-methoxy-quinazoline

(d)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

(e)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

(f)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline

(g)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

(h)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { [3- (morpholin-4-yl) -propyl ] sulfonylamino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

(i)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline

(k)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4- { [3- (morpholin-4-yl) -propyl ] sulfonylamino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

(l)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline

(m)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

(n)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (methoxymethyl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

(o)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline

(p)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) sulfonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

(q)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline

(r)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (dimethylamino) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

(s)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

(t)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholin-4-yl) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

(u)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline

(v)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylaminoethoxy) -quinazoline, and

(w)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline,

(x)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline,

(y)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (morpholin-4-yl) sulfonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline,

(z)4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-acetyl-N-methyl-amino-) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline,

or a salt thereof.

5. Physiologically acceptable salts of compounds according to at least one of claims 1 to 4 with inorganic or organic acids or bases.

6. Pharmaceutical composition comprising a compound according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5, and optionally one or more inert carriers and/or diluents.

7. Use of compounds according to at least one of claims 1 to 4 for the preparation of pharmaceutical compositions suitable for the treatment of benign or malignant tumors, for the prophylaxis and treatment of diseases of the airways and lung and for the treatment of diseases of the gastrointestinal tract, bile ducts and gallbladder.

8. A process for the preparation of a pharmaceutical composition as claimed in claim 6, characterized in that a compound as claimed in at least one of claims 1 to 4 is added by non-chemical means to one or more inert carriers and/or diluents.

9. A process for preparing compounds of the general formula I according to claims 1 to 4, characterized in that:

a) reacting a compound of the following general formula (II) with a compound of the general formula (III)

In the formula (II)

R^a、R^b、R^dAnd X are as defined in claims 1 to 4,

Z¹-R^c (III)

in the formula (III)

R^cIs as defined in claims 1 to 4, and Z¹Represents a leaving group, or

(b) To prepare wherein R^dA compound of the general formula I, representing one of the optionally substituted alkyloxy groups described in claims 1 to 4:

reacting a compound of the following general formula (IV) with a compound of the general formula (V),

r in the formula (IV)^a、R^b、R^cAnd X are as defined in claims 1 to 4,

Z²-R^d′ (V)

r in the formula (V)^d' represents C_1-4Alkyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, by the radical R⁷Radical substituted C_2-4-alkyl, wherein R⁷As defined in claims 1 to 4, and

Z²represents a leaving group, or

(c) To prepare wherein R^dRepresents a compound of the general formula I which is substituted by optionally substituted amino, alkylamino or dialkylamino or by an optionally substituted heterocyclyl radical bound via the imino nitrogen atom and having one of the alkyloxy radicals described in claims 1 to 4,

reacting a compound of the following formula (VI)

Wherein R in formula VI^a、R^b、R^cAnd X are as defined in claims 1 to 4, Z³Represents a leaving group, and represents a leaving group,

with ammonia, the corresponding optionally substituted alkylamine, dialkylamine or imino compound, or a suitable salt or derivative thereof, or

(d) To prepare R therein^dA compound of the general formula I which represents a hydroxyl group,

cleaving the protecting group from a compound of the formula

Wherein R is^a、R^b、R^cAnd X are as defined in claims 1 to 4, and R^d"represents a group convertible to a hydroxyl group, or

(e) To prepare wherein R^cA compound of formula I containing an-NH-group:

cleaving the protecting group from a compound of the formula

Wherein R is^a、R^b、R^dAnd X are as defined in claims 1 to 4, and R^cThe meaning of' with R in claims 1 to 4^cSame, with the proviso that R^cContaining a protected nitrogen atom, or

(f) To prepare R therein^cIs a compound of the general formula I which contains an alkyl group which is substituted by an optionally substituted amino, alkylamino or dialkylamino group or by an optionally substituted heterocyclic group bonded via a nitrogen atom,

reacting a compound of the formula

Wherein R in formula IX^a、R^b、R^cAnd X is as defined in claims 1 to 4, Z³Represents a leaving group, and R^c"has the meaning of R in claims 1 to 4^cProvided that the hydrogen atom bonded to the aliphatic carbon is replaced by Z³The substitution of the base group is carried out,

with ammonia, the corresponding optionally substituted alkylamine, dialkylamine or imino compound or a suitable salt or derivative thereof.

10. The process as claimed in claim 9, wherein the amino-, alkylamino-or imino-containing compounds of the general formula I prepared in this way are converted into the corresponding acyl, cyano or sulfonyl compounds of the general formula I by acylation, cyanation or sulfonylation, and/or

The compounds of the formula I containing amino, alkylamino or imino groups thus prepared are converted by alkylation or reductive alkylation into the corresponding alkyl compounds of the formula I and/or

Thus prepared chlorine-C_1-4-alkylsulfonyl or bromo-C_1-4-alkylsulfonyl compounds of the general formula I are converted into the corresponding amino-C by reaction with amines_1-4-an alkylsulfonyl compound, and-Or

The compounds of the general formula I containing tert-butyloxycarbonylamino, N-alkyl-N- (tert-butyloxycarbonyl) amino or N-tert-butyloxycarbonylimino thus prepared are the corresponding amino, alkylamino or imino compounds which are converted into the compounds of the general formula I by treatment with an acid.

11. The process of claim 9 or 10, wherein any-protecting groups used in the above reaction are re-cleaved.

12. A process according to claim 9 or 10, wherein the compound of general formula I thus prepared is resolved into its stereoisomers, and/or

The compounds of the general formula I thus prepared are converted into their salts.

13. The process according to claim 12, wherein the compound of the general formula I thus prepared is converted into a physiologically acceptable salt thereof for pharmaceutical use.