WO2002018351A1 - Bicyclic heterocycles, medicaments containing these compounds, their use, and methods for the production thereof - Google Patents

Abstract

The invention relates to bicyclic heterocycles of general formula (I), in which Ra to Rc are defined as referred to in Claims Nos. 1 to 7, to their tautomers, their stereoisomers, and to their salts, particularly their physiologically compatible salts with inorganic or organic acids or bases, which have valuable pharmacological properties, in particular, an inhibitive effect on the signal transduction imparted by tyrosine kinases. The invention also relates to the use of said bicyclic heterocycles for treating diseases, especially tumor diseases, disorders of the lung and of the respiratory tract, and to the production thereof.

Description

 Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and process for their preparation

The present invention relates to bicyclic heterocycles of the general formula

their tautomers, their stereoisomers and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, which have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by tyrosine kinases, their use for the treatment of diseases, in particular tumor diseases , diseases of the lungs and respiratory tract and their production.

In the above general formula I means

R _{a is} a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R _λ and R ₂ , where

R _{x represents} a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyan or ethynyl group and R _{2 represents} a hydrogen or fluorine atom,

one of the radicals R _b or R _{c is} an R ₃ - (CH ₂ ) _m -0 group and the other of the radicals R _b or R _{c is} a methoxy, cyclobutyloxy, cyclopenty-1oxy, Cyc1oprop 1met oxy-, Cyc1obuty1methoxy- , Cyc1openyl methoxy-, tetrahydrofuran-3-yloxy-, tetrahydropyran-3- yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where

R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) methylamino or N- (2-oxo-tetrahydrofuran-4-yl) ethylamino group,

an R ₄ -0-CO-CH ₂ -N-CH ₂ CH ₂ -OH group substituted on the methylene groups by one or two methyl or ethyl groups, in which

R _{4 represents} a hydrogen atom or a C 1-4 alkyl group,

or a 2-oxomorpholin-4-yl group substituted by one or two methyl or ethyl groups and

m represents the number 2, 3 or 4,

with the proviso that the connections

4- [(3-chloro-4-fluorophenyl) amino] -β-cyclopentyloxy-

7- (2- {N- (2-hydroxy-2-methyl-prop-l-yl -N- [(ethoxycarbonyl) methyl] amino} ethoxy) quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-

7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] quinazoline,

4- [(3-bromophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline and

4- [(3-bromophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) N-methylamino] ethoxy} -7-methoxy-quinazoline

excluded are,

their tautomers, their stereoisomers and their salts. Preferred compounds of the above general formula I are those in which

R _{a is} a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R _x and R ₂ , where

R _{x represents} a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyan or ethynyl group and R _{2 represents} a hydrogen or fluorine atom,

one of the radicals R _b or R _{c is} an R ₃ ~ (CH ₂ ) _m -O group and the other of the radicals R _b or R _{c is} a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentyl ethoxy , Tetrahydrofuran-3-yloxy-,

Tetrahydropyran-3-y1oxy, tetrahydrop ran-4-y1oxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where

R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) methyl ino- or N- (2-oxo-tetrahydrofuran-4-yl) ethylamino group,

an R ₄ -0-CO-CH ₂ -N-CH ₂ CH ₂ -OH group substituted on the methylene groups by one or two methyl or ethyl groups, in which

R _{4 is} a hydrogen atom or a C ₁ . _{4 represents} alkyl group,

or a 2-oxomorpholin-4-yl group substituted by one or two methyl or ethyl groups and

m represents the number 2, 3 or 4,

it means that the connections 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-

7- (2- {N- (2-hydroxy-2-methyl-prop-l-yl) -N- [(ethoxycarbonyl) methyl] amino} ethoxy) quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-

7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] quinazoline,

4- [(3-bromophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-bromophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) N-methylamino] ethoxy} -7-methoxy-quinazoline,

4- [(3-Bromophenyl) amino] -6- (2- {N- (2-hydroxy-2-methylprop-1-yl) -N- [(ethoxycarbonyl) methyl] amino} ethoxy ) -7-methoxy-quinazoline,

4- [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclobutyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopropylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl] amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentylmethoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentyloxy-china- zolin,

4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentylmethoxy- quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline,

4- _' [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentylmethoxy-quinazoline,

(R) -4- [(1-phenylethyl) amino] -6- [3- (6, 6-dimethyl-2-oxo-morpholino-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline .

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclobutyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopropylmethoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl] amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentylmethoxy-quinazoline,. ,

4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentyloxy-china- zolin,

4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentylmethoxy- quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxy-quinazoline and

(R) -4- [(1-phenyl-ethyl) amino] -7- [3- (6, 6-dimethyl-2-oxo-morphol-lin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline

excluded are,

especially those in which

R _{a represents} a 1-phenylethyl group or a phenyl group substituted by the radicals R _x and R ₂ , where R is a fluorine, chlorine or bromine atom, a methyl or

Ethynyl group and

R _{2 represents} a hydrogen or fluorine atom,

one of the radicals R _b or R _{c is} an R ₃ - (CH ₂ ) _m -0 group and the other of the radicals R _b or R _{0 is} a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy -, Tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where

R _{3 is} an N- (2-0xo-tetrahydrofuran-4-yl) methylamino group,

an R ₄ -0-CO-CH ₂ -N-CH ₂ CH ₂ -OH group substituted on the methylene groups by one or two methyl groups, in which

R _{4 represents} a C ₁ _ ₄ alkyl group,

or a 2-0xo-morpholin-4-yl group substituted by one or two methyl groups and

represent the number 2, 3 or 4,

with the proviso that the connections

4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- (2- {N- (2-hydroxy-2-methyl-prop-l-yl) -N- [(ethoxycarbonyl ) - methyl] -amino} -ethoxy) -quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-

7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] quinazoline,

4- [(3-bromophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpho-lin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-bromophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) N-methylamino] ethoxy} -7-methoxy-quinazoline,

4- [(3-Bromophenyl) amino] -6- (2- {N- (2-hydroxy-2-methylprop-1-yl) -N- [(ethoxycarbonyl) methyl] amino} ethoxy ) -7-methoxy-quinazoline,

4- [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [• (3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclobutyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopropylmethoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl] amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentylmethoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentyloxy-china- zolin, 4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentylmethoxy- quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentylmethoxy-quinazoline,

(R) -4- [(1-phenyl-ethyl) amino] -6- [3- (6, 6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline .

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclobutyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopropylmethoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl] amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentylmethoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentyloxy-china- zolin,

4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentylmethoxy- quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholine-4-1) propyloxy] -6-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxy-quinazoline and

(R) -4- [(1-phenyl-ethyl) amino] -7- [3- (6, 6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline

excluded are,

their tautomers, their stereoisomers and their salts.

Particularly preferred compounds of the general formula I are those in which

R _{a represents} a 1-phenylethyl group or a phenyl group substituted by the radicals R _x and R ₂ , where.

R _{a is} a fluorine, chlorine or bromine atom and

R _{2 represents} a hydrogen or fluorine atom,

one of the radicals R _b or R _{c is} an R ₃ - (CH ₂ ) _m -O group and the other of the radicals R _b or R _{c is} a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclo- pentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where

R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) methylamino group or a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and

m represents the number 2, 3 or 4,

with the proviso that the connections

4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-

7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] quinazoline,

4- [(3-bromophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-bromophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) - N-methylamino] ethoxy} -7-methoxy-quinazoline,

4- [(3-bromophenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclobutyloxy-quinazoline,

4.- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopropylmethoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl] amino] -6- [2 - (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentylmethoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- {2 - [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentyloxy-china- zolin,

4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentylmethoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentylmethoxy-quinazoline,

(R) -4- [(1-phenyl-ethyl) amino] -6- [3- (6, 6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline .

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclobutyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopropylmethoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl] amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentylmethoxy-quinazoline, '

4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentyloxy-china- zolin,

4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentylmethoxy- quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxy-quinazoline and

(R) -4- [(1-phenyl-ethyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline

excluded are,

their tautomers, their stereoisomers and their salts. Very particularly preferred compounds of general formula I are those in which

R _{a is} a 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,

R _{b is} an R ₃ - (CH ₂ ) _m -0 group in which

R _{3 represents} a 2-oxomorpholin-4-yl group substituted by one or two methyl groups and m represents the number 2 or 3,

and R _{c is} a methoxy, cyclobutyloxy, cyclopentoxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group with the proviso that the compounds

4- [(3-bromophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclobutyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopropylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline and

(R) -4- [(1-phenylethyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline

excluded are,

their tautomers, their stereoisomers and their salts.

Very particularly preferred compounds of the general formula I are also those in which

R _{a is} a 3-chloro-4-fluorophenyl group,

R _{b is} a cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group and

R _{c is} an R ₃ - (CH ₂ ) _m -0 group in which

R _{3 is} a 2-oxomorpholin-4-yl group substituted by one or two methyl groups and

m represents the number 2,

with the proviso that the connections 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-

7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentyloxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopropylmethoxy-quinazoline and

4- [(3-chloro-4-fluorophenyl] amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentylmethoxy-quinazoline,

excluded are,

their tautomers, their stereoisomers and their salts,

The following are mentioned as particularly preferred compounds:

(1) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy- 7- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] - quinazoline,

(2) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] -ethoxy} - quinazoline,

(3) 4- [(3-chloro-4-fluorophenyl) mino] -6-cyclopropylmethoxy- 7- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] - quinazoline,

(4) 4- [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-

6- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) propyloxy] quinazoline, (5) 4- [(3-Chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy- 6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) propyloxy] - quinazoline,

(6) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy- 7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] -ethoxy} - quinazoline,

(7) 4- [(3-bromophenyl) amino] -6- [2- ((S) -6-methyl-2-oxo-morpholine-4-yl) ethoxy] -7-methoxy- quinazoline,

(8) 4- [(3-bromophenyl) amino] -6- [2- ((R) -6 ~ methyl-2-oxomorphol-lin-4-yl) ethoxy] -7-methoxy- quinazoline,

(9) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- ((R) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -7- methoxy-quinazoline,

(10) 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- ((R) -6-methyl-

2-oxo-morpholin-4-yl) propyloxy] -7-methoxy-quinazoline,

(11) 4- [(R) - (1-phenylethyl) amino] -6- [3- ((S) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7 - methoxy-quinazoline,

(12) 4- [(JR) - (1-phenyl-ethyl) amino] -6- [2- ((S) -6-methyl-2-oxomorpholin-4 -yl) -ethoxy] -7- methoxy-quinazoline and

(13) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -7- methoxy-quinazoline,

their tautomers, their stereoisomers and their salts.

The compounds of the general formula I can be prepared, for example, by the following processes: a) implementation of a compound of the general formula

in the

R _a is defined as mentioned at the outset, one of the radicals R _b 'or R _c ' is a methoxy, cyclobutyloxy,

Cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or

Represents cyclopentylmethoxy group and the other of the radicals R _b 'or R _c ' represents a Z _x - (CH ₂ ) _ra -O group in which

m is defined as mentioned at the beginning and Z _{x denotes} a leaving group such as a halogen atom or a sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group,

with a compound of the general formula

H R,, (HD

in the

R ₃ is defined as mentioned at the beginning.

The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, acetonitrile, dirthylformamide, dimethyl sulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane in the presence of a tertiary organic base such as triethylamine or N-ethyl -diisopropylamine, these organic bases also being used as can serve medium, or in the presence of an inorganic base such as sodium carbonate or potassium carbonate, conveniently at temperatures between -20 and 200 ° C, preferably at temperatures between 0 and 150 ° C.

b) cyclization of a compound of the general formula optionally formed in the reaction mixture

in der

in the

R _{a is} as defined at the outset, one of the radicals R _b "or R _c " represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and the other of the radicals R _b "or R _c " represents an R ₃ '- (CH ₂ ) _m -0 group in which

m is defined as mentioned at the beginning and R ₃ 'is a substituted on the methylene groups by one or two methyl or ethyl groups

R _{4 is} -0-CO-CH ₂ -N-CH ₂ CH ₂ -OH group in which

R _{4 represents} a hydrogen atom or a C ₁ _ ₄ alkyl group.

The reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, acetonitrile, dimethylformamide, dimethyl sulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane in the presence of an anhydrous acid such as trifluoroacetic acid, methanesulfonic acid or sulfuric acid or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N '-dicyclohexylcarbodimide / N-hydroxysuccinimide, n-triazole, or 1-hydroxyl-niazole, n-triazolimide, or 1-hydroxyl-n-triazole, n-triazole-niazole, or 1-hydroxyl-niazole, n-triazole-1-hydroxyl, n-triazole-1-hydroxyl, n-triazole-1-hydroxyl, n-triazole-1-hydroxy, 1-hydroxy, 1-hydroxy, 1-hydroxy, 1-hydroxy, 1-hydroxy, or 1-hydroxy-1-hydroxy, 1-hydroxy, 1-hydroxy, 1-hydroxyl, or 1-hydroxynuccinimide, '-Carbonyldiimidazol or triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.

In the reactions described above, any reactive groups present, such as hydroxyl, carboxy or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.

For example, the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group,

as protective residues for a carboxy group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and

as protective residues for an imino group, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group are considered.

The subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in 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 base such as

Sodium hydroxide or potassium hydroxide or aprotic, for example in Presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and. 100 ° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. with..hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, if appropriate - with addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a

Solvents such as methylene chloride, dioxane, methanol or

Diethyl ether.

A trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.

Furthermore, the compounds of general formula I obtained, as already mentioned at the beginning, can be separated into their enantiomers and / or diastereomers. For example, cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers. For example, the cis / trans mixtures obtained can be chromatographed into their eis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.

The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Examples of suitable optically active alcohols are (+) or (-) menthol and optically active acyl radicals in amides are, for example, (+) or (-) menthyloxycarbonyl.

Furthermore, the compounds of formula I obtained in their salts, in particular for pharmaceutical use in their physiologically compatible salts with inorganic or organic acids are converted. Examples of suitable acids for this are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the new compounds of the formula I obtained in this way, if they contain a carboxy, hydroxyphosphoryl, sulfo or 5-tetrazolyl group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for pharmaceutical use in their physiologically tolerable salts , convict. Suitable bases here are, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Some of the compounds of the general formulas II to IV used as starting materials are known from the literature or can be obtained by processes known per se from the literature (see Examples I to XIV).

As already mentioned at the beginning, the compounds of the general formula I according to the invention and their physiologically tolerated salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), this being achieved, for example, by inhibiting the Ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected. It is also possible that the signal transmission on further downstream components may be blocked.

The biological properties of the new compounds were tested as follows: The inhibition of EGF-R-mediated signal transmission can be demonstrated, for example, with cells which express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha. An interleukin-3 (IL-3) -dependent cell line of murine origin was used here, which has been genetically modified in such a way that it expresses functional human EGF-R. The proliferation of these cells called F / L-HERc can therefore be stimulated either by murine IL-3 or by EGF (see von Rüden, T. et al. In EMBO J. 2, 2749-2756 (1988) and Pierce, JH et al. in Science, Sept. 23, 628-631 (1988)).

As starting material for the F / L-HERc cells, the cell served line FDC-PI _Λ their preparation by Dexter, TM et al. in J. Exp. Med. 152, 1036-1047 (1980). Alternatively, other growth factor-dependent cells can also be used (see, for example, Pierce, JH et al. In Science 223., 628-631 (1988), Shibuya, H. et al. In Cell IQ., 57-67 (1992) and Alexander, WS et al. in EMBO J. Lu, 3683-3691 (1991)). Recombinant retroviruses were used to express the human EGF-R cDNA (see Ullrich, A. et al. In Nature 309, 418-425 (1984)), as described in von Rüden, T. et al. , EMBO J. 1, 2749-2756 (1988), with the difference that to express the EGF-R cDNA the retroviral vector LXSN (see Miller, AD et al. In BioTechniques _Z, 980-990

(1989)) and the line GP + E86 (see Markowitz, D. et al. In J. Virol. £ 2., 1120-1124 (1988)) was used as the packaging cell.

The test was carried out as follows:

F / L-HERc cells were in RPMl / 1640 medium (BioWhittaker), supplemented with 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotics and 20 ng / ml human EGF (Promega), at 37 ° C and 5% CO ₂ cultivated fourth. To investigate the inhibitory activity of the compounds according to the invention, 1.5 × 10 ⁴ cells per well in triplicates in 96-well plates were cultivated in the above medium (200 μl), the proliferation of the cells either with EGF (20 ng / ml) or murine IL-3 was stimulated. Culture supernatants from cell line X63 / 0 mIL-3 served as the source for IL-3 (see Karasuyama, H. et al. In Eur. J. Immunol. IS., 97-104 (1988)). The compounds according to the invention were dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated at 37 ° C for 48 hours.

To determine the inhibitory activity of the compounds according to the invention, the relative cell number was determined using the Cell

Titer 96 ™ AQ _ue ous Non-Radioactive Cell Proliferation Assay (Promega) measured in OD units. The relative cell number was calculated as a percentage of the control (F / LHERc cells without inhibitor) and the active substance concentration, which inhibits the proliferation of the cells by 50% (IC ₅₀ ), was derived. The following results were obtained:

The compounds of the general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as has been shown using the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes caused by overactive tyrosine kinases become. These are, for example, benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).

The compounds of the invention are also useful for the prevention and treatment of respiratory and lung diseases associated with increased or altered mucus production caused by stimulation of tyrosine kinases such as e.g. for inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic

Fibrous, αl-antitrypsin deficiency, or for cough, emphysema, pulmonary fibrosis and hyperreactive airways.

The compounds are also suitable for the treatment of diseases of the gastrointestinal tract and the bile ducts and bladder which are associated with impaired activity of the tyrosine kinases, such as e.g. in chronic inflammatory

Changes can be found, such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or how they occur in diseases of the gastrointestinal tract that are associated with increased secretion, such as M. Menetrier, secreting Adenomas and protein loss syndromes,

furthermore for the treatment of nasal polyps as well as polyps of the gastrointestinal tract of different origins such as villous or adenomatous polyps of the colon, but also of polyps in familial polyposis coli, in intestinal polyps as part of the Gardner syndrome, in polyps in the entire gastrointestinal tract at Peutz -Jeghers syndrome, with inflammatory pseudopolyps, with juvenile polyps, with colitis cystica profunda and with Pneumatosis cystoides intestinales. In addition, the compounds of general formula I and their physiologically tolerable salts for the treatment of kidney diseases, in particular in the case of cystic changes such as in cystic kidneys, for the treatment of kidney cysts, which may be of idiopathic origin or occur in the context of syndromes, for example in tuberous sclerosis von Hippel-Lindau syndrome, which uses nephronophthisis and marrow sponge kidney as well as other diseases caused by aberrant function of tyrosine kinases, such as epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells etc.

Because of their biological properties, the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (for example etoposide), mitotic inhibitors (e.g. vinblastine), with

Compounds interacting with nucleic acids (e.g. cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc), cytokines (e.g. interferons), antibodies etc. These compounds can be used to treat respiratory diseases used alone or in combination with other respiratory therapies, such as secretolytic, broncholytic and / or anti-inflammatory substances. For the treatment of diseases in the gastrointestinal tract, these compounds can also be given alone or in combination with substances which influence motility or secretion or which have anti-inflammatory effects. These combinations can be administered either simultaneously or sequentially. These compounds can be used either alone or in combination with other active compounds, intravenously, subcutaneously, intramuscularly, intrarectally, intraperitoneally, intranasally, by inhalation or transdermally or orally, aerosol formulations in particular being suitable for inhalation.

In pharmaceutical use, the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in doses of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg. For administration, these are mixed with one or more conventional inert carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol ,. Carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures are incorporated into conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.

The following examples are intended to illustrate the present invention without restricting it:

Preparation of the starting compounds:

Example I

4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-

7- (2-brnτn-hoxy) -quinazoline

To 3.50 g of 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyl-methoxy-7-hydroxy-quinazoline and 6.89 ml of 1,2-dibromoethane in 40 ml of N, N-dimethylformamide are 4.84 g Potassium carbonate. The reaction mixture is stirred under a nitrogen atmosphere at 80 ° C. for 1.5 hours. After cooling to room temperature The reaction mixture is filtered and the filtrate is concentrated in vacuo. The oily, brown residue is cooled in an ice bath and triturated with a little methanol, a yellowish solid crystallizing out. The precipitate is filtered off, washed with cold methanol and dried in a vacuum desiccator.

Yield: 2.60 g (58% of theory),

R _f value: 0.82 (silica gel, methylene chloride / methanol 9: 1) mass spectrum (ESI ⁺ ): m / z = 494, 496, 498 [M + H] ⁺

The following compounds are obtained analogously to Example I:

(1) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy- 7- (2-bromoethoxy) -quinazoline (the reaction is carried out in acetonitrile as solvent)

R _f value: 0.72 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ^" ): m / z = 464, 466, 468 [MH] ^"

(2) 4- [(3-Chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- (2-bromoethoxy) quinazoline

R _f value: 0.65 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ^" ): m / z = 478, 480, 482 [MH] ^"

(3) 4- [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-

6- (3-bromo-propyloxy) -quinazoline (the reaction is carried out in acetonitrile as solvent)

R _f value: 0.62 (silica gel, methylene chloride / methanol ^' 9: 1) mass spectrum (ESI ^" ): m / z = 478, 480, 482 [MH] ^"

(4) 4- [(3-chloro-4-fluorophenyl) amino] - 7 -cyclopropylmethoxy- 6- (3-bromo-propyloxy) -quinazoline (the reaction is carried out in acetonitrile as solvent) R _f value: 0.74 (silica gel, methylene chloride / methanol 9: 1) mass spectrum (ESI ^" ): m / z = 478, 480, 482 [MH] ^" (5) 4- [(3-bromo-phenyl) amino] -6- (2-bromo-ethoxy) -7-methoxy-quinazoline

Melting point: 244 ° C mass spectrum (ESI ⁺ ): m / z = 452, 454, 456 [M + H] ⁺

(6) 4- [(R) - (1-phenyl-ethyl) amino] -6- (3-bromo-propyloxy) - 7-methoxy-quinazoline (the reaction is carried out with potassium tert-butoxide as the base) R _£ value: 0.60 (silica gel, ethyl acetate / methanol 9: 1)

(7) 4- [(R) - (1-phenyl-ethyl) amino] -6- (2-bromo-ethoxy) -7-methoxy-quinazoline (the reaction is carried out with potassium te .butylate as the base) melting point : 255 ° C

Mass spectrum (ESI ⁺ ): m / z = 402, 404 [M + H] ⁺

(8) 4- [(3-Chloro-4-fluorophenyl) amino] -6- (3-hydroxypropyloxy) - 7-cyclobutyloxy-quinazoline Rf value: 0.50 (silica gel, methylene chloride / methanol = 90:10 ) Mass spectrum (ESI ⁺ ): m / z = 418, 420 [M + H] ⁺

(9) 4- [(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxypropyloxy) - 7-cyclopropylmethoxy-quinazoline R _f value: 0.21 (silica gel, methylene chloride / methanol = 95: 5) Mass spectrum (ESI ⁺ ): m / z = 418, 420 [M + H] ⁺

(10) 4- [(3-chloro-4-fluorophenyl) amino] -6- (2-bromo-ethoxy) -7-cyclopentyloxy-quinazoline R _f value: 0.67 (silica gel, methylene chloride / methanol = 90: 10) Mass spectrum (ESI ⁺ ): m / z = 480, 482, 484 [M + H] ⁺ (11) 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- (2-bromo-ethoxy) -7-cyclopropylmethoxy-quinazoline

R _f value: 0.68 (silica gel, methylene chloride / methanol = 90:10) mass spectrum (ESI ⁺ ): m / z = 466, 468, 470 [M + H] ⁺

(12) 4- [(3-Chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3-hydroxy-propyloxy) quinazoline

R _f value: 0.53 (silica gel, methylene chloride / methanol = 90:10) mass spectrum (ESI ⁺ ): m / z = 418, 420 [M + H] ⁺

(13) 4- [(3-chloro-4-fluoro-phenyl) amino] -6- (4-hydroxy-butyloxy) ^■ 7-cyclopentyloxy-quinazoline

R _f value: 0.46 (silica gel, ethyl acetate)

(14) 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- (2-bromo-ethoxy) -7- ((R) -tetrahydrofuran-3-yloxy) -quinazoline

R _f value: 0.37 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI-): m / z = 480, 482, 484 [MH] ^"

(15) 4- [(3-chloro-4-fluoro-phenyl) amino] -6- (2-bromoethoxy) -7- [[R) - (tetrahydrofuran-2-yl) methoxy] quinazoline mass spectrum ( ESI-): m / z = 494, 496, 498 [MH] ^"

(16) 4- [(3-chloro-4-fluorophenyl) amino] -7- (2-bromoethoxy) -6- [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline

Mass spectrum (ESI ^" ): m / z = 494, 496, 498 [MH] ^"

Example IT

4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-hyroxy-quin ol in 4.99 g of 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline are suspended in 80 ml of methanol and mixed with 1.80 ml of concentrated, aqueous ammonia solution. The reaction mixture is stirred at 5 room temperature overnight. For working up, the reaction mixture is diluted with 500 ml of methylene chloride, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 4.30 g of a brownish solid are obtained. The raw product is treated with tert-butyl

10 methyl ether stirred, suction filtered, washed with a little tert-butyl methyl ether and dried in vacuo at room temperature.

Yield: 3.59 g (80% of theory),

R _f value: 0.48 (silica gel, methylene chloride / methanol / concentrated 15 aqueous ammonia solution = 90: 10: 0.1)

Mass spectrum (ESI ⁺ ): m / z = 388, 340 [M + H] ⁺

The following compounds are obtained analogously to Example II:

'20 (1) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7-hydroxy-quinazoline

R _f value: 0.56 (silica gel, methylene chloride / methanol 9: 1) mass spectrum (ESI ^" ): m / z = 358, 360 [MH] ^"

25 (2) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7-hydroxy-quinazoline

R _f value: 0.53 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ⁺ ): m / z = 374, 376 [M + H] ⁺

30

(3) 6-Benzyloxy-4- [(3-chloro-4-fluoro-phenyl) amino] -7-hydroxyquinazoline

R _f value: 0.54 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1)

35 mass spectrum (ESI ⁺ ): m / z = 396, 398 [M + H] ⁺ (4) 4- [(3-bromophenyl) amino] -6-hydroxy-7-methoxyquinazoline (the reaction is carried out using sodium hydroxide solution in ethanol as solvent) R _f value: 0.23 (silica gel, ethyl acetate)

Mass spectrum (ESI ⁺ ): m / z = 346, 348 [M + H] ⁺

(5) 4- [(3-chloro-4-fluorophenyl) amino] -7-hydroxy-6- ((S) - tetrahydrofuran-3-yloxy) -quinazoline R _f value: 0.57 (silica gel, methylene chloride / Methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 376, 378 [M + H] ⁺

(6) 4- [(3-Chloro-4-fluorophenyl) amino] -7-hydroxy-6- [(S) - (tetrahydrofuran-2-yl) ethoxy] -quinazoline R _f value: 0.42 (silica gel , Methylene chloride / methanol = 9: 1)

Example U_I

4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline

4.03 g of 4-chloro-6-cyclopentylmethoxy-7-methylcarbonyloxy-chinazoline are suspended in 70 ml of isopropanol and mixed with 1.95 g of 3-chloro-4-fluoro-aniline. The reaction mixture is refluxed under a nitrogen atmosphere for two hours. After cooling to room temperature, the light precipitate formed is suction filtered, washed with a little isopropanol and air-dried.

Yield: 4.99 g (92% of theory),

R _f value: 0.80 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1)

Mass spectrum (ESI ⁺ ): m / z = 430, 432 [M + H] ⁺

The following compounds are obtained analogously to Example II: (1) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7-methylcarbonyloxy-quinazoline

R _f value: 0.86 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 402, 404 [M + H] ⁺

(2) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline

R _f value: 0.73 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ⁺ ): m / z = 416, 418 [M + H] ⁺

(3) 6-Benzyloxy-4- [(3-chloro-4-fluoro-phenyl) amino] -7-methylcarbonyloxy-quinazoline

R _f value: 0.76 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1)

Mass spectrum (ESI ⁺ ): m / z = 438, 440 [M + H] ⁺

(4) 4- [(3-bromophenyl) amino] -6-methylcarbonyloxy-7-methoxyquinazoline R _f value: 0.50 (silica gel, ethyl acetate)

Mass spectrum (ESI ⁺ ): m / z = 388, 390 [M + H] ⁺

(5) 4- [(R) - (1-phenyl-ethyl) amino] -6-hydroxy-7-methoxy-quinazoline (the acetoxy protective group is already split off under the reaction conditions)

R _f value: 0.46 (silica gel, ethyl acetate) mass spectrum (ESI ⁺ ): m / z = 296 [M + H] ⁺

(6) 6-Benzyloxy-4- [(3-chloro-4-fluoro-phenyl) amino] -7-cyclopentyloxy-quinazoline

(Pyridine is added as an auxiliary base)

R _f value: 0.51 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 464, 466 [M + H] ⁺ (7) 4- [(3-chloro-4-fluoro-phenyl) amino] -7 -methylcarbonyloxy-6- ((S) -tetrahydrofuran-3-yloxy) -quinazoline

R _f value: 0.67 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 416, 418 [MH] ^~

(8) 4- [(3-Chloro-4-fluorophenyl) amino] -7-methylcarbonyloxy-6- [(S) - (tetrahydrofuran-2-yl) ethoxy] quinazoline hydrochloride melting point: 274-276 ° C

Mass spectrum (ESI ⁺ ): m / z = 432, 434 [M + H] ⁺

Example IV.

4-Chloro-6-cyclopentylmethoxy-7-methylcarbonyloxy-china ol _l 3.80 g of 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxyquinazoline are suspended in 90 ml of thionyl chloride and heated to boiling under a nitrogen atmosphere. After adding four drops of N, N-dimethylformamide, the reaction mixture is heated under reflux for a further two hours. After cooling to room temperature, the excess thionyl chloride is distilled off in a water jet vacuum. The brown residue is stirred with 30 ml of toluene. The solvent is distilled off and 4.30 g of a gray-brown solid remain, which is reacted further without further purification. R _f value: 0.89 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1)

The following compounds are obtained analogously to Example IV:

(1) 4-chloro-6-cyclopropylmethoxy-7-methylcarbonyloxy-chinazoline

R _f value: 0.84 (silica gel, methylene chloride / methanol = 9: 1)

(2) 4-Chloro-6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline R _f value: 0.69 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1)

(3) 6-Benzyloxy-4-chloro-7-methylcarbonyloxy-quinazoline R _f value: 0.77 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1)

(4) 6-Benzyloxy-4-chloro-7-cyclopentyloxy-quinazoline R _f value: 0.91 (silica gel, methylene chloride / methanol = 9: 1)

(5) 4-chloro-7-methylcarbonyloxy-6- ((S) -tetrahydrofuran-3-yloxy) -quinazoline

R _f value: 0.83 (silica gel, ethyl acetate / methanol = 9: 1)

(6) 4-chloro-7-methylcarbonyloxy-6- [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline R _f value: 0.48 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Example V

4-Hy roxy-6-cyclopenty1methoxy-7-methylcarbony1oxy-ch1.nazoline 4.30 g of 4, 7-dihydroxy-6-cyclopentylmethoxy-quinazoline in 100 ml of pyridine are heated to 80 ° C. under a nitrogen atmosphere. 1.80 ml of acetic anhydride are added to the dark brown suspension. The reaction mixture is stirred for three hours at 80 ° C., a complete solution being formed. After cooling to room temperature, the reaction mixture is poured onto about 800 ml of ice water. The resulting precipitate is filtered off and washed thoroughly with water. The light gray solid is dried in a vacuum desiccator. Yield: 3.82 g (77% of theory),

R _f value: 0.49 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 301 [MH] ^" The following compounds are obtained analogously to Example V:

(1) 4-Hydroxy-6-cyclopropylmethoxy-7-methylcarbonyloxy-chinazolin R _f value: 0.53 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 273 [MH] ^"

(2) 4-Hydroxy-6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline Melting point: 209-212 ° C mass spectrum (ESI ^" ): m / z = 287 [MH] ^"

(3) 6-Benzyloxy-4-hydroxy-7-methylcarbonyloxy-quinazoline R _f value: 0.48 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ^" ): m / z = 309 [MH] ^"

(4) 4-Hydroxy-7-methylcarbonyloxy-6- ((S) -tetrahydrofuran-3-yloxy) quinazoline

R _f value: 0.62 (reversed phase DC finished plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1) mass spectrum (ESI ⁺ ): m / z = 291 [M + H] ⁺

(5) 4-Hydroxy-7-methylcarbonyloxy-6- [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline R _f value: 0.50 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 305 [M + H] ⁺

Example VI

4,7-dihydroxy-6-cyclopentylmethoxy-china ol i

5.76 g of 2-amino-5-cyclopentylmethoxy-4-hydroxy-benzoic acid and 6.52 g of formamidine acetate in 140 ml of ethanol are heated under reflux for about three hours. For working up, the reaction mixture is concentrated to about 100 ml and 300 ml Ice water added, whereby a gray precipitate fails. The precipitate is filtered off, washed with water and dried in a vacuum desiccator. Yield: 4.57 g (77% of theory), R _f value: 0.25 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 259 [MH] ^"

The following compounds are obtained analogously to Example VI:

(1) 4, 7-Dihydroxy-6-cyclopropylmethoxy-quinazoline

R _f value: 0.45 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ^" ): m / z = 231 [MH] ^"

(2) 4, 7-Dihydroxy-6-cyclopentyloxy-quinazoline

R _f value: 0.42 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) mass spectrum (EI): m / z = 246 [M] ⁺

(3) 6-Benzyloxy-4, 7-dihydroxy-quinazoline

R _f value: 0.44 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10.-0.1) mass spectrum (ESI ^" ): m / z = 267 [MH] ^"

(4) 6-Benzyloxy-7-cyclopentyloxy-4-hydroxy-quinazoline Melting point: 221-223 ° C mass spectrum (ESI ⁺ ): m / z = 337 [M + H] ⁺

(5) 4, 7-Dihydroxy-6- ((S) -tetrahydrofuran-3-yloxy) -quinazoline R _f value: 0.69 (reversed phase TLC plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1) mass spectrum (ESI-): m / z = 247 [MH] ^~ (6) 4, 7-Dihydroxy-6- [(S) - (tetrahydrofuran-2-yl) ethoxy] quinazoline

R _f value: 0.56 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI-): m / z = 261 [MH] ^"

Example VTT

2-Αmino- -cyclopentylmethoxy-4-hydroxy-ben7: oleic acid

6.50 g of 5-cyclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid are dissolved in 130 ml of methanol, mixed with 2.00 g of Raney nickel and hydrogenated under a hydrogen pressure of 50 psi for about three hours at room temperature until the calculated amount of hydrogen is recorded. The catalyst is filtered off and washed with hot methanol. The filtrate is concentrated in vacuo. A brownish solid remains, which is reacted further without further purification. Yield: 5.79 g (100% of theory),

R _f value: 0.67 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 250 [MH] ^"

The following compounds are obtained analogously to Example VII:

(1) 2-Amino-5-cyclopropylmethoxy-4-hydroxy-benzoic acid R _f value: 0.51 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ^" ): m / z = 222 [MH] ^"

(2) 2-Amino-5-cyclopentyloxy-4-hydroxy-benzoic acid

R _f value: 0. 38 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ⁺ ): m / z = 238 [M + H] ⁺

(3) 2-Amino-5-benzyloxy-4-hydroxy-benzoic acid

R _f value: 0.52 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Mass spectrum (ESI ^" ): m / z = 258 [MH] ^"

(4) 2-Amino-5-benzyloxy-4-cyclopentyloxy-benzoic acid cyclopentyl ester (the reaction is carried out in a 1: 1 mixture of methanol and tetrahydrofuran)

R _f value: 0.84 (silica gel, ethyl acetate / cyclohexane = 1: 1) mass spectrum (ESI ⁺ ): m / z = 396 [M + H] ⁺

(5) 2-Amino-4-hydroxy-5- ((S) -tetrahydrofuran-3-yloxy) benzoic acid

R _f value: 0.70 (reversed phase DC finished plate (E. Merck),

Acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass spectrum (ESI ^" ): m / z = 238 [MH] ^"

(6) 2-Amino-4-hydroxy-5- [(S) - (tetrahydrofuran-2-yl) methoxy] benzoic acid

R _f value: 0.59 (reversed phase DC finished plate (E. Merck),

Acetonitrile / water / trifluoroacetic acid = 50: 50: 1) mass spectrum (ESI ^" ): m / z = 252 [MH] ^"

Example VIII

-Cyclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid 15.37 g 4, 5-methylenedioxy-2-nitro-benzoic acid and 51.84 ml

Cyclopentylmethanol are dissolved in 100 ml of dimethyl sulfoxide and cooled in an ice bath under a nitrogen atmosphere. 3.90 g of sodium are now added in portions. The reaction mixture is stirred for 30 minutes with ice bath cooling, then briefly warmed to 35-40 ° C. and then stirred for a further three hours with ice bath cooling. The ice bath is then removed and the reaction mixture is stirred at room temperature overnight. The dark brown-red reaction solution is poured onto about 800 ml of acetone, whereby a dark brown precipitate precipitates. The precipitate is filtered off, washed with acetone, dissolved in 300-400 ml of water and adjusted to about pH 2 with 60 ml of 2N hydrochloric acid. The aqueous solution is extracted several times with methylene chloride. The combined extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The dark brown, oily flask residue is dissolved in 800 ml of methylene chloride and cleaned over a silica gel pack with methylene chloride / methanol (9: 1). A brown oil is obtained, which is crystallized by stirring with water while cooling with an ice bath. The resulting brownish precipitate is filtered off, washed with a little water and dried in a vacuum desiccator. Yield: 9.55 g (47% of theory),

R _f value: 0.67 (silica gel, toluene / dioxane / ethanol / glacial acetic acid

90: 10: 10: 6)

Mass spectrum (ESI ^" ): m / z = 280 [MH] ^"

The following compounds are obtained analogously to Example VIII:

(1) 5-Cyclopropylmethoxy-4-hydroxy-2-nitro-benzoic acid R _f value: 0.61 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6) mass spectrum (ESI ^" ): m / z = 252 [MH] ^"

(2) 5-Cyclopentyloxy-4-hydroxy-2-nitro-benzoic acid R _f value: 0.62 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6) mass spectrum (ESI ^" ): m / z = 266 [MH] ^"

(3) 5-Benzyloxy-4-hydroxy-2-nitro-benzoic acid Melting point: 176-178 ° C

Mass spectrum (ESI ^" ): m / z = 288 [MH] ^" (4) 4-Hydroxy-2-nitro-5- ((S) -tetrahydrofuran-3-yloxy) benzoic acid

R _f value: 0.58 (reversed phase DC finished plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1) mass spectrum (ESI ^~ ): m / z = 268 [MH] ^"

(5) 4-Hydroxy-2-nitro-5- [(S) - (tetrahydrofuran-2-yl) ethoxy] benzoic acid

R _f value: 0.53 (reversed phase DC finished plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1) mass spectrum (ESI ~): m / z = 282 [MH] ^"

Example] X

(2-Hydroxy-2-methyl-propylamino) -acetic acid, ethyl ester

100.00 g of sodium carbonate are added with cooling to 50.00 g of glycine ethyl ester hydrochloride in 100 ml of saturated potassium carbonate solution. The resulting mass is extracted several times with a total of about 600 ml of diethyl ether. The combined ether extracts are dried over sodium sulfate and the

Dry evaporated. There remain 28.60 g of glycine ethyl ester. This is mixed with 26.00 ml of isobutylene oxide and 40 ml of absolute ethanol and heated in a Roth bomb at 90 ° C for six hours. After cooling to room temperature, the reaction mixture is concentrated, leaving a thin oil.

Yield: 45.80 g (73% of theory), mass spectrum (ESI ⁺ ): m / z = 176 [M + H] ⁺

When playing] X

4-Me y] am o-ihydro-furan-2-one

2.00 g of 4- (N-benzyl-N-methylamino) dihydro-furan-2-one in

25 ml of methanol are in the presence of 250 mg of palladium (10% on activated carbon) at a hydrogen pressure of 50 psi for about two hours at room temperature until the calculated amount of hydrogen is absorbed. For working up, the catalyst is filtered off and the filtrate is concentrated in vacuo. A colorless oil remains, which is immediately reacted without further purification. Yield: 1.20 g

R _f value: 0.13 (silica gel, ethyl acetate) mass spectrum (ESI ⁺ ): m / z = 116 [M + H] ⁺

Example XI

4- (N-benzyl-N-mefhy] amino) dihydro-furan-2-one

23.20 ml of N-methylbenzylamine are added to 15.00 g of 5H-furan-2-one in 150 ml of methylene chloride. The reaction mixture is stirred for about 48 hours at room temperature. For working up, the reaction mixture is concentrated and chromatographed in portions over a silica gel column using ethyl acetate / petroleum ether (3: 1) as the eluent. The desired product is obtained as a yellowish oil.

Yield: 19.77 g (54% of theory), R _f value: 0.57 (silica gel, ethyl acetate) mass spectrum (ESI ⁺ ): m / z = 228 [M + Na] ⁺

Ex XTT

4- [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6-hydroxy-πhinazoline

10 ml of tri- • fluoroacetic acid are added dropwise to 5.60 g of 6-benzyloxy-4- [(3-chloro-4-fluorophenyl) amino] - 7-cyclobutyloxy-quinazoline with stirring. The reaction mixture heats up to about 40 ° C. After 20 hours of stirring at room temperature, another 3 ml of trifluoroacetic acid are added. After the reaction has hardly progressed even after stirring for a further three hours at room temperature, the reaction mixture becomes heated to 50 ° C. After four hours the reaction is complete and the excess trifluoroacetic acid is largely distilled off on a rotary evaporator. The residue is mixed with water and made alkaline with concentrated, aqueous ammonia solution. The resulting light brown precipitate is filtered off, washed with plenty of water and dried in a desiccator. The product obtained still contains trifluoroacetic acid. Yield: 5.82 g R _f value: 0.61 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ΞSI ⁺ ): m / z = 360, 362 [M + H] ⁺

The following compounds are obtained analogously to Example XII:

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

R _f value: 0.65 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 360, 362 [M + H] ⁺

(2) 4- [(3-chloro-4-fluorophenyl) amino] -7-cyclopentyloxy-6-hydroxy-quinazoline

R _f value: 0.65 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 374, 376 [M + H] ⁺

(3) 4- [(3-chloro-4-fluorophenyl) amino] -6-hydroxy-7- ((R) -tetrahydrofuran-3-yloxy) -quinazoline R _f value: 0.32 (silica gel, methylene chloride / Methanol = 9: 1)

(4) 4- [(3-chloro-4-fluorophenyl) amino] -6-hydroxy-7- [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline

Mass spectrum (ESI-): m / z = 388, 390 [MH] ^~

Example XIII 6-benzyloxy-4- [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-quinazoline _:

7.00 g of potassium carbonate and 4.50 g of cyclobutyl methanesulfonate are added to 7.00 g of 6-benzyloxy-4- [(3-chloro-4-fluorophenyl) amino] -7-hydroxy-quinazoline in 60 ml of N, N-dimethylformamide , The reaction mixture is stirred at 80 ° C for two hours. Then another 2.00 g of methanesulfonic acid cyclobutyl ester and 3.00 g of potassium carbonate are added and the mixture is stirred at 60 ° C. over the weekend. Since the reaction is still not complete, 3.50 g of cyclobutyl methanesulfonic acid and 5.00 g of potassium carbonate are again added. After a further 20 hours at 80 ° C, the reaction is almost complete. For working up, the reaction mixture is mixed with 300 ml of ethyl acetate and washed with water and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is stirred with methanol, giving a brownish precipitate. This is suctioned off, washed with methanol and dried in a desiccator. Yield: 5.10 g (64% of theory),

R _f value: 0.69 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 448, 450 [MH] ^"

The following compounds are obtained analogously to Example XIII:

(1) 6-benzyloxy-4- [(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-quinazoline (bromomethylcyclopropane is used)

R _f value: 0.72 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 448, 450 [MH] ^"

(2) 6-Benzyloxy-4- [(3-chloro-4-fluoro-phenyl) amino] -7-cyclopentyloxy-quinazoline

(Bromocyclopentane is used) R _f value: 0.78 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum (ESI ⁺ ): m / z = 464, 466 [M + H] ⁺

Example XIV

I S) - (2-Hydroxy-propylamino) acetic acid tert. Butyl ester

15.00 g of (S) - (+) -l-amino-2-propanol are dissolved in 100 ml of N, N-dimethylformamide and mixed with 6.97 ml of diisopropylethylamine. Then 5.91 ml of bromoacetic acid are tert-cooled with an ice bath. Butyl ester added dropwise within 30 minutes. The cooling bath is removed and the reaction mixture is stirred overnight at room temperature. For working up, the reaction mixture is concentrated in vacuo. The flask residue is dissolved in 50 ml of water and saturated with 15 g of sodium chloride. The aqueous solution is extracted several times with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo, leaving a yellowish oil. Yield: 7.36 g (97% of theory), R _f value: 0.46 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 190 [M + H] ⁺

The following compounds are obtained analogously to Example XIV:

(1) (R) - (2-hydroxypropylamino) acetic acid, butyl ester R _f value: 0.46 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 190 [M + H] ⁺

(2) (1, l-Dimethyl-2-hydroxyethylamino) acetic acid tert. - Butyl ester mass spectrum (ESI ⁺ ): m / z = 204 [M + H] ⁺

R _f value: 0.47 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) Example XV

4- [(3-chloro-4-fluorophenyl) amino] -6- (3-methanesulfonyloxypropyloxy) -7-cyclobutyloxy-quinazoline The compound is obtained by reacting 4- [(3-chloro-4-fluoro- phenyl) amino] -6- (3-hydroxy-propyloxy) -7-cyclobutyloxy-quinazoline with methanesulfonic acid chloride in methylene chloride in the presence of diisopropylethylamine at room temperature. R _f value: 0.37 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ^" ): m / z = 494, 496 [MH] ^"

The following compounds are obtained analogously to Example XV:

(1) 4- [(3-chloro-4-fluorophenyl) amino] -6- (3-methanesulfonyloxypropyloxy) -7-cyclopropylmethoxy-quinazoline

R _f value: 0.65 (silica gel, methylene chloride / methanol = 90:10) mass spectrum (ESI ^" ): m / z = 494, 496 [MH] ^"

(2) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3-methanesulfonyloxypropyloxy) quinazoline

R _f value: 0.73 (silica gel, methylene chloride / methanol = 90:10) mass spectrum (ESI ⁺ ): m / z = 496, 498 [M + H] ⁺

(3) 4- [(3-chloro-4-fluorophenyl) amino] -6- (4-methanesulfonyloxy-butyloxy) -7-cyclopentyloxy-quinazoline

R _f value: 0.76 (silica gel, methylene chloride / methanol = 90:10) mass spectrum (ESI ⁺ ): m / z = 524, 526 [M + H] ⁺

Example XVI 4- [(3-chloro-4-fluorophenyl) amino] -6-hydroxy-7 ~ cyclopropylethoxy-quinazoline

The compound is obtained by hydrogenation of 6-benzyloxy-4- [(3-chloro-4-fluorophenyl) amino] -7-cylcopropylmethoxy-quinazoline

Presence of 10% Pd / C in a mixture of methylene chloride,

Ethanol and conc. Hydrochloric acid (500: 210: 3.5) in a Parr

Obtain equipment.

Yield: 73% of theory

Mass spectrum (ESI ⁺ ): m / z = 360, 362 [M + H] ⁺

Example XVII

5-Benzyloxy-4-cyclopentyloxy-2-nitro-benzoic acid, cyclopentyl ester, The compound is obtained by reacting 5-benzyloxy-4-hydroxy-2-nitro-benzoic acid with 2.2 equivalents of bromocyclopentane in the presence of potassium carbonate as auxiliary base in dimethyl sulfoxide at room temperature , Yield: 87% of theory R _f value: 0.92 (silica gel, ethyl acetate / cyclohexane = 1: 1) mass spectrum (ESI ⁺ ): m / z = 426 [M + H] ⁺

Example XVIII

4- [(3-chloro-4-fluorophenyl) amino] -6-benzyloxy-7- ((R) -tetrahydrofuran-3-yloxy) quinazoline

To a solution of 8.00 g of 4- [(3-chloro-4-fluorophenyl) amino] - 6-benzyloxy-7-hydroxyquinazoline (see WO 0055141 AI) and 2.42 ml of (S) - (+) - 3 hydroxy-tetrahydrofuran and 7.95 g of triphenylphosphine in 160 ml of tetrahydrofuran 5:03 ml ^'of diethyl azodicarboxylate dropwise. The reaction mixture is stirred at room temperature overnight and then on Rotary evaporator concentrated. The flask residue is purified chromatographically on a silica gel column using methylene chloride / ethyl acetate (gradient from 2: 1 to 1: 2) as the eluent.

Yield: 7.34 g (78% of theory) Melting point: 165-168 ° C mass spectrum (ESI ⁺ ): m / z = 466, 468 [M + H] ⁺

The following compounds are obtained analogously to Example XVIII:

(1) 4- [(3-Chloro-4-fluorophenyl) amino] -6-benzyloxy-7- [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline

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

R _f value: 0.38 (silica gel, methylene chloride / methanol = 15: 1)

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

R _f value: 0.35 (silica gel, methylene chloride / methanol = 20: 1)

Making the end connections:

example 1

4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-

7- [2- (2,2-dimethyl-6-oxo-mor-polin-4-y]) ethoxylquinazoline 250 mg 4- [(3-chloro-4-fluorophenyl) amino] -6- Cyclopentylmethoxy- 7- (2-bromo-ethoxy) -quinazoline and 341 mg (2-hydroxy-2-methyl-propylamino) -acetic acid ethyl ester are dissolved in 20 ml of acetonitrile and with 50 mg of sodium iodide, 275 mg of potassium carbonate and 0.70 ml of diisopropylethylamine added. The reaction mixture is heated under reflux for about 90 hours. After cooling to room temperature, the reaction mixture is filtered and the The filtrate was concentrated in vacuo. The flask residue is chromatographed on a silica gel column using petroleum ether / ethyl acetate (50:50, later 0: 100) as the eluent. The cyclized product is obtained as a beige solid. Yield: 62 mg (23% of theory), R _f value: 0.29 (silica gel, ethyl acetate) mass spectrum (ESI ^" ): m / z = 541, 543 [MH] ^"

The following compounds are obtained analogously to Example 1:

(1) 4- [(3-chloro-4-fluorophenyl) amino] - 6-cyclopropylmethoxy- 7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] - quinazoline R _f value: 0.58 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 513, 515 [MH] ^"

(2) 4- [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-

6- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) propyloxy] quinazoline

Melting point: 212-214 ° C

Mass spectrum (ESI ^" ): m / z = 527, 529 [MH] ^"

(3) 4- [(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-

6- [3- (2,2-dimethyl-6-oxomorpholin-4-yl) propyloxy] quinazoline

Melting point: 200-202 ° C

Mass spectrum (ESI ^" ): m / z = 527, 529 [MH] ^"

(4) 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) propyloxy] -7-methoxy- quinazoline melting point: 222-224 ° C

Mass spectrum (ESI ^" ): m / z = 487, 489 [MH] ^"

Example 2

4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy- 7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} quinazoline 300 mg of 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy- 7- (2-bromo-ethoxy) -quinazoline and 400 mg of 4-methylamino-dihydro-furan-2-one in 20 ml of acetonitrile are mixed with 240 mg of potassium carbonate and 70 mg of sodium iodide and heated under reflux for 24 hours. After cooling to room temperature, the reaction mixture is filtered and the filtrate is concentrated in vacuo. The flask residue is chromatographed on a silica gel column using methylene chloride / methanol / concentrated, aqueous ammonia solution (97: 3: 0.05) as the eluent. The title compound is obtained as a light beige solid. Yield: 70 mg (22% of theory),

R _f value: 0.47 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ⁺ ): m / z = 501, 503 [M + H] ⁺

The following compounds are obtained analogously to Example 2:

(1) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] -ethoxy} - quinazoline

R _f value: 0.42 (silica gel, methylene chloride / methanol / concentrated aqueous ammonia solution = 90: 10: 0.1) mass spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺

(2) 4- [(3-chloro-4-fluorophenyl) amino] -6- {3- [N- (2-oxotetrahydrofuran-4-yl) -N-methylamino] propyloxy} - 7- cyclobutyloxy-quinazoline Melting point: 147.5-151 ° C mass spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺

Example 3

4- [(3-bromophenyl) amino] -6- [2- ((S) ~ 6-methyl-2-oxo-morpholin-4-yl) ethox 1 -7-methoxy-china ol n To 380 mg of 4- [(3-bromophenyl) amino] -6- (2- {N- [(ert.butyloxycarbonyl) methyl] -N- ((S) -2-hydroxypropyl) amino } -ethoxy) -7-meth-oxy-quinazoline in 8 ml acetonitrile, 90 μl methanesulfonic acid are added. The reaction mixture is refluxed for about three hours, then another equivalent of methanesulfonic acid is added and the reflux is continued until the reaction is complete. For working up, the reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The flask residue is stirred with diethyl ether and suction filtered. The title compound is obtained as a white solid. Yield: 280 mg (85% of theory), melting point: 190 ° C.

Mass spectrum (ESI ^" ): m / z = 485, 487 [MH] ^"

The following compounds are obtained analogously to Example 3:

(1) 4- [(3-Bromophenyl) amino] -6- [2- ((i?) -6-methyl-2-oxomorphol-lin-4-yl) ethoxy] -7-methoxy -quinazoline

Melting point: 193 ° C

Mass spectrum (ESI ⁺ ): m / z = 487, 489 [M + H] ⁺

(2) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- ((R) -6-methyl-

2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile) Melting point: 208 ° C mass spectrum (ESI ^" ): m / z = 459, 461 [MH] ^"

(3) 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- ((R) -6-methyl-

2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile) R _f value: 0.33 (silica gel, ethyl acetate) mass spectrum (ESI ^" ): m / z = 473, 475 [MH] ^"

(4) 4- [(R) - (1-phenyl-ethyl) amino] -6- [3- ((S) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7- methoxy-quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile) R _f value: 0.41 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 449 [MH] ^"

(5) 4- [(R) - (1-phenylethyl) amino] -6- [2- ((S) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7- methoxy-quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile) R _f value: 0.49 (silica gel, ethyl acetate / methanol / concentrated, aqueous ammonia solution = 9: 1: 0.1) mass spectrum (ESI ^" ): m / z = 435 [MH ] ^"

(6) 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- ((R) -6-methyl-2-oxo-morpholin-4-yl) propyloxy] -7- cyclobutyloxy-quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile)

Melting point: 185.5-189.5 ° C

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

(7) 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (5, 5-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7-cyclobutyloxy- quinazoline

(The reaction is carried out with triluoroacetic acid in acetonitrile)

Melting point: 214-216 ° C

Mass spectrum (ESI ^" ): m / z = 527, 529 [MH] ^"

(8) 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- ((R) -6-methyl-2-oxo-morpholin-4-yl) propyloxy] -7- cyclopropylmethoxy-quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile) Melting point: 160.5-163 ° C

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

(9) 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- ((S) -6-methyl-2-oxo-morpholin-4-yl) propyloxy] -7- cyclopropylmethoxy-quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile) Melting point: 160-162 ° C

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

(10) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -7- cyclopentyloxy-quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile)

R _f value: 0.31 (silica gel, ethyl acetate) mass spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺

(11) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- ((R) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -7- cyclopentyloxy-quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile) Melting point: 176-178 ° C mass spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺

(12) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -7- cyclopropylmethoxy-quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile)

R _f value: 0.37 (silica gel, ethyl acetate) Mass spectrum (ESI ⁺ ): m / z = 501, 503 [M + H] ⁺

(13) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- ((R) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -7- cyclopropylmethoxy-quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile)

R _f value: 0.37 (silica gel, ethyl acetate) mass spectrum (ESI ⁺ ): m / z = 501, 503 [M + H] ⁺

(14) 4- [(3-Chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) ethoxy ] -quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile)

R _f value: 0.48 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 501, 503 [M + H] ⁺

(15) 4- [(3-Chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2- ((R) -6-methyl-2-oxo-morpholin-4-yl) ethoxy ] -quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile)

Mass spectrum (ESI ⁺ ): m / z = 501, 503 [M + H] ⁺

(16) 4- [(3-Chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [3- ((R) -6-methyl-2-oxo-morpholin-4-yl) propyloxy ] -quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile)

R _f value: 0.67 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 513, 515 [MH] ^"

(17) 4- [(3-Chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [3- ((S) -6-methyl-2-oxo-morpholin-4-yl) propyloxy ] -quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile)

R _f value: 0.67 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESI ^" ): m / z = 513, 515 [MH] ^"

(18) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] -7-cyclopentyloxy- quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile) R _f value: 0.56 (silica gel, ethyl acetate)

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

(19) 4- [(3-Chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-7- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) ethoxy ] -quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile)

R _f value: 0.60 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 515, 517 [M + H] ⁺

(20) 4- [(3-Chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- ((R) -6-methyl-2-oxo-morpholin-4-yl) ethoxy ] -quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile)

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

(21) 4- [(3-chloro-4-fluorophenyl) amino] -6- [4- ((S) -6-methyl-2-oxo-morpholin-4-yl) butyloxy] -7- cyclopentyloxy-quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile) R _f value: 0.51 (silica gel, ethyl acetate)

Mass spectrum (ESI ⁺ ): m / z = 543, 545 [M + H] ⁺ (22) 4- [(3-chloro-4-fluorophenyl) amino] -6- [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) butyloxy] -7- cyclopentyloxy-quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile)

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

(23) 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- ((S) -6-methyl-2-oxo-morpholin-4-yl) propyloxy] -7- methoxy-quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile) Melting point: 183-186 ° C mass spectrum (ESI ⁺ ): m / z = 475, 477 [M + H] ⁺

(24.) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [3- (5, 5-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7-methoxy -quinazoline (the reaction is carried out with trifluoroacetic acid in acetonitrile) R _f -value: 0.43 (silica gel, ethyl acetate) mass spectrum (ESI ^" ): m / z = 487, 489 [MH] ^"

(25.) 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -7 methoxy-quinazoline

(The reaction is carried out with trifluoroacetic acid in acetonitrile)

Melting point: 212-213 ° C

Mass spectrum (ESI ⁺ ): m / z = 461, 463 [M + H] ⁺

(26) 4- [(3-Chloro-4-fluorophenyl) amino] -6- {2- [N- (carboxymethyl) -N- ((S) -2-hydroxypropyl) amino] ethoxy } -7- methoxy quinazoline (By-product in the manufacture of 3 (25))

Melting point: 187-190 ° C

Mass spectrum (ESI ⁺ ): m / z = 479, 481 [M + H] ⁺

(27) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] -7-methoxy- quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile) Melting point: 229-232 ° C. Mass spectrum (ESI ^~ ): m / z = 473, 475 [MH] ^"

(28) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] -7- (( R) -tetrahydrofuran-3-yloxy) - quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile) Melting point: 195-196 ° C mass spectrum (ESI ⁺ ): m / z = 531, 533 [M + H] ⁺

(29) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] -7- [( R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile) Melting point: 18 ° C.

Mass spectrum (ESI ⁺ ): m / z = 545, 547 [M + H] ⁺

(30) 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] -6- (( S) -tetrahydrofuran-3-yloxy) quinazoline

Melting point: 202-205 ° C Mass spectrum (ESI ⁺ ): m / z = 531, 533 [M + H] ⁺

(31) 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] -6- [( S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline Melting point: 182 ° C mass spectrum (ESI ⁺ ): m / z = 545, 547 [M + H] ⁺

Example 4.

4- [(3-bromo-phenyl) amino] -6- (2- {N- [(ert.butyloxycarbonyl) methyl] -N- ((S) -2-hydroxypropyl) amino} ethoxy) - 7-methoxy china zoline

To 650 mg of 4- [(3-bromo-phenyl) amino] -6- (2-bromo-ethoxy) -7-meth-oxy-quinazoline and 1.10 g of (£>) - (2-hydroxypropylamino) acetic acid - tert.butyl ester in 15 ml acetonitrile 0.25 ml diisopropylethylamine are added. The reaction mixture is stirred at 50 ° C. overnight. Since no reaction is discernible, the reaction mixture is concentrated, 20 ml of N, N-dimethylformamide are added and the mixture is stirred at 60 ° C. for eight hours. The temperature is then raised to 80 ° C. After another eight hours, the implementation is complete. The reaction mixture is concentrated and chromatographed on a silica gel column using ethyl acetate as the eluent. The desired product is obtained as a white solid.

Yield: 410 mg (51% of theory), R _f value: 0.27 (silica gel, ethyl acetate) mass spectrum (ESI ^" ): m / z = 559, 561 [MH] ^"

The following compounds are obtained analogously to Example 4:

(1) 4- [(3-bromophenyl) amino] -6- (2- {N- [(ert.butyloxycarbonyl) methyl] -N- ((R) -2-hydroxypropyl) amino} -ethoxy) -7-methoxy-quinazoline Melting point: 130 ° C

Mass spectrum (ESI ^" ): m / z = 559, 561 [MH] ^"

(2) 4- [(3-chloro-4-fluorophenyl) amino] -6- (2- {N- [(tert. Butyloxycarbonyl) methyl] -N- ((R) -2 -hydroxy- propyl) -amino} -ethoxy) -

7-methoxy-quinazoline (the reaction is carried out in N, N-dimethylformamide)

R _f value: 0.40 (silica gel, ethyl acetate / petroleum ether = 4: 1)

(3) 4- [(3-chloro-4-fluorophenyl) amino] -6- (3- {N- [(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxypropyl) -amino} -propyloxy) -

7-methoxy-quinazoline (the reaction is carried out in N, N-dimethylformamide)

R _f value: 0.37 (silica gel, ethyl acetate / petroleum ether = 4: 1) mass spectrum (ESI ^" ): m / z = 547, 549 [MH] ^"

(4) 4- [(R) - (1-phenyl-ethyl) amino] -6- (3- {N- [(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxypropyl) -amino} -propyloxy) -

7-methoxy-quinazoline (the reaction is carried out in N, N-dimethylformamide)

R _f value: 0.65 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (EI): m / z = 524 [M] ⁺

(5) 4- [(R) - (1-phenylethyl) amino] -6- (2- {N- [(tert. Butyloxycarbonyl) methyl] -N- ((S) -2 -hydroxy- propyl) -amino} -ethoxy) -

7-methoxy-quinazoline (the reaction is carried out in N, N-dimethylformamide)

R _f value: 0.57 (silica gel, ethyl acetate / methanol / concentrated aqueous ammonia solution = 9: 1: 0.1)

(6) 4- [(3-chloro-4-fluoro-phenyl) amino] -6- (3- {N- [(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxypropyl ) -amino} - propyloxy) -7-cyclobutyloxy-quinazoline R _f value: 0.31 (silica gel, methylene chloride / methanol = 95: 5) (7) 4- [(3-Chloro-4-fluorophenyl) amino] -6- (3- {N- [(tert-butyloxycarbonyl) ethyl] -N- (1,1-dimethyl-2-hydroxy -ethyl) - amino} -propyloxy) -7-cyclobutyloxy-quinazoline R _f value: 0.29 (silica gel, methylene chloride / methanol = 95: 5) mass spectrum (ESI ⁺ ): m / z = 603, 605 [M + H] ⁺

(8) 4- [(3-Chloro-4-fluorophenyl) amino] -6- (3- {N- [(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxypropyl ) -amino} - propyloxy) -7-cycloproρylmethoxy-quinazoline

R _f value: 0.37 (silica gel, methylene chloride / methanol = 95: 5)

(9) 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- (3- {N- [(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxypropyl ) -amino} - propyloxy) -7-cycloproρylmethoxy-quinazoline R _f value: 0.50 (silica gel, ethyl acetate)

(10) 4- [(3-chloro-4-fluorophenyl) amino] -6- (2- {N- [(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxypropyl ) -amino} -ethoxy) -7-cyclopentyloxy-quinazoline

R _f value: 0.54 (silica gel, ethyl acetate / cyclohexane = 9: 1)

(11) 4- [(3-Chloro-4-fluorophenyl) amino] -6- (2- {N- [(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxypropyl ) -amino} - ethoxy) -7-cyclopentyloxy-quinazoline R _f value: 0.66 (silica gel, ethyl acetate)

(12) 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- (2- {N- [(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxypropyl ) -amino} - ethoxy) -7-cyclopropylmethoxy-quinazoline R _f value: 0.60 (silica gel, ethyl acetate) (13) 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- (2- {N- [(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxypropyl ) -amino} - ethoxy) -7-cyclopropylmethoxy-quinazoline R _f value: 0.60 (silica gel, ethyl acetate)

(14) 4- [(3-Chloro-4-fluoro-phenyl) amino] -β-cyclopropylmethoxy-7- (2- {N- [(tert-butyloxycarbonyl) ethyl] -N- ((S) -2 -hydroxy-propyl) -amino} -ethoxy) -quinazoline R _f -value: 0.30 (silica gel, ethyl acetate)

(15) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2- {N- [(tert-butyloxycarbonyl) methyl] -N- ((R) -2 -hydroxy-propyl) -amino} -ethoxy) -quinazoline R _f -value: 0.30 (silica gel, ethyl acetate)

(16) 4- [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopropylmethoxy-7- (3- {N- [(tert-butyloxycarbonyl) methyl] -N- ((R) -2 -hydroxy-propyl) -amino} -propyloxy) -quinazoline R _f -value: 0.35 (silica gel, ethyl acetate)

(17) 4- [(3-chloro-4-fluoro-phenyl) amino] -6-cyclopropylmethoxy-7- (3- {N- [(tert-butyloxycarbonyl) methyl] -N- ((S) -2 -hydroxy-propyl) -amino} -propyloxy]) -quinazoline R _f -value: 0.35 (silica gel, ethyl acetate)

(18) 4- [(3-chloro-4-fluorophenyl) amino] -6- (2- {N-

[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl-propyl) -amino} - ethoxy) -7-cyclopentyloxy-quinazoline R _f value: 0.64 (silica gel, methylene chloride / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 575, 577 [M + H] ⁺ (19) 4- [(3-Chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N- [(tert-butyloxycarbonyl) methyl] -N- ((S) -2 -hydroxy-propyl) - amino} -ethoxy) -quinazoline R _f value: 0.51 (silica gel, ethyl acetate)

(20) 4- [(3-Chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N- [(tert -butyloxycarbonyl) methyl] -N- ((R) -2 -hydroxy-propyl) - amino} -ethoxy) -quinazoline R _f value: 0.51 (silica gel, ethyl acetate)

(21) 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- (4- {N- [(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxypropyl ) -amino} - butyloxy) -7-cyclopentyloxy-quinazoline R _f value: 0.61 (silica gel, ethyl acetate) ^■

(22) 4- [(3-Chloro-4-fluorophenyl) amino] -6- (4- {N- [(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxypropyl ) -amino} - butyloxy) -7-cyclopentyloxy-quinazoline R _f value: 0.61 (silica gel, ethyl acetate)

(23) 4- [(3-Chloro-4-fluorophenyl) amino] -6- (3- {N- [(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxypropyl ) -amino} - propyloxy) -7-methoxy-quinazoline R _f value: 0.46 (silica gel, ethyl acetate)

Mass spectrum (ESI ^" ): m / z = 547, 549 [MH] ^"

(24) 4- [(3-Chloro-4-fluorophenyl) amino] -6- (3- {N- [(tert-butyloxycarbonyl) methyl] -N- (1, l-dimethyl-2-hydroxy -ethyl) - amino} -propyloxy) -7-methoxy-quinazoline

Mass spectrum (ESI ⁺ ): m / z = 563, 565 [M + H] ⁺ (25) 4- [(3-Chloro-4-fluorophenyl) amino] -6- (2- {N- [(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxypropyl ) -amino} - ethoxy) -7-methoxy-quinazoline R _f value: 0.66 (silica gel, ethyl acetate / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 535, 537 [M + H] ⁺

(26) 4- [(3-chloro-4-fluorophenyl) amino] -6- (2- {N-

[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methylpropyl) amino} - ethoxy) -7-methoxy-quinazoline

(Is available as a mixture with already cyclized substance) R _f value: 0.44 (silica gel, ethyl acetate) mass spectrum (ESI ⁺ ): m / z = 521, 523 [M + H] ⁺

(27) 4- [(3-chloro-4-fluorophenyl) amino] -6- (2- {N-

[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl-propyl) -amino} - ethoxy) -7- ((R) -tetrahydrofuran-3-yloxy) -quinazoline (lies as a mixture with already cyclized substance in front)

R _f value: 0.30 (silica gel, methylene chloride / methanol = 9: 1)

(28) 4- [(3-chloro-4-fluorophenyl) amino] -6- (2- {N-

[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl-propyl) -amino} - ethoxy) -7- [(R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline mass spectrum (ESI ^" ) : m / z = 589, 591 [MH] ^"

(29) 4- [(3-chloro-4-fluoro-phenyl) amino] -7- (2- {N-

[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl-propyl) -amino} -ethoxy) -6- ((S) -tetrahydrofuran-3-yloxy) -quinazoline R _f value: 0.16 (silica gel , Methylene chloride / methanol = 20: 1) (30) 4- [(3-Chloro-4-fluorophenyl) amino] -7- (2- {N- [(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methylpropyl) amino } - ethoxy) -6- [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline R _f value: 0.68 (silica gel, ethyl acetate / methanol = 15: 1)

The following compounds can be prepared analogously to the examples above and other processes known from the literature:

(1) 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6-methoxy-quinazoline

(2) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [3- (6-methyl-2-oxomorpholin-4-yl) propyloxy] -6-methoxy-quinazoline

(3) 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- ((S) -6-methyl-

2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline

(4) 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- ((S) -6-methyl-2-oxo-morpholin-4-yl) propyloxy] -7- methoxy-quinazoline

(5) 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (5, 5-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy- quinazoline

(6) 4- [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- quinazoline

(7) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [3- (3-methyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy-quinazoline

(8) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline

(9) 4- [(R) - (1-phenyl-ethyl) amino] -6- [3- ((R) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7- methoxy-quinazoline (10) 4- [(R) - (1-phenylethyl) amino] -6- [2- ((R) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7- methoxy-quinazoline

(11) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [4- (6-methyl-2-oxomorpholin-4-yl) butyloxy] -6-methoxy-quinazoline

(12) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [3- (6-methyl-2-oxomorpholin-4-yl) propyloxy] -6-methoxy-quinazoline

(13) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [4- (6-methyl-2-oxomorpholin-4-yl) butyloxy] -7-methoxy-quinazoline

(14) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -7- (tetrahydrofuran-3 -yloxy) -quinazoline

(15) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -7- (tetrahydropyran-3 -yloxy) -quinazoline

(16) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -7- (etrahydropyran-4 -yloxy) -quinazoline

(17) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-σxomorpholin-4-yl) ethoxy] -7- (tetrahydrofuran-2 -ylmethoxy) - quinazoline

(18) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -1- (tetrahydro-pyran-4 -ylmethoxy) - quinazoline

(19) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7- (tetrahydrofuran -3-yloxy) quinazoline (20) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7- (tetrahydrofuran -3 -yloxy) quinazoline

(21) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [4- (6, 6-dimethyl-2-oxo-morpholin-4-yl) butyloxy] -7- (tetrahydrofuran -3 -yloxy) quinazoline

(22) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7- (tetrahydrofuran -2-ylmethoxy) quinazoline

(23) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7- (tetrahydrofuran -2-ylmethoxy) quinazoline

(24) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [4- (6, 6-dimethyl-2-oxo-morpholin-4-yl) butyloxy] -7- (tetrahydrofuran -2 -ylmethoxy) quinazoline

(25) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydrofuran-3 -yloxy) -quinazoline

(26) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydropyran-3 -yloxy) -quinazoline

(27) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydropyran-4 -yloxy) -quinazoline

(28) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydrofuran-2 -ylmethoxy) - quinazoline

(29) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) ethoxy] -6- (tetrahydropyran-4 -ylmethoxy) - quinazoline (30) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -6- (tetrahydrofuran -3 -yloxy) quinazoline

(31) 4- [(3-Chloro-4-fluorophenyl) amino] - 1- [3- (6, 6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6- (tetrahydrofuran -3 -yloxy) quinazoline

(32) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [4- (6, 6-dimethyl-2-oxo-morpholin-4-yl) butyloxy] -6- (tetrahydrofuran -3 -yloxy) quinazoline

(33) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -6- (tetrahydrofuran -2 -ylmethoxy) quinazoline

(34) 4- [(3-Chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6- (tetrahydrofuran -2-ylmethoxy) quinazoline

(35) 4- [(3-chloro-4-fluorophenyl) amino] -7- [4- (6, 6-dimethyl-2-oxo-morpholin-4-yl) butyloxy] -6- (tetrahydrofuran -2 -ylmethoxy) quinazoline

Example 5

Dragees with 75 mg of active substance

1 coated tablet contains:

Active substance 75.0 mg

Calcium phosphate 93.0 mg

Corn starch 35.5 mg

Polyvinylpyrrolidone 10.0 mg hydroxypropylmethyl cellulose 15.0 mg

Magnesium stearate 1.5 mg 230.0 mg

manufacture;

The active substance is mixed with calcium phosphate, corn starch,

Polyvinylpyrrolidone, hydroxypropylmethylcellulose and - half of the stated amount of magnesium stearate mixed. Pressings with a diameter of approx. 13 mm are produced on a tabletting machine, these are rubbed through a sieve with a 1.5 mm mesh size on a suitable machine and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape.

Core weight: 230 mg

Stamp: 9 mm, domed

The dragee cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl cellulose. The finished film coated tablets are polished with beeswax. Drage weight: 245 mg.

Example] 6.

Tablets with 100 mg substance

Composition:

1 tablet contains: active substance 100.0 mg

Milk sugar 80.0 mg

Corn starch 34.0 mg

Polyvinyl pyrrolidone 4.0 mg

Magnesium stearate 2.0 mg 220.0 mg Driving her llungve:

Active ingredient, milk sugar and starch are mixed and moistened uniformly with an aqueous solution of the polyvinylpyrrolidone. After screening the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C, sieving is again carried out (1.5 mm mesh size) and the lubricant is added. The ready-to-press mixture is processed into tablets. Tablet weight: 220 mg

Diameter: 10 mm, biplane with facet on both sides and partial notch on one side.

Step Example. 1

Tablets with 150 mg Wi ksubs an ^

Composition:

1 tablet contains: active substance 150.0 mg

Milk sugar powder 89.0 mg

Corn starch 40.0 mg

Colloidal silica 10.0 mg

Polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg

300.0 mg

Herste] ing:

The active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a mesh size of 1.5 mm. The granules dried at 45 ° C are again rubbed through the same sieve and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture. Tablet weight: 300 mg stamp: 10 mm, flat

Example] 8.

Hard gelatin capsule with 150 mg of active substance

1 capsule contains: Active ingredient 150.0 mg corn starch dr. approx.180.0 mg powdered milk sugar approx.87.0 mg magnesium stearate 3,0 mg approx.420.0 mg

production:

The active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device. The final mix is filled into size 1 hard gelatin capsules.

Capsule filling: approx. 320 mg capsule shell: hard gelatin capsule size 1.

When playing] 9

Sπppositorien with 150 mg W ksubstanz

1 suppository contains: active ingredient 150.0 mg

Polyethylene glycol 1500 550.0 mg

Polyethylene glycol 6000 460.0 mg

Polyoxyethylene sorbitan monostearate 840.0 mg

2,000.0 mg

production: After the suppository mass has melted, the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds.

At spi e] 10

Suspension with 50 mg of active substance

100 ml suspension contain:

Active ingredient 1.00 g

Carboxymethylcellulose Na salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g cane sugar 10.00 g

Glycerin 5.00 g

Sorbitol solution 70% 20.00 g

Aroma 0.30 g

Distilled water ad 100 ml

production:

Dest. Water is heated to 70 ° C. P-Hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethyl cellulose sodium salt are dissolved therein with stirring. It is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously. After adding and dissolving the sugar, the sorbitol solution and the aroma, the suspension is evacuated with stirring for deaeration. 5 ml of suspension contain 50 mg of active ingredient.

Example 11

Ampoules with 10 mg active substance

Composition: Active ingredient 10.0 mg

0.0IN hydrochloric acid s.q.

Aqua bidest ad 2.0 ml

production:

The active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.

Example 12

Ampoules with 50 mg of active substance

Composition:

Active ingredient 50.0 mg

0.0IN hydrochloric acid s.q.

Aqua bidest to 10.0 ml

production:

The active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules. , , ,

Example] 13.

Capsules for powder inhalation with 5 mg of active substance

1 capsule contains:

Active substance 5.0 mg

Lactose for inhalation purposes 1.0 mg

20.0 mg

production: The active substance is mixed with lactose for inhalation purposes. The mixture is filled into capsules on a capsule machine (weight of the empty capsule approx. 50 mg). Capsule weight: 70.0 mg capsule size: 3

Example 14

Inhalation solution for hand-held nebulizers with 2.5 mg active substance

1 hub includes:

Active substance 2,500 mg benzalkonium chloride 0.001 mg IN hydrochloric acid q.s.

Ethanol / water (50/50) ad 15,000 mg

production:

The active substance and benzalkonium chloride are dissolved in ethanol / water (50/50). The pH of the solution is adjusted with IN hydrochloric acid. The resulting solution is filtered and filled into suitable containers for hand-held nebulisers ^■ (cartridges).

Filling mass of the container: 4.5 g

Claims

claims 1. Bicyclic heterocycles of the general formula R. ^a \ / ^H

in the R _{a is} a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R _x and R ₂ , where R- _{L represents} a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyan or ethynyl group and R _{2 represents} a hydrogen or fluorine atom, one of the radicals R _b or R _{0 is} an R ₃ - (CH ₂ ) _ra -0 group and the other of the radicals R _b or R _{c is} a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopen - tylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) methylamino or N- (2-oxo-tetrahydrofuran-4-yl) ethylamino group, an R ₄ -0-CO-CH ₂ -N-CH ₂ CH ₂ -OH group substituted on the methylene groups by one or two methyl or ethyl groups, in which R _{4 represents} a hydrogen atom or a C 1-4 alkyl group, or a 2-oxomorpholin-4-yl group substituted by one or two methyl or ethyl groups and m represents the number 2, 3 or 4, with the proviso that the connections 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- (2- {N- (2-hydroxy-2-methyl-prop-l-yl) -N- [(ethoxycarbonyl) methyl] amino} ethoxy) quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpholih-4-yl) ethoxy] -7-methoxy-quinazoline and 4- [(3-bromophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) N-methylamino] ethoxy} -7-methoxy-quinazoline excluded are, their tautomers, their stereoisomers and their salts. 2. Compounds of general formula I according to claim 1, in which R _{a is} a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R _x and R ₂ , where R _{x represents} a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyan or ethynyl group and R _{2 represents} a hydrogen or fluorine atom, one of the radicals R _b or R _{c is} an R ₃ - (CH ₂ ) _m -0 group and the other of the radicals R _b or R _{c is} a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) methylamino or N- (2-oxo-tetrahydrofuran-4-yl) ethylamino group, an R ₄ -0-CO-CH ₂ -N-CH ₂ CH ₂ -OH group substituted on the methylene groups by one or two methyl or ethyl groups, in which R _{4 represents} a hydrogen atom or a C 1-4 alkyl group, or a 2-oxomorpholin-4-yl group substituted by one or two methyl or ethyl groups and m represents the number 2, 3 or 4, with the proviso that the connections 4- [(3-Chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N- [(ethoxycarbonyl ) - methyl] -amino} -ethoxy) -quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] quinazoline, 4- [(3-bromophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-bromophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) N-methylamino] ethoxy} -7-methoxy-quinazoline, 4- [(3-Bromophenyl) amino] -6- (2- {N- (2-hydroxy-2-methylprop-1-yl) -N- [(ethoxycarbonyl) methyl] amino} ethoxy ) -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclobutyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopropylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl] amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 methoxy-quinazoline, 4- [(3-Chloro-4-fluorophenyl) amino] -6- (2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentyloxy-china- zolin, 4- [(3-chloro-4-fluorophenyl) amino] - 6 - (2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentylmethoxy- quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentylmethoxy-quinazoline ,. (R) -4- [(1-phenylethyl) amino] -6- [3- (6, 6-dimethyl-2-oxo-morpholino-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline . 4- ['(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclobutyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -1 - [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopropylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl] amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- (2- [N- (2-oχo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentyloxy-china- zolin, 4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentylmethoxy- quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxy-quinazoline and (R) -4- [(1-phenyl-ethyl) amino] -7- [3- (6, 6-dimethyl-2-oxo-morphol-lin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline excluded are, their tautomers, their stereoisomers and their salts. 3. Compounds of general formula I according to claim 1, in which R _{a represents} a 1-phenylethyl group or a phenyl group substituted by the radicals R _x and R ₂ , where R _{x is} a fluorine, chlorine or bromine atom, a methyl or Ethynyl group and R _{2 represents} a hydrogen or fluorine atom, one of the radicals R _b or R _{c is} an R ₃ - (CH ₂ ) _ra -0 group and the other of the radicals R _b or R _{c is} a methoxy, cyclobutyloxy, cyclo- pentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where R _{3 is} an N- (2-oxotetrahydrofuran-4-yl) methylamino group, an R ₄ -0-CO-CH ₂ -N-CH ₂ CH ₂ -0H group substituted on the methylene groups by one or two methyl groups, in which R _{4 is} a C ₁ . _{4 represents} alkyl group, or a 2-oxomorpholin-4-yl group substituted by one or two methyl groups and m represents the number 2, 3 or 4, with the proviso that the connections 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- (2- {N- (2-hydroxy-2-methyl-prop-l-yl) -N- [(ethoxycarbonyl ) - methyl] -amino} -ethoxy) -quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] quinazoline, 4- [(3-bromophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-bromophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) N-methylamino] ethoxy} -7-methoxy-quinazoline, 4- [(3-Bromophenyl) amino] -6- (2- {N- (2-hydroxy-2-methylprop-1-yl) -N- [(ethoxycarbonyl) methyl] amino} ethoxy ) -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclobutyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopropylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl] amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentyloxy-china- zolin, 4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentylmethoxy- quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentylmethoxy-quinazoline, (R) -4- [(1-phenyl-ethyl) amino] -6- [3- (6, 6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline . 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclobutyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopropylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl] amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentyloxy-china- zolin, 4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentylmethoxy- quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholine-4-1) propyloxy] -6-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxy-quinazoline and (R) -4- [(1-phenyl-ethyl) amino] -7- [3- (6, 6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline excluded are, their tautomers, their stereoisomers and their salts. 4. Compounds of general formula I according to claim 1, in which R _{a represents} a 1-phenylethyl group or a phenyl group substituted by the radicals R _x and R ₂ , where R _{x is} a fluorine, chlorine or bromine atom and R _{2 represents} a hydrogen or fluorine atom, one of the radicals R _b or R _{c is} an R ₃ - (CH ₂ ) _m -O group and the other of the radicals R _b or R _{c is} a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclo pentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where R _{3 is} an N- (2-oxo-tetrahydrofuran-4-yl) methylamino group or a 2-oxo-morpholine -yl group substituted by one or two methyl groups and m represents the number 2, 3 or 4, with the proviso that the connections 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] quinazoline, 4- [(3-bromophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) mino] -6- (2- [N- (2-oxo-tetrahydrofuran-4-yl) - N-methylamino] ethoxy} -7-methoxy-quinazoline, 4- [(3-bromophenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) mino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclobutyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) mino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oχomorpholin-4-yl) ethoxy] -7-cyclopropylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl] amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- (2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentyloxy-china- zolin, 4- [(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -7 -cyclopentylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentylmethoxy-quinazoline, (R) -4- [(1-phenyl-ethyl) amino] -6- [3- (6, 6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline . 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclobutyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopropylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl] amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} -6 -cyclopentylmethoxy- quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2 ~ oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentylmethoxy-quinazoline and (R) -4- [(1-phenyl-ethyl) amino] -7- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline excluded are, their tautomers, their stereoisomers and their salts. 5. Compounds of general formula I according to claim 1, in which R _{a is} a 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group, R _{b is} an R ₃ - (CH ₂ ) _ra -0 group in which R _{3 represents} a 2-oxomorpholin-4-yl group substituted by one or two methyl groups and ■ m represents the number 2 or 3, and R _{c is} a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group with the proviso that the compounds 4- [(3-bromophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) mino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclobutyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopropylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) amino] -6- [3- (6, 6-dimethyl-2-oxo _r morpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline and (R) -4- [(1-phenyl-ethyl) amino] -6- [3- (6, 6-dimethyl-2-oxomorpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline excluded are, their tautomers, their stereoisomers and their salts. 6. Compounds of general formula I according to claim 1, in which R _{a is} a 3-chloro-4-fluorophenyl group, R _{b is} a cyclopentyloxy, cyclopropyl methoxy, cyclopentyl methoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranyl. methoxy group and R _{c is} an R ₃ - (CH ₂ ) _ra -0 group in which R _{3 represents} a 2-oxomorpholin-4-yl group substituted by one or two methyl groups and m represents the number 2, with the proviso that the connections 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] -6-cyclopropylmethoxy-quinazoline and 4- [(3-Chloro-4-fluorophenyl] amino] -7- [2- (6, 6-dimethyl-2-oxomorpholin-4-yl) ethoxy] - 6-cyclopentylmethoxy-quinazoline excluded are, their tautomers, their stereoisomers and their salts. 7. The following compounds of general formula I according to claim 1: (1) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy- 7- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] - quinazoline, (2) 4- [(3-chloro-4-fluorophenyl) amino] - 6-cyclopentyloxy- 7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] ethoxy} quinazoline, (3) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy- 7- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] - quinazoline, (4) 4- [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy- 6- [3- (2, 2-dimethyl-6-oxomorpholin-4-yl) propyloxy] quinazoline, (5) 4- [(3-Chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy- 6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) propyloxy] - quinazoline, (6) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy- 7- (2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methylamino] -ethoxy} - quinazoline, (7) 4- [(3-bromo-phenyl) amino] -6- [2- ((S) -6-methyl-2-oxo-morphol-lin-4-yl) ethoxy] -7-methoxy- quinazoline, (8) 4- [(3-bromo-phenyl) amino] -6- [2- ((R) -6-methyl-2-oxo-morpholine-4-yl) ethoxy] -7-methoxy- quinazoline, (9) 4- [(3-chloro-4-fluoro-phenyl) amino] -6- [2- ((R) -6-methyl-2-oxo-morpholin-4 -yl) -ethoxy] -7 - methoxy-quinazoline, (10) 4- [(3-Chloro-4-fluorophenyl) amino] -6- [3- ((R) -6-methyl-2-pxo-morpholin-4-yl) propyloxy] -7- methoxy-quinazoline, (11) 4- [(R) - (1-phenylethyl) amino] -6- [3- ((S) -6-methyl-2-oxomorpholin-4-yl) propyloxy] -7 - methoxy-quinazoline, (12) 4- [(R) - (1-phenylethyl) amino] -6- [2- ((S) -6-methyl-2-oxomorpholin-4-yl) ethoxy] -7- methoxy-quinazoline and (13) 4- [(3-Chloro-4-fluoro-phenyl) amino] -6- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy -quinazoline, their tautomers, their stereoisomers and their salts. 8. Physiologically acceptable salts of the compounds according to claims 1 to 7 with inorganic or organic acids or bases. 9. Medicament containing a compound according to claims 1 to 7 or a physiologically acceptable salt according to claim 8 in addition to optionally one or more inert carriers and / or diluents. 10. Use of a compound according to claims 1 to 8 for the manufacture of a medicament for the treatment of benign or malignant tumors, for the prevention and treatment of diseases of the respiratory tract and lungs, for the treatment of polyps, of diseases of the gastrointestinal tract, bile ducts and bladder, as well as the kidney and skin. 11. A method for producing a medicament according to claim 9, characterized in that a compound according to claims 1 to 8 is incorporated in one or more inert carriers and / or diluents in a non-chemical way. 12. A process for the preparation of the compounds of general formula I according to claims 1 to 8, characterized in that a) a compound of the general formula R ^a \ / ^H

in the R _{a is} as defined in claims 1 to 7, one of the radicals R _b 'or R _c ^? represents a methoxy, cyclobutyloxy,> • cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and the other of the radicals R _b 'or R _c ' represents a Z _x - (CH ₂ ) _m -0 group in which m is as defined in claims 1 to 7 and Z _x denotes a leaving group, with a compound of the general formula H - R ₃ , (III) in which R _{3 is defined} as mentioned in claims 1 to 7, is implemented or b) a compound of the general formula optionally formed in the reaction mixture

in the R _{a is} as defined in claims 1 to 7, one of the radicals R _b "or R _c " represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and the other of the radicals R _b "or R _c "represents an R ₃ '- (CH ₂ ) _m -0 group in which is as defined in claims 1 to 7 and R ₃ 'is a R ₄ -0-CO-CH ₂ -N-CH ₂ CH ₂ -OH group substituted on the methylene groups by one or two methyl or ethyl groups, in which R _{4 represents} a hydrogen atom or a C - ^ - alkyl group, is cyclized and if necessary, a protective residue used in the reactions described above is split off again and / or if desired, a compound of the general formula I thus obtained is separated into its stereoisomers and / or a compound of the general formula I thus obtained is converted into its salts, in particular for its pharmaceutical use into its physiologically tolerable salts.