BG107559A - Bicyclic heteroycles, medicaments containing these compounds, their use and methods for the production thereof - Google Patents

Abstract

The invention relates to bicyclic heterocycles of general formula in which Ra to Rc have the meanings given in the description, 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. 12 claims

Description

BICYCLIC HETEROCYCLES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS, THEIR APPLICATION AND THE METHOD OF PREPARATION

Technical field

The subject of this application are bicyclic heterocycles with

their tautomers, their stereoisomers and their salts, in particular their physiologically acceptable salts with inorganic organic acids or bases, which have valuable pharmacological properties, in particular inhibitory effect on thyroid kinase mediated signal transduction, their irrigation for the treatment of diseases, -specifically to tumors, lung diseases and diseases / respiratory diseases and their production. X /

SUMMARY OF THE INVENTION

In the above general / rmula X

Ra denotes a benzyl or 1-fendlethyl group or a phenyl group substituted by the radicals R 1 and R ₂ , wherein

R 1 represents a hydrogen, fluorine chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group, and R ₂ Xq ^ CTaBnaBa is a hydrogen or fluorine atom,

2449/03-GP

BICYCLIC HETEROCYCLES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS, THEIR APPLICATION AND THE METHOD FOR THE PREPARATION thereof

Technical field

The subject of this application are bicyclic heterocycles of the general formula

(I) their tautomers, their stereoisomers and their salts, in particular their physiologically acceptable salts of inorganic or organic acids or bases, which have valuable pharmacological properties, in particular, an inhibitory effect on tyrosine kinase-mediated signal transduction, their use for treatment diseases, in particular tumors, lung diseases and respiratory diseases and their production.

SUMMARY OF THE INVENTION

In the above general formula

Ra represents a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R 1 and R ₂ , wherein

R 1 represents a hydrogen, fluorine, chlorine or bromine atom, methyl, trifluoromethyl, cyano or ethynyl group, and R ₂ represents a hydrogen or fluorine atom, one of the radicals R b or R c represents R ₃ - (CH ₂ ) _m- O-rpyna, and the other of the radicals Rb or Rc represents methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy-, tetrahydrofuran-3yloxy-, tetrahydropyran-3-yloxy-, tetrahydropyran-4-yl-tetrahydro-tetrahydro-4-yl whereby

R ₃ represents an N- (2-oxo-tetrahydrofuran-4-yl) -methylaminoyl-N- (2-oxo-tetrahydrofuran-4-yl) -ethylamino group, one for methylene groups with one or two methyl or ethyl groups substituted R 4 - O-CO-CH ₂ -N-CH ₂ CH ₂ -OH-pyrene in which

R 4 represents a hydrogen atom or a C 1-4 alkyl group or with one or two methyl or ethyl groups substituted a 2 oxo-morpholin-4-yl group and m represents the number 2, 3 or 4, provided that the compounds are excluded

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-oxo-morpholin-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- [1- (2-oxo-tetrahydrofuran-4-yl) -methyl-amino] -ethoxy-7-methoxy-quinazoline, their tautomers, their stereoisomers and their salts.

Preferred compounds of the above general formula I are those wherein

R _a represents a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R 1 and R ₂ , wherein

R1 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group, and

R ₂ represents a hydrogen or fluorine atom, one of the radicals Rb or Rc represents R 3 - (CH ₂ ) mO-rpyna and the other of the radicals Rb or Rc represents methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy- , tetrahydrofuran-3yloxy-, tetrahydropyran-3-yloxy-, tetrahydropyran-4-yloxy-, tetrahydrofuranylmethoxy- or tetrahydropyranylmethoxy, wherein

R3 represents N- (2-oxo-tetrahydrofuran-4-yl) -methylaminoyl or N- (2-oxo-tetrahydrofuran-4-yl) -ethylamino group, one for methylene groups with one or two methyl or ethyl groups substituted R4-O- CO-CH ₂ -N-CH ₂ CH ₂ -OH-pyrene in which

R 4 represents a hydrogen atom or a C 1-4 alkyl group, or with one or two methyl or ethyl groups substituted 2 oxo-morpholin-4-yl group, and m represents the number 2, 3 or 4, provided that the compounds are excluded

4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2-N- (2-hydroxy-2-methyl-prop-1-yl) -N - [(ethoxycarbonyl) -methyl] - aminoethoxy) -quinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclo-pentyloxy-7- [2- (6,6 dimethyl-2-oxo-morpholin-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) methyl-amino] -ethoxy-7-methoxy-quinazoline,

4 - [(3-bromophenyl) amino] -6- (2-1 N- (2-hydroxy-2-methyl-prop-1-yl) -N [(ethoxycarbonyl) methyl] -amino-ethoxy) -7 -methoxy-quinazoline,

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

4- [(3-bromophenyl) 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-methyl-amino] -ethoxy-7-methoxy-quinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6-2- [1 '[- (2-oxo-tetrahydrofuran-4yl) -1H-methyl-amino] -ethoxy-7-cyclopentyloxy-quinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6-2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -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) -propyl oxy] -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-methyl-amino] -ethoxy-6-methoxy-quinazoline,

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

4 - [(3-chloro-4-fluorophenyl) amino] -7-2-N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -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 (4-yl) -4 - [(1-phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline, especially those in which

Ra represents a 1-phenylethyl group or a phenyl group substituted by the radicals Ri and R ₂ , wherein

R 1 represents a fluorine, chlorine or bromine atom, a methyl or ethynyl group and

R ₂ represents a hydrogen or fluorine atom, one of the radicals Rb or Rc represents R 3 - (CH ₂ ) mO-rpyna and the other of the radicals Rb or Rc represents methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy- , tetrahydrofuran-3yloxy-, tetrahydropyran-3-yloxy-, tetrahydropyran-4-yloxy-, tetrahydrofuranylmethoxy- or tetrahydropyranylmethoxy, wherein

R3 represents an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group, one in methylene groups with one or two methyl groups substituted by R ₄ -O-CO-CH ₂ -N-CH ₂ CH ₂ -OH-pyrene, wherein

R4 represents C1. _{A 4-} alkyl group or one or two methyl groups substituted a 2-oxo-morpholin4-yl group, and w represents the number 2, 3 or 4, provided that the compounds are excluded

4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2-b1- (2-hydroxy-2-methyl-prop-1-yl) -1 N - [(ethoxycarbonyl) methyl] - aminoethoxy) -quinazoline,

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

4 - [(3-bromophenyl) amino] -6- (2-N- (2-hydroxy-2-methyl-prop-1-yl) -N1 [(ethoxycarbonyl) methyl] -amino-ethoxy) -7-methoxy -quinazoline,

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

4- [(3-bromophenyl) 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-methyl-amino] -ethoxy-7-methoxy-quinazoline,

4- [(3-chloro-4-fluorophenyl) amino] -6-2-p4- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy-7-cyclopentyloxy-quinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6-2- [N- (2-oxo-tetrahydrofuran-4-yl) -1 N-methyl-amino] -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) -propyl oxy] -7-cyclopentyl oxy-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) -Nomethyl-amino] -ethoxy-6-methoxy-quinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7-2-pM- (2-oxo-tetrahydrofuran-4-yl) -Nomethyl-amino] -ethoxy-6-cyclopentyloxy-quinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -7-2- [1 N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -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 (K) - 4 - [(1-phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline, their tautomers, their stereoisomers and their salts .

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

Ra represents a 1-phenylethyl group or a phenyl group substituted by the radicals R 1 and R ₂ , wherein

R 1 represents a fluorine, chlorine or bromine atom, a

R ₂ represents a hydrogen or fluorine atom, one of the radicals Rb or Rc represents R 3 - (CH ₂ ) mO-rpyna and the other of the radicals Rb or Rc represents methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy- , tetrahydrofuran-3-yloxy-, tetrahydropyran-3-yloxy-, tetrahydropyran-4-yloxy-, tetrahydrofuranylmethoxy- or tetrahydropyranylmethoxy, wherein

The gap represents the N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group or with one or two methyl groups substituted by 2-oxomorpholin-4-yl group, and m represents the number 2, 3 or 4, provided that compounds excluded

4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6 dimethyl-2-oxo-morpholin-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- [1 N- (2-oxo-tetrahydrofuran-4-yl) -L-methyl-amino] -ethoxy-7-methoxy-quinazoline,

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

4- [(3-bromophenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-410 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-cyclo-butyl oxy-quinazoline,

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

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

4 - [(3-chloro-4-fluorophenyl) amino] -6-2- [14- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -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-cycle of opentyloxy-quinazoline,

4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyl oxy] -7-cyclopentylmethoxy-quinazoline, (R) - 4- [(1-phenylethyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyl oxy] -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-oxo-morpholin-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- [T4- (2-oxo-tetrahydrofuran-4-yl) -1H-methyl-amino] -ethoxy-6-methoxy-quinazoline,

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

4 - [(3-chloro-4-fluorophenyl) amino] -7-2- [N- (2-oxo-tetrahydrofuran-4-yl) -1H-methyl-amino] -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-phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline, their tautomers, their stereoisomers and their salts.

Extremely preferred compounds of the general Formula I are those in which

Ra is a 1-phenylethyl, 3-bromophenyl or 3-chloro-4fluorophenyl group,

R b is R ₃ - (CH ₂ ) m O -pyrene in which

R ₃ represents one with one or two methyl groups substituted

2-oxo-morpholin-4-yl-group and m represents the number 2 or 3, and Rc stands for methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, tetrahydropyran-3-yloxy- or tetrahydrofuranylmethoxy-group, provided that compounds excluded

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

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

4- [(3-bromophenyl) 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 and

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

N- -4 - [(1-phenylethyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyl oxy] -7-cyclopentyloxy-quinazoline tautomers, stereoisomers and their salts.

Extremely preferred compounds of general formula I are those in which

Ra is a 3-chloro-4-fluorophenyl group,

Rb stands for cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydropyran-3-yloxy, or tetrahydrofuranylmethoxy,

Rc denotes R3- (CH2) m-O-pyrene in which

R3 represents one with one or two methyl groups substituted

2-oxo-morpholin-4-yl-group and m represents the number 2, provided that the compounds are excluded

4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6 dimethyl-2-oxo-morpholin-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, their tautomers, their stereoisomers and their salts.

For example, the following are 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-methyl-amino] -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-oxo-morpholin-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-7-2P9- (2-oxo-tetrahydrofuran-4-yl) -1H-methyl-amino] -ethoxy-quinazoline, (7) 4- [ (3-bromophenyl) amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, (8) 4- [(3-bromophenyl) ) amino] -6- [2 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, (9) 4 - [(3-chloro-4-fluorophenyl) ) amino] -6- [2 - ((R) -6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, (10) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((1 ' -6-methyl-2-oxomorpholin-4-yl) -propyl oxy] -7-methoxy-quinazoline, (11) 4- [(R) - (1 -phenylethyl) amino] -6- [3 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7 -methoxy-quinazoline, (12) 4- [(R) - (1-phenylethyl) amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7 -methoxy-quinazoline, (13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((S) -6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7 -methoxy-quinazoline, their tautomers, their stereoisomers and their salts.

The compounds of general formula I can be prepared by the following methods, for example:

a) reacting a compound of the general formula (II) f · in which

Ra is defined as initially, one of the radicals Rb 'or Rc' represents methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy- or cyclopentylmethoxy-group and the other radicals Rb 'or Rc' represents Z1- (CH ₂ ) mO-rpyna, in which m is defined as in the beginning and

Ζ _Ί means a leaving group such as a halogen atom or a sulfonyloxy group, for example a chlorine or bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group, with a compound of the general formula

HR ₃ , (III) in which

R ₃ is defined as in the beginning.

The reaction may be carried out optionally in a solvent or in a mixture of solvents such as methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, as appropriate, tertiary ethyl esters of tertiary ethyl ester diisopropylamine, wherein these organic bases may also serve as solvents or in the presence of an inorganic base such as sodium carbonate or potassium carbonate, preferably at temperatures between -20 and 200 ° C, smoke at temperatures between 0 and 150 ° C.

B) cyclization of any compound of the general formula formed in the reaction mixture

(Iv) in which

Ra is defined as initially, one of the radicals Rb or Rc represents methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy- or cyclopentylmethoxy-group and the other radicals Rb or Rc represents R3 '- (CH ₂ ) mO- rpyna, in which m is defined as in the beginning and

R ₃ 'means one in the methylene groups with one or two methyl or ethyl groups substituted R 4 -O-CO-CH ₂ -N-CH ₂ CH ₂ -OH-pyrene in which

R ₄ represents a hydrogen atom or Cl. _{A 4-} alkyl group.

The reaction is optionally carried out in a solvent or in a mixture of solvents such as methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, preferably in sulfolane, benzene, toluene, chlorobenzene, benzene / tetrahydrofuran, dioxalic acid, dioxalic acid, dioxaline, acid or in the presence of a water-withdrawing agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, Ν, Ν'-dicyclohexy however, carbodiimide, Ν, Ν'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benztriazole, Ν, кар'carbonyldiimidazole or triphenylphosphine / tetrachloromethane, at temperatures between -20 and 200 ° C, preferably between -20 and 200 ° C, preferably between -20 and 200 ° C, preferably -10 ° C .

In the reactions described above, the possibly present reactive groups such as hydroxy, carboxy or imino groups can be protected during the reaction by the usual protecting groups which are cleaved after the reaction.

For example, the protecting group of one hydroxy group refers to trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group, the protecting group of one carboxy group - trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or benzyl tetrahydropyranyl group and as a protecting group of one imino group - formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4 dimethoxybenzyl group.

Any subsequent cleavage of the protecting group used is carried out, for example, hydrolytically in an aqueous solvent, for example 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 acid or in the presence of an alkaline base such as sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

However, the cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl group is carried out, for example, by hydrogenolysis, for example with hydrogen in the presence of a catalyst such as palladium / charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally by the addition of an acid such as hydrochloric acid. temperatures between 0 and 100 ° C, preferably at room temperatures between 20 and 60 ° C, and at hydrogen pressures of from 1 to 7 bar, but preferably from 3 to 5 bar.

However, cleavage of a 2,4-dimethoxybenzyl group takes place mainly in trifluoroacetic acid in the presence of anisole.

The cleavage of a tert-butyl or tert-butyloxycarbonyl group is preferably accomplished by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The cleavage of a trifluoroacetyl group is preferably effected by treatment with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid, at temperatures between 50 and 120 ° C, or by treatment with a sodium base, optionally in the presence of a solvent such as tetrahydrofuran, at temperatures between 0 and 50 ° C.

In addition, the compounds of general formula I obtained can be separated, as mentioned above, into their enantiomers and / or diastereomers. For example, cis / trans mixtures can be separated into their cis and trans isomers, and compounds with at least one optically active carbon atom to their enantiomers.

For example, the resulting cis / trans mixtures can be separated by chromatography of their cis and trans isomers, and the resulting compounds of general formula I, which are racemates, can be separated by known methods (see Allinger NL and Eliel EL in Topics in Stereochemistry, Vol. 6, Wiley Interscience, 1971) of their optical antipodes, and compounds of general formula I with at least 2 asymmetric carbon atoms can be separated based on their physicochemical differences by known methods, e.g. by chromatography and / or fractional crystallization of their diastereoisomers which, if present in racemic form, may then, as mentioned above, be separated into enantiomers.

Separation of enantiomers is carried out preferably by column chromatography on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives with the racemic compound, e.g. esters or amides, in particular with acids and their reactive derivatives or with alcohols, and the separation of the mixture thus obtained from diastereoisomeric salts or derivatives, for example on the basis of different solubilities, whereby free antipodes can be obtained from pure diastereoisomeric salts or derivatives by treatment with appropriate means. The most commonly used optically active acids are, for example, the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-otolyltartaric acid, malic acid, almond acid, camphorsulfonic acid, glutamic, aspartic acid or quinic acid. For example, optically active alcohol means (+) - or (-) - menthol, and as optically active acyl group in amides, for example (+) - or (-) - methyloxycarbonyl group.

Further, the compounds of formula I obtained can be converted into their salts, in particular for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids. For example acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid may be used as acids.

In addition, the new compounds of formula I thus obtained, if they contain a carboxy-, hydroxyphosphoryl-, sulfo- or 5-tetrazolyl group, may, if desired, be converted to their salts with inorganic or organic bases, in particular for pharmaceutical use, in their physiologically acceptable salts. For example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine may be used as bases for this purpose.

The compounds of general formulas II to IV used as starting materials are partly known in the literature or can be prepared by methods known in the literature (see Examples I to XIV).

As mentioned initially, the compounds of general formula I and their physiologically acceptable salts according to the invention exhibit valuable pharmacological properties, in particular an inhibitory effect on epidermal growth factor receptor (EGF-R) signal transduction, which may is achieved, for example, by inhibiting ligand binding, receptor dimerization, or tyrosine kinase itself. It is also possible to block the transmission of signals to the lower components.

The biological properties of the new compounds are tested as follows:

Inhibition of EGF-R-mediated signal transduction can be demonstrated, for example, by cells that express human EGF-R and whose survival and proliferation depends on EGF or TGF-alpha stimulation. A cell line of mouse origin dependent on interleukin-3- (IL-3) was used that was genetically modified to express functional human EGF-R. The proliferation of these cells, known as F / L-HERc, can therefore be stimulated with either murine IL-3 or EGF (compare von Rueden, T. et al., EMBO J. 7, 2749-2756 (1988) and Pierce , JH et al., Science 239, 628-631 (1988).

The starting material for F / L-HERc cells is the FDC-P] cell line, whose production is described by Dexter, T.M. et al., J. Exp. Med. 152, 1036-1047 (1980). Alternatively, however, other growth factor-dependent cells may be used (cf. e.g. Pierce, JH et al., Science 239, 628-631 (1988), Shibuya, H. et al., Cell 70, 57-67 (1992 and Alexander, WS et al., EMBO J., 10, 3683-3691 (1991). 3a expression of human EGF-R cDNA (compare Ullrich, A. et al., Nature

309, 418-425 (1984) used recombinant retroviruses as described by von Rueden, T. et al., EMBO J. 7 2749-2756 (1988), except that the retroviral vector LXSN (compare Miller, AD et al., BioTechniques 7, 980-990 (1989)) was used for the expression of EGF-R cDNA and the GP + E86 line (compare Markowitz, D. et al., J. Virol., 62, 1120-1124 (1988)) is used as a host.

The study is carried out as follows:

F / L-HERc cells were cultured in RPMI / 1640 medium (BioWhittaker) equipped with 10% fetal bovine serum (FCS, Boehringer Manheim), 2 mM glutamine (BioWhittaker), standard w antibiotics and 20 ng / ml human EGF (Promega ) npH 37 ° C and 5% CO2 · In order to test the inhibitory activity of the compounds of the invention, 1.5x10 4 cells per well in the upper medium (200 μΐ) were cultured three times in 96 well plates, stimulating cell proliferation with either EGF ( 20 ng / ml) or with mouse IL-3. IL3 used was obtained from culture supernatants of cell line X63 / 0 mIL-3 (compare Karasuyama, H. et al., Eur. J. Immunol. 18, 97-104 (1988)). The compounds of the invention were dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures at various dilutions, with a maximum concentration of DMSO of 1%. The cultures were incubated for 48 hours at 37 ° C.

In order to determine the inhibitory activity of the compounds according to the invention, the relative number of cells was measured in optical density units O.D using non-radioactive analysis for cell proliferation Cell Titer 96 ^ M Aqueous Nonradioactive Cell Proliferation Assay (Promega). The relative number of cells was calculated as a percentage of the control (F / LHERc cells without inhibitor) to obtain the concentration of the active substance that inhibited cell proliferation by 50% (IC50). The following results are obtained.

compound (example #) inhibition of EGF-dependent proliferation IC ₅₀ [nM] 1 59 1 (2) 29 1 (2) 29 2 (1) 36

Thus, the compounds of general formula I according to the invention inhibit signal transduction by tyrosine kinases, as exemplified by the human EGF receptor, and are therefore useful for treating pathophysiological processes that are induced by tyrosine kinase hyperfunction. These are, for example, benign and malignant tumors, especially tumors of epithelial and neuroepithelial origin, metastases as well as 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 that are associated with increased or altered mucus secretion, which is caused by the stimulation of tyrosine kinases, such as in inflammatory respiratory diseases such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic and non-allergic rhinitis or sinusitis, cystic fibrosis, αΐ-antitrypsin deficiency or cough, pulmonary emphysema, pulmonary fibrosis and breathing high reactivity roads.

The compounds are also suitable for the treatment of diseases of the gastrointestinal tract and bile ducts and gall bladder that are associated with impaired tyrosine kinase activity, such as can be detected, for example, in chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis. and tumors of the gastrointestinal tract or those that occur in diseases of the gastrointestinal tract associated with increased secretion, such as Menetrier's disease, secreting adenoma and protein loss syndrome, and for the treatment of nasal gastrointestinal lymph and polyps of various origins, such as colon or adenomatous colon polyps, as well as polyps for congenital bowel polyposis, bowel polyps for Gardner syndrome, polyps all over the gastrointestinal tract for syndrome Peutz-Jeghers, in inflammatory pseudopolyps, juvenile polyps, Colitis cystica profunda and Pneumatosis cystoides intestinales.

In addition, the compounds of general formula I and their physiologically acceptable salts can be used to treat kidney disease, in particular cystic changes such as cystic kidney, to treat renal cysts that may be idiopathic in origin or occur in syndromes such as tuberculous sclerosis, in von-Hippel-Lindau syndrome, in nephronophthisis, and in spongic kidneys and other diseases caused by altered 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 of the invention can be used alone or in combination with other pharmacologically active compounds, for example in the treatment of tumors such as monotherapy or in combination with other antitumor therapeutic agents, for example in combination with topoisomerase inhibitors (eg etoposides) , mitotic inhibitors (eg vinblastine), nucleic acid-interacting compounds (eg cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (eg tamoxifen), inhibitors of metabolic processes (eg 5-FU, etc.), cytokines (eg interferons), antibodies, etc. For the treatment of respiratory diseases, these compounds may be used alone or in combination with other therapeutic agents for the respiratory tract, such as substances with secretolytic, bronchodilator and / or anti-inflammatory activity. For the treatment of diseases of the digestive tract, these compounds may also be administered alone or in combination with motility or secretion or anti-inflammatory substances. These combinations may be administered either simultaneously or sequentially.

These compounds may be administered either alone or in combination with other active substances intravenously, subcutaneously, intramuscularly, intrarectally, intraperitoneally, intranasally, by inhalation or transdermally or orally, aerosol formulations particularly suitable for inhalation.

For pharmaceutical administration, the compounds of the invention are commonly used in warm-blooded vertebrate animals, especially in humans, at doses of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg. To be applied, they are processed together with one or more conventional inert carriers and / or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carloyl alcohol for example, solid fat or their suitable mixtures in conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.

Examples of carrying out the invention

The following examples illustrate the present invention without limitation:

Preparation of starting materials:

Example 1

4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- (2-bromoethoxy) -quinazoline

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

Yield: 2.60 g (58% of theory),

Rf value: 0.82 (silica gel, methylene chloride / methanol 9: 1)

Mass Spectrum (ESI): m / z = 494, 496, 498 [M + H]

The following compounds were prepared analogously to Example I:

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

Rf value: 0.72 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1)

Mass Spectrum (ESI): m / z = 464, 466, 468 [M-H] (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2-bromoethoxy) -quinazoline

Rf value: 0.65 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1)

Mass Spectrum (ESI): m / z = 478, 480, 482 [M-H] (3) 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6- (3-bromopropyloxy) -quinazoline (The reaction is carried out in acetonitrile as solvent)

Rf value: 0.62 (silica gel, methylene chloride / methanol 9: 1)

Mass Spectrum (ESI): m / z = 478, 480, 482 [M-H] (4) 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6- (3-bromo-propyloxy) -quinazoline (The reaction is carried out in acetonitrile as solvent)

Rf value: 0.74 (silica gel, methylene chloride / methanol 9: 1)

Mass Spectrum (ESI): m / z = 478, 480, 482 [M-H] (S) 4 - [(3-bromophenyl) amino] -6- (2-bromo-ethoxy) -7-methoxy-quinazoline mp: 244 ° C

Mass Spectrum (ESI): m / z = 452, 454, 456 [M + H] (6) 4- [(R) - (1-phenyl ethyl) amino] -6- (3-bromo-propyloxy) -7 - methoxyquinazoline (Reaction is carried out with potassium tert-butylate as base)

Rf value: 0.60 (silica gel, ethyl acetate / methanol 9: 1)

7) 4- [(R) - (1-phenyl ethyl) amino] -6- (2-bromo-ethoxy) -7-methoxyquinazoline (Reaction was carried out with potassium tert-butylate as base) Melting point: 255 ° C

Mass Spectrum (ESI ⁴ ·): m / z = 402, 404 [M + H] ⁺ (S) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxy-propyloxy) -7cyclobutyloxy- quinazoline

Rf value: 0.50 (silica gel, methylene chloride / methanol 90:10)

Mass Spectrum (ESF): m / z = 418, 420 [M + H] ⁺ (9) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxy-propyloxy) -7-

cyclopropylmethoxy-quinazoline Rf value: 0.21 (silica gel, methylene chloride / methanol 95: 5) Mass spectrum (ESF): m / z = 418, 420 [M + H] ⁺ (10) 4 - [(3-chloro-4-fluorophenyl) ) amino] -6- (2-bromoethoxy) -7-cyclopentyloxy-quinazoline Rf value: 0.21 (silica gel, methylene chloride / methanol 90:10) Mass spectrum (ESf): m / z = 480, 482, 484 [M + H] ] ⁺ (11) 4 - [(3-chloro-4-fluorophenyl) amino} -6- (2-bromoethoxy) -7-cyclopropylmethoxy-quinazoline Rf value: 0.68 (silica gel, methylene chloride / methanol 90:10) Mass spectrum (ESf): m / z = 466, 468, 470 [M + Hf (12) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3-hydroxy-propyloxy) -quinazoline Rf-value: 0.53 (silica gel, methylene chloride / methanol 90:10) Mass spectrum (ESf): m / z = 418, 420 [M + H] ⁺ (13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (hydroxy-butyloxy) -7-cyclopentyloxy-quinazoline Rf value: 0.46 (silica gel, ethyl acetate) (14) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2-bromoethoxy) -7 - (R) - tetrahydrofuran-3-yloxy) -quinazoline Mass Spectrum (ESF): m / z = 480, 482, 484 [M-H] ' (15) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2-bromoethoxy) -7 - [^) - (tetrahydrofuran-2-yl) methoxy] -quinazoline Mass Spectrum (ESF): m / z = 494, 496, 498 [M-H] ' (16) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2-bromoethoxy) -7 - [(8) - (tetrahydrofuran-2-yl) methoxy] -quinazoline Mass Spectrum (ESP): m / z = 494, 496, 498 [M-H] ' Example II

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

4.99 g of 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline were suspended in 80 ml of methanol and mixed with 1.80 ml of concentrated aqueous ammonia. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with 500 ml of methyl enchloride, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 4.30 g of a brownish solid are obtained. The crude material was stirred with tert-butyl methyl ether, filtered under vacuum, washed with a little tert-butyl methyl ether and dried at room temperature in vacuo.

Yield: 3.59 g (80% of theory),

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

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

The following compounds were prepared analogously to Example II:

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

Rf value: 0.56 (silica gel, methylene chloride / methanol 9: 1) Mass spectrum (ESP): m / z = 358, 360 [MH] '(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7-hydroxyquinazoline

Rf 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] ⁺ (3) 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-hydroxyquinazoline

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

Mass Spectrum (ESr ^1- ): m / z = 396, 398 [M + H] ⁺ (4) 4 - [(3-bromophenyl) amino] -6-hydroxy-7-methoxy-quinazoline (The reaction was carried out with sodium hydroxide in ethanol as solvent) Rf value: 0.23 (silica gel, ethyl acetate)

Mass Spectrum (ESf): m / z = 346, 348 [M + H] ⁺ (S) 4 - [(3-chloro-4-fluorophenyl) amino] -7-hydroxy-6 - ((8) tetrahydrofuran-3- yloxy) -quinazoline

Rf value: 0.57 (silica gel, methylene chloride / methanol 9: 1) Mass spectrum (ESC): m / z = 376, 378 [M + H] ⁺ (6) 4- [(3-chloro-4-fluorophenyl) amino] -7-hydroxy-6 - [(S) tetrahydrofuran-2-yl) methoxy] -quinazoline

Rf value: 0.42 (silica gel, methylene chloride / methanol 9: 1)

Example III

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

4.03 g of 4-chloro-6-cyclopentylmethoxy-7-methylcarbonyloxyquinazoline were suspended in 70 ml of isopropanol and mixed with 1.95 g of 3-chloro-4-fluoroaniline. The reaction mixture was boiled under reflux for two hours. After cooling to room temperature, the resulting light precipitate was filtered off, washed with a little isopropanol and air-dried.

Yield: 4.99 g (92% of theory),

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

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

The following compounds were prepared analogously to Example II:

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

Rf value: 0.86 (silica gel, methylene chloride / methanol = 9: 1)

Mass Spectrum (ESE): m / z = 402, 404 [M + H] ⁺ (2) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7methylcarbonyloxy-quinazoline

Rf value: 0.73 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1)

Mass Spectrum (ESE): m / z = 416, 418 [M + H] ⁺ (3) 6-benzyloxy-4- [(3-chloro-4-fluorophenyl) amino] -7-methyl-1 * carbonyloxy-quinazoline

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

Mass Spectrum (ESE): m / z = 438, 440 [M + H] ⁺ (4) 4 - [(3-bromophenyl) amino] -6-methylcarbonyloxy-7-methoxyquinazoline

Rf value: 0.50 (silica gel, ethyl acetate)

Mass Spectrum (ESE): m / z = 388, 390 [M + H] ⁺ (S) 4 - [(R) - (1-phenyl ethyl) amino] -6-hydroxy-7-methoxy-quinazoline (acetoxy-protective group under reaction conditions cleaves) Rf value: 0.46 (silica gel, ethyl acetate)

Mass Spectrum (ESE): m / z = 296 [M + H] ⁺ (6) 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopentyloxy-quinazoline (pyridine is added as an auxiliary base )

Rf value: 0.51 (silica gel, methylene chloride / methanol = 95: 5)

Mass Spectrum (ESE): m / z = 464, 466 [M + H] ⁺ (7) 4 - [(3-chloro-4-fluorophenyl) amino] -7-methyl-carbonyloxy-6 - ((8) tetrahydrofuran- 3-yloxy) -quinazoline

Rf value: 0.67 (silica gel, methyl enchloride / methanol = 9: 1) Mass spectrum (ESP): m / z = 416, 418 [M-H] '(S) 4 - [(3-chloro-4-fluorophenyl) amino] -7-methyl-carbonyloxy-6 - [(8) tetrahydrofuran-3-yl) methoxy] -quinazoline hydrochloride

Melting point: 274-276 ° C

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

Example IV

4-chloro-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline

C3.80 g of 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxyquinazoline were suspended in 90 ml of thionyl chloride and heated to reflux under nitrogen. After the addition of four drops of N, N-dimethylformamide, the reaction mixture was stirred for two hours under reflux. After cooling to room temperature, excess thionyl chloride is distilled off in a vacuum from a water pump. The brown residue was stirred with 30 ml of toluene. The solvent was distilled off leaving 4.30 g of a grayish brown solid, which was used further without further purification.

Rf value: 0.89 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1)

The following compounds were prepared analogously to Example IV:

(1) 4-chloro-6-cyclopropylmethoxy-7-methylcarbonyloxy-quinazoline Rf value: 0.84 (silica gel, methylene chloride / methanol = 9: 1) (2) 4-chloro-6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline

Rf value: 0.69 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1) (3) 6-benzyloxy-4-chloro-7-methylcarbonyloxy-quinazoline Rf value: 0.77 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1) (4) 6-benzyloxy-4-chloro-7-cyclopentyloxyquinazoline Rf value: 0.91 (silica gel, methylene chloride / methanol = 9: 1) (5) 4 -chloro-7-methylcarbonyloxy-6 - ((8) -tetrahydrofuran-3yloxy) -quinazoline

Rf value: 0.83 (silica gel, ethyl acetate / methanol = 9: 1) (6) 4-chloro-7-methylcarbonyloxy-6 - [(S) -tetrahydrofuran-2yl) methoxy] -quinazoline

Rf value: 0.48 (silica gel, cyclohexane / ethyl acetate = 1: 1) Example V 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline

4.30 g of 4,7-dihydroxy-6-cyclopentylmethoxy-quinazoline in 100 ml of pyridine are heated under nitrogen to 80 ° C. 1.80 ml of acetic anhydride are added to the dark brown suspension. The reaction mixture was stirred for three hours at 80 ° C to give a solution. After cooling to room temperature, the reaction mixture was poured onto approximately 800 ml of ice water. The resulting precipitate was filtered off under vacuum and washed thoroughly with water. The light gray solid was dried in a vacuum desiccator.

Yield: 3.82 g (77% of theory),

Rf value: 0.49 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum (ESP): m / z = 301 [M-H] '

The following compounds were prepared analogously to Example V:

(1) 4-hydroxy-6-cyclopropylmethoxy-7-methylcarbonyloxyquinazoline

Rf value: 0.53 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum (ESP): m / z = 273 [M-H] '(2) 4-hydroxy-6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline mp: 209-212θ C

Mass Spectrum (ESI '): m / z = 287 [MH]' (3) 6-Benzyloxy-4-hydroxy-7-methylcarbonyloxyquinazoline Rf value: 0.48 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90 : 10: 0.1)

Mass Spectrum (ESP): m / z = 309 [M-H] (4) 4-hydroxy-6-methylcarbonyloxy-6 - ((S) -tetrahydrofuran-3yloxy) -quinazoline

Rf value: 0.62 (reversed phase thin layer chromatography plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass spectrum (ESI ⁺ ): m / z = 291 [M + H] ⁺ (5) 4-hydroxy-7-methylcarbonyloxy-6 - [(8) - (tetrahydrofuran-2yl) methoxy] -quinazoline

Rf 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-quinazoline

5.76 g of 2-Amino-5-cyclopentylmethoxy-4-hydroxy-benzoic acid and 6.52 g of formamidine acetate in 140 ml of ethanol were refluxed for about three hours. The reaction mixture was worked up by concentrating to about 100 ml and mixing with 300 ml of ice water to give a gray precipitate. The precipitate was filtered off with vacuum, washed with water and dried in a vacuum desiccator.

Yield: 4.57 g (77% of theory),

Rf value: 0.25 (silica gel, methylene chloride / methanol = 95: 5) Mass spectrum (ESP): m / z = 259 [M-H]

The following compounds were prepared analogously to Example VI:

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

Rf value: 0.45 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1)

Mass Spectrum (ESI ^- ): m / z = 231 [M-H] (2) 4,7-dihydroxy-6-cyclopentyloxy-quinazoline

Rf value: 0.42 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1)

Mass spectrum (El): m / z = 246 [M] ⁺ (3) 6-benzyloxy-4,7-dihydroxy-quinazoline

Rf value: 0.44 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1)

Mass Spectrum (ESI ^- ): m / z = 267 [M-H] (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 Rf-value: 0.69 (reversed phase, thin-layer chromatography (E. Merck) prepared plate, acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass Spectrum (ESI): m / z = 247 [M-H] (6) 4,7-dihydroxy-6 - [(S) -tetrahydrofuran-2-yl) methoxy] quinazoline

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

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

Example VII

2-amino-5-cyclopentylmethoxy-4-hydroxy-benzoic acid

6.50 g of 5-Cyclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid were dissolved in 130 mL of methanol, and mixed with 2.00 g of Raneykelel and hydrogenated under hydrogen pressure of 50 psi for about three hours at room temperature until the calculated temperature was taken up. the amount of hydrogen. The catalyst was filtered off and washed with hot methanol. The filtrate was concentrated in vacuo. A brownish solid remained, which was used further without further purification.

Yield: 5.79 g (100% of theory),

Rf value: 0.67 (silica gel, methylene chloride / methanol = 9: 1)

Mass Spectrum (ESI ^- ): m / z = 250 [M-H] '

The following compounds were prepared analogously to Example VII:

(1) 2-amino-5-cyclopropylmethoxy-4-hydroxy-benzoic acid Rf 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

Rf 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

Rf value: 0.52 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1)

Mass Spectrum (ESI): m / z = 258 [M-H] ^- (4) 2-amino-5-benzyloxy-4-cyclopentyloxy-benzoic acid cyclopentyl ester (The reaction was carried out in a 1: 1 mixture of methanol and tetrahydrofuran)

Rf value: 0.84 (silica gel, ethyl acetate / cyclohexane = 1: 1) Mass spectrum (ESI ⁺ ): m / z = 396 [M + H] ⁺ (5) 2-amino-4-hydroxy-5 - ((8) -tetrahydrofuran-3-yloxy) -benzoic acid

Rf value: 0.70 (reversed phase, thin layer chromatography plate prepared (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass Spectrum (ESP): m / z = 238 [M-H] (6) 2-amino-4-hydroxy-5 - [(S) -tetrahydrofuran-2-yl) methoxy] benzoic acid

Rf value: 0.59 (reversed phase, thin layer chromatography plate prepared (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass Spectrum (ESI ^- ): m / z = 252 [MH]

With Example VIII

5-Cyclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid

15.37 g of 4,5-Methylenedioxy-2-nitro-benzoic acid and 51.84 ml of cyclopentylmethanol were dissolved in 100 ml of dimethyl sulfoxide and cooled in an ice bath under nitrogen. 3.90 g of sodium was added portionwise. The reaction mixture was stirred for 30 minutes while cooling in an ice bath, then briefly warmed to 35-40θ C, and then stirred for another 3 hours while cooling in an ice bath. Finally, the ice bath was removed and the reaction was stirred overnight at room temperature. The dark brown reaction solution was poured into about 800 ml of acetone, causing a dark brown precipitate. The precipitate was filtered off under vacuum, washed with acetone, dissolved in 300-400 ml of water and adjusted to pH 2 with 60 ml of 2 N hydrochloric acid. The aqueous solution was repeatedly extracted with methylene chloride. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The dark brown oily residue in the flask was dissolved in 800 ml of methylene chloride and purified through a silica gel column with methylene chloride / methanol (9: 1). A brown oil is obtained which crystallizes after being mixed with water when cooled in an ice bath. The resulting brownish precipitate was filtered off under vacuum, washed with a little water and dried in a vacuum desiccator.

Yield: 9.55 g (47% of theory),

Rf value: 0.67 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6)

Mass Spectrum (ESP): m / z = 280 [MH] "

The following compounds were prepared analogously to Example VIII:

(1) 5-cyclopropylmethoxy-4-hydroxy-2-nitro-benzoic acid Rf-value: 0.61 (silica gel, toluene / dioxane / ethanol / glacial acetic acid - 90: 10: 10: 6)

Mass Spectrum (ESI '): m / z = 252 [M-H] ^- (2) 5-Cyclopentyloxy-4-hydroxy-2-nitro-benzoic acid Rf value: 0.62 (silica gel, toluene / dioxane / ethanol / glacial acetic acid acid = 90: 10: 10: 6)

Mass Spectrum (ESP): m / z = 266 [M-H] '(3) 5-Benzyloxy-4-hydroxy-2-nitro-benzoic acid

Melting point: 176-178θ C

Mass Spectrum (ESP): m / z = 288 [M-H] ^- (4) 4-hydroxy-2-nitro-5 - ((S) -tetrahydrofuran-3-yloxy) -benzoic acid

Rf value: 0.58 (reversed phase, thin layer chromatography plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass Spectrum (ESP): m / z = 268 [M-H] ^- (S) 4-hydroxy-2-nitro-5 - [(S) -tetrahydrofuran-2-yl) methoxy] benzoic acid

Rf value: 0.53 (reversed phase, thin layer chromatography plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1)

Mass Spectrum (ESP): m / z = 282 [MH]

Example IX

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

To 50.00 g of glycine ethyl ester hydrochloride in 100 ml of saturated potassium carbonate solution, upon cooling, 100.00 g of sodium carbonate are added. The resulting mass was repeatedly extracted with a total of about 600 ml of diethyl ether. The combined extracts were dried over sodium sulfate and concentrated to dryness. 28.60 g of glycine ethyl ester is obtained. It was mixed with 26.00 ml of isobutylene oxide and 40 ml of absolute ethanol and heated in a Roth bomb for six hours to 90θ C. After cooling to room temperature, the reaction C mixture was concentrated to give a rare oil.

Yield: 45.80 g (73% of theory),

Mass Spectrum (ESI ' ¹ '): m / z = 176 [M + H] ⁺

Example X

4-methylamino-dihydro-furan-2-one

2.00 g of 4- (N-benzyl-1 N-methyl-amino) -dihydrofuran-2-one in 25 ml of methanol is hydrogenated in the presence of 250 mg of palladium (10% on activated carbon) at hydrogen pressure of 50 psi for about two hours at room temperature until the calculated amount of hydrogen is absorbed. The reaction mixture was subjected to processing, the catalyst filtered and the filtrate concentrated in vacuo. It remains a colorless oil which is used without further purification.

Yield: 1.20 g

Rf value: 0.13 (silica gel, ethyl acetate)

Mass Spectrum (ESI ⁺ ): m / z = 116 [M + H] ⁺

Example XI

4- (1-Benzyl-N-methyl-amino) -dihydro-furan-2-one

To 15.00 g of 5H-furan-2-one in 150 ml of methylene chloride was added 23.20 ml of N-methylbenzylamine. The reaction mixture was stirred for approx. 48 hours at room temperature. The reaction mixture was reacted by concentrating and chromatographed through a silica gel column using ethyl acetate / petroleum ether (3: 1). The desired substance is obtained as a yellowish oil.

Yield: 19.77 g (54% of theory),

Rf value: 0.67 (silica gel, ethyl acetate) Mass spectrum (ESI ⁺ ): m / z = 228 [M + Na] ⁺

Example XII 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6-hydroxyquinazoline

To 5.60 g of 6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7cyclobutyloxy-quinazoline 10 ml of trifluoroacetic acid were added dropwise with stirring. The reaction mixture was then heated to approximately 40θ C. After 20 hours stirring at room temperature, another 3 ml of trifluoroacetic acid were added. After the reaction was barely advanced after an additional three hours of stirring at room temperature, the reaction mixture was heated at 500 ° C. After four hours, the reaction was complete and the excess trifluoroacetic acid was distilled off almost completely on a rotary evaporator. The residue was mixed with water and concentrated with alkaline aqueous ammonia. The resulting light brown precipitate was filtered off under vacuum, washed with sufficient water and dried in a desiccator. The resulting substance also contains trifluoroacetic acid.

Yield: 5.82 g

Rf value: 0.61 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum (ESI ⁺ ): m / z = 360, 362 [M + H] ⁺

The following compounds were prepared analogously to Example XII:

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

Rf 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

Rf 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- (4-tetrahydrofuran-3-yloxy) -quinazoline

Rf value: 0.32 (silica gel, methylene chloride / methanol = 9: 1) (4) 4 - [(3-chloro-4-fluorophenyl) amino] -6-hydroxy-7 - [(4) tetrahydrofuran-2-yl) methoxy ] -quinazoline

Mass Spectrum (ESI): m / z = 388, 390 [M-H] '

Example XIII

6-benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxyquinazoline

7.50 g of potassium carbonate and 4.50 g of methanesulfonic acid cyclobutyl ester were 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 was stirred for two hours at 80 ° C. Then again 2.00 g of methanesulfonic acid cyclobutyl ester and 3.00 g of potassium carbonate were added and the mixture was stirred Saturday and Sunday at 60θ C. Since the reaction did not proceed completely, 3.50 g of methanesulfonic acid cyclobutyl ester and 5.00 g of potassium carbonate were added again. carbonate. After an additional 20 hours at 80θ C, the reaction was almost complete. The reaction mixture was treated by mixing with 300 ml of ethyl acetate and washing with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated. The residue was stirred with methanol to give a brownish precipitate. It is filtered off under vacuum, washed with methanol and dried in a desiccator

Yield: 5.10 g (64% of theory),

Rf-value: 0.69 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum ^{(ESI _): m / z} = 448, 450 [M-H]

The following compounds were prepared analogously to Example XIII:

(1) 6-Benzyloxy-4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-quinazoline (Bromomethylcyclopropane used). Rf 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) -fluorophenyl) amino] -7-cyclopropyloxy-quinazoline (Bromocyclopentane is used).

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

Example XIV

(S) - (2-Hydroxy-propylamino) -acetic acid tert-butyl ester

15.00 g of (S) - (+) -1-amino-2-propanol are dissolved in 100 ml of dimethylformamide and mixed with 6.97 ml of diisopropylethylamine. 5.91 ml of bromoacetic acid tert-butyl ester was then added dropwise under ice bath cooling for 30 minutes. The cooling bath was removed and the reaction was stirred overnight at room temperature. The reaction mixture was treated by concentrating in vacuo. The residue in the flask was dissolved in 50 ml of water and saturated with 15 g of sodium chloride. The aqueous solution was repeatedly extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to leave a yellowish oil.

Yield: 7.36 g (97% of theory),

Rf value: 0.46 (silica gel, ethyl acetate / methanol = 9: 1)

Mass Spectrum (ESI ⁺ ): m / z = 190 [M + H] ⁺

The following compounds were prepared analogously to Example XIV:

(1) (R) - (2-Hydroxy-propylamino) -acetic acid tert-butyl ester

Rf value: 0.46 (silica gel, ethyl acetate / methanol = 9: 1)

Mass spectrum (ESI ⁺ ): m / z = 190 [M + H] ⁺ (2) (1,1, -dimethyl-2-hydroxy-ethylamino) acetic acid tert-butyl ester

Mass Spectrum (ESI ⁺ ): m / z = 204 [M + H] ⁺

Rf value: 0.47 (silica gel, methylene chloride / methanol / conc. Aqueous ammonia solution = 90: 10: 0,1)

Example XV 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (3-methanesulfonyloxypropyloxy) -7-cyclobutyloxy-quinazoline

The compound is prepared by reacting 4 - [(3-chloro-4fluorophenyl) amino] -6- (3-hydroxypropyloxy) -7-cyclobutyloxyquinazoline with methanesulfonyl chloride in methylene chloride in the presence of diisopropylethylamine at room temperature.

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

Mass Spectrum (ESI ^- ): m / z = 494, 496 [MH] ^-

The following compounds were prepared analogously to Example XV:

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

Rf value: 0.65 (silica gel, methylene chloride / methanol = 90: 10) Mass spectrum (ESI): m / z = 496, 496 [M-H] (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3methanesulfonyloxy-propyloxy) -quinazoline

Rf 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-methanesulfonyloxybutyloxy) -7-cyclopentyloxy-quinazoline

Rf 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-cyclopropylmethoxy-quinazoline

The compound was prepared by hydrogenation of 6-benzyloxy-4 - [(3chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-quinazoline in the presence of 10% Pd / C in a mixture of methylene chloride, ethanol and conc. hydrochloric acid (500: 210: 3.5) in a Parr apparatus.

Yield: 73% of theory.

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

Example XVII 5-Benzyloxy-4-cyclopentioxy-2-nitrobenzoic acid cyclopentyl ester

The compound was prepared by reacting 5-benzyloxy-4-hydroxy-2-nitrobenzoic acid with 2.2 equivalents of bromocyclopentane in the presence of potassium carbonate as an auxiliary base in dimethyl sulfoxide at room temperature.

Yield: 87% of theory.

Rf 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- (S) -tetrahydro-furan-3-yloxy) -quinazoline

To a solution of 8.00 g of 4 - [(chloro-4-fluorophenyl) amino] -6-benzyloxy-7-hydroxy-quinazoline (see WO 0055141 A1) and 2.42 ml (S) (+) - 3-hydroxytetrahydrofuran, and 7.95 g of triphenylphosphine 5.03 ml of azodicarboxylic acid diethyl ester were added dropwise into 160 ml of THF. The reaction mixture was stirred overnight at room temperature and then concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel with methylene chloride / ethyl acetate (gradient from 2: 1 to 1: 2) as eluent.

Yield: 7.34 g (78% of theory).

Melting point: 165-168 ° C.

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

The following compounds were prepared analogously to Example XVIII:

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

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

Rf value: 0.38 (silica gel, methylene chloride / methanol = 15: 1) (2) 4 - [(3-chloro-4-fluorophenyl) amino] -7- (2-bromoethoxy) -6 - ((8) tetrahydrofuran- 3-yloxy) -quinazoline

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

Preparation of the final compounds:

Example 1

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

250 mg of 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- (2-bromo-ethoxy) -quinazoline and 341 mg of (2-hydroxy-2-methyl-propylamino) -acetic acid ethyl ester were dissolved in 20 ml of acetonitrile and 50 mg of sodium iodide, 275 mg of potassium carbonate and 0.70 ml of diisopropylethylamine were added. The reaction mixture was heated to reflux for about 90 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue in the flask was chromatographed on a silica gel column with petroleum ether / ethyl acetate (50: 50, then 0: 100) as eluent. The cyclized product is obtained as a beige solid.

Yield: 62 mg (23% of theory),

Rf value: 0.29 (silica gel, ethyl acetate)

Mass Spectrum (ESF): m / z = 541, 543 [M-H] '

The following compounds were prepared 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

Rf value: 0.58 (silica gel, methylene chloride / methanol = 9: 1) Mass spectrum (ESP): m / z = 513, 515 [M-H] '(2) 4 - [(3-chloro-4-fluorophenyl) amino ] -7-Cyclobutyloxy-6- [3- (2,2dimethyl-6-oxo-morpholin-4-yl) -propyloxy] -quinazoline

Melting point: 212-214 ° C

Mass Spectrum (ESF): m / z = 527, 529 [M-H] '(3) 4 - [(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6- [3 (2,2-dimethyl) -6-oxo-morpholin-4-yl) -propyloxy] -quinazoline

Melting point: 200-202 ° C

Mass Spectrum (ESF): m / z = 527, 529 [M-H] '(4) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (2,2-dimethyl-6-) oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline

Melting point: 222-224 ° C

Mass Spectrum (ESF): m / z = 527, 529 [M-H] '

Example 2

4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7-2- [N- (2-oxo-tetrahydrofuran-4-yl) -X- [1 -styl-amino] -ets) xyquinazoline

300 mg of 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2-bromo-ethoxy) -quinazoline and 400 mg of 4-methylaminodihydrofuran-2-one in 20 ml of acetonitrile are mixed with 240 mg of potassium carbonate and 70 mg of sodium iodide and heated at reflux for 24 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue in the flask was chromatographed on a column of silica gel with methyl enchloride / methanol / concentrated aqueous ammonia (97: 3: 0.05) as eluent. The title compound was obtained as a light beige solid.

Yield: 70 mg (22% of theory),

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

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

The following compounds were prepared analogously to Example 2:

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

Rf value: 0.42 (silica gel, methylene chloride / methanol / concentrated, aqueous ammonia solution = 90: 10: 0.1)

Mass Spectrum (ESf): m / z = 515, 517 [M + H] ⁺ (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6- {3- [N- (2-oxo-tetrahydrofuran) -4-yl) -E1-methyl-amino] -propyl oxy} -7-cyclobutyloxyquinazoline

Melting point: 147.5-151 ° C

Mass Spectrum (ESI ⁴ ): m / z = 515, 517 [M + H] ⁺

Example 3

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

To 380 mg of 4 - [(3-bromophenyl) amino] -6- (2-N - [(tert-butyloxycarbonyl) methyl] -N - ((S) -2-hydroxy-propyl) -amino-ethoxy) -7 -methoxyquinazoline in 8 ml of acetonitrile was added 90 μϊ methanesulfonic acid. The reaction mixture was heated at reflux for about three hours, then another methanesulfonic acid was added and the reflux was continued until the reaction was complete. The reaction mixture was treated by diluting with ethyl acetate and washing with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue in the flask was triturated with diethyl ether and sucked off. The title compound was obtained as a white solid.

Yield: 280 mg (85% of theory),

Melting point: 190 ° C

Mass Spectrum (ESP): m / z = 485, 487 [M-H] '

The following compounds were prepared analogously to Example 3:

(1) 4 - [(3-bromophenyl) amino] -6- [2 - ((1 ' -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline

Melting point: 193 ° C

Mass Spectrum (ESC): m / z = 487, 489 [M + H] ⁺ (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((R) -6-methyl- 2-Oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 208 ° C

Mass Spectrum (ESF): m / z = 459, 461 [M-H] '(3) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((1 H) -6-methyl -2-Oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.33 (silica gel, ethyl acetate)

Mass Spectrum (ESF): m / z = 473, 475 [M-H] '(4) 4 - [(R) - (1-phenylethyl) amino] -6- [3 - ((8) -6-methyl-2 -oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.41 (silica gel, ethyl acetate / methanol = 9: 1) w Mass spectrum (ESF): m / z = 449 [M-H] '(5) 4- [(R) - (1-phenyl ethyl) ) amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (The reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.49 (silica gel, ethyl acetate / methanol / concentrated, aqueous ammonia solution = 9: 1: 0.1)

Mass Spectrum (ESF): m / z = 435 [M-H] '(6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((R) -6-methyl-2- oxomorpholin-4-yl) -propyloxy] -7-cyclobutyloxy-quinazoline (The reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 185.5 - 189.5 ° C

Mass Spectrum (ESI ^4- ): m / z = 435 [M + H] ⁺ (7) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (5,5-dimethyl-2- oxomorpholin-4-yl) -propyloxy] -7-cyclobutyloxy-quinazoline (The reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 214-216 ° C

Mass Spectrum (ESF): m / z = 435 [M-H] '(S) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (S) -6-methyl-2-oxomorpholine -4-yl) -propyloxy] -7-cyclopropylmethoxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 160.5-163 ° C

Mass Spectrum (ΕδΓ): m / z = 515, 517 [M + H] ⁺ (9) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((8) -6-methyl- 2-Oxomorpholin-4-yl) -propyloxy] -7-cyclopropylmethoxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 160-162 ° C

Mass Spectrum (ESP): m / z = 515, 517 [M + H] ⁺ (10) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((8) -6-methyl- 2-Oxomorpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.31 (silica gel, ethyl acetate)

Mass Spectrum (ESP): m / z = 515, 517 [M + H] ⁺ (11) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((P) -6-methyl- 2-Oxomorpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 176 - 178 ° C

Mass Spectrum (ESP): m / z - 515, 517 [M + H] ⁺ (12) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((8) -6-methyl- 2-Oxomorpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline (The reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.37 (silica gel, ethyl acetate)

Mass Spectrum (ESI ^4- ): m / z = 501, 503 [M + H] ⁺ (13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (S) - 6-methyl -2-Oxomorpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.37 (silica gel, ethyl acetate)

Mass Spectrum (ESt ^- ): m / z = 501, 503 [M + H] ⁺ (14) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2 ((8) - 6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline (The reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.48 (silica gel, ethyl acetate / methanol = 9: 1)

Mass Spectrum (ESU): m / z = 501, 503 [M + H] ⁺ (15) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2 ((K) -6 -methyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline (The reaction was carried out with trifluoroacetic acid in acetonitrile)

Q Mass spectrum (ESf): m / z = 501, 503 [M + H] ⁺ (16) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [3 ((K) - 6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.67 (silica gel, ethyl acetate / methanol = 9: 1)

Mass Spectrum (ESI '): m / z = 513, 515 [M-H]' (17) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [3 ((8) - 6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.67 (silica gel, ethyl acetate / methanol = 9: 1)

Mass Spectrum (ESI '): m / z = 513, 515 [M-H]' (18) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2-2,2-dimethyl-6- oxomorpholin-4-yl) ethoxy] -7-cyclopentyloxyquinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.56 (silica gel, ethyl acetate)

Mass Spectrum (ΕδΓ): m / z = 529, 531 [M + H] ⁺ (19) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2 - ((8) -

6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline (The reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.60 (silica gel, ethyl acetate / methanol = 9: 1)

Mass Spectrum (ESE): 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 was carried out with trifluoroacetic acid in acetonitrile)

Mass Spectrum (ESE): m / z = 515, 517 [M + H] ⁺ (21) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4 - ((5) -6-methyl- 2-Oxomorpholin-4-yl) -butyloxy] -7-cyclopentyloxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Resistance: 0.51 (silica gel, ethyl acetate)

Mass Spectrum (ESE): m / z = 543, 545 [M + H] ⁺ (22) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4 - ((P) -6-methyl- 2-Oxomorpholin-4-yl) -butyloxy] -7-cyclopentyloxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Mass Spectrum (ESE): m / z = 543, 545 [M + H] ⁺ (23) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3 - ((8) -6-methyl- 2-Oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 183-186 ° C

Mass Spectrum (ESE): m / z = 457, 477 [M + H] ⁺ (24) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (5,5-dimethyl-2- oxomorpholin-4-yl) -propyloxy] -7-methoxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Rf value: 0.43 (silica gel, ethyl acetate)

Mass Spectrum (ESF): m / z = 487, 489 [M-H] ⁺ (25) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((8) -6-methyl- 2-Oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 212-213 ° C

Mass Spectrum (ESI ^4- ): m / z = 461, 463 [M + H} ⁺ (26) 4 - [(3-chloro-4-fluorophenyl) amino] -6- {2- [L-carboxymethyl) -K - ((S) -2-Hydroxypropyl) -amino] -ethoxy} -7-methoxy-quinazoline (By-product of 3 (25))

Melting point: 187-190 ° C

Mass Spectrum (ΕδΓ): m / z - 479, 481 [M + H] ⁺ (27) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-) oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (The reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 229-232 ° C

Mass Spectrum (EST): m / z = 473, 475 [M-H] '(28) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-) oxomorpholin-4-yl) ethoxy] -7 - ((R) -tetrahydrofuran-3-yloxy) -quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 195-196 ° C

Mass Spectrum (ESI ⁴ ·): m / z = 531, 533 [M + H] ⁺ (29) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl- 6-oxomorpholin-4-yl) ethoxy] -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline (Reaction was carried out with trifluoroacetic acid in acetonitrile)

Melting point: 184 ° C

Mass Spectrum (ΕδΓ): m / z = 545, 547 [M + H] ⁺ (30) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (2,2-dimethyl-6-) oxomorpholin-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) -oxomorpholin-4-yl) ethoxy] -6 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline (The reaction is carried out with trifluoroacetic acid in acetonitrile) Melting point: 182 ° C

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

Example 4

4 - [(3-bromophenyl) amino | -6- (2 -? \ ^- [(tert-butyloxycarbonyl) methyl] -N- ((8) -2-hydroxy-propyl) -amino-ethoxy) -7-methoxy -quinazoline

To 650 mg of 4 - [(3-bromophenyl) amino] -6- (2-bromo-ethoxy) -7-methoxy-quinazoline and 1.10 g of (S) - (2-hydroxypropylamino) -acetic acid tert-butyl ester in 15 ml acetonitrile was added 0.25 ml of diisopropylethylamine. The reaction mixture was stirred overnight at 50 ° C. As no reaction was observed, the reaction mixture was concentrated, mixed with 20 ml N, N-dimethylformamide and stirred for eight hours at 60 ° C. Finally, the temperature rises to 80 ° C. After another eight hours, the reaction was over. The reaction mixture was concentrated and chromatographed on a silica gel column with eluent ethyl acetate. The desired substance is obtained as a white solid. Yield: 410 mg (51% of theory),

Rf value: 0.27 (silica gel, ethyl acetate)

Mass Spectrum (ESI ^- ): m / z = 559, 561 [M-H] '

The following compounds were prepared analogously to Example 4:

(1) 4 - [(3-bromophenyl) amino] -6- (2-T4 - [(tert-butyloxycarbonyl) methyl] -L1 - ((R) -2-hydroxy-propyl) -amino-ethoxy) -7 -methoxy-quinazoline Melting point: 130 ° C

Mass Spectrum (ESI ^- ): m / z = 559, 561 [M-H] ^- (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2-N - [(tert-butyloxycarbonyl) methyl] -L - (R) -2-hydroxy-propyl) -amino-ethoxy) -7-methoxy-quinazoline (The reaction was carried out in N, N-dimethylformamide)

Rf value: 0.40 (silica gel, ethyl acetate / petroleum ether = 4: 1) (3) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3-H - [(tert-butyloxycarbonyl) methyl] -14 - (((R) -2-hydroxy-propyl) -amino} -propyloxy) -7methoxy-quinazoline (The reaction is carried out in N, N-dimethylformamide)

Rf value: 0.37 (silica gel, ethyl acetate / petroleum ether = 4: 1)

Mass spectrum (ESI '): m / z = 547, 549 [M-H] (4) 4 - [(R) - (1-phenylethyl) amino] -6- (3-H - [(tert-butyloxycarbonyl) methyl ] -H - ((S) -2-hydroxy-propyl) -amino-propyloxy) -7methoxy-quinazoline (The reaction is carried out in N, N-dimethylformamide)

Rf value: 0.65 (silica gel, ethyl acetate / methanol = 9: 1)

Mass Spectrum (El): m / z = 524 [M] ⁺ (S) 4 - [(R) - (1-phenylethyl) amino] -6- (2-H - [(tert-butyloxycarbonyl) methyl] -H- ((S) -2-Hydroxy-propyl) -amino-ethoxy) -7-methoxyquinazoline (The reaction is carried out in N, N-dimethylformamide)

Rf value: 0.57 (silica gel, ethyl acetate / methanol / concentrated, aqueous ammonia solution = 9: 1: 0.1) (6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3-H - [ (tert-butyloxycarbonyl) methyl] -N- (R) -2-hydroxy-propyl) -amino} -propyloxy) -7cyclobutyloxy-quinazoline

Rf value: 0.31 (silica gel, methylene chloride / methanol = 95: 5)

Mass Spectrum (ESI): m / z = 547, 549 [M-H] (7) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3- {N - [(tert-butyloxycarbonyl) ) methyl] -E1- (1,1-dimethyl-2-hydroxy-ethyl) -amino} propyloxy) -7-cyclobutyloxy-quinazoline

Rf value: 0.29 (silica gel, methylene chloride / methanol = 95: 5)

Mass Spectrum (ESI ⁺ ): m / z = 603, 605 [M + H] ⁺ (S) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3- {M - [(tert-butyloxycarbonyl) ) methyl] -E1 - ((R) -2-hydroxy-propyl) -amino} -propyloxy) -7cyclopropylmethoxy-quinazoline

Rf value: 0.37 (silica gel, methylene chloride / methanol = 95: 5) (9) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3- {^ [(tert-butyloxycarbonyl) methyl] -N - ((S) -2-hydroxy-propyl) -amino} -propyloxy) -7cyclopropylmethoxy-quinazoline

Rf value: 0.50 (silica gel, ethyl acetate) (10) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {N - [(tert-butyloxycarbonyl) methyl] -N - ((8 ) -2-hydroxy-propyl) -amino} -ethoxy) -7cyclopentyloxy-quinazoline

Rf value: 0.54 (silica gel, ethyl acetate / cyclohexane = 9: 1) (11) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {M - [(tert-butyloxycarbonyl) methyl] -N - ((R) -2-hydroxy-propyl) -amino} -ethoxy) -7cyclopentyloxy-quinazoline

Rf value: 0.66 (silica gel, ethyl acetate) (12) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {M - [(tert-butyloxycarbonyl) methyl] -L - ((8 ) -2-hydroxy-propyl) -amino} -ethoxy) -7cyclopropylmethoxy-quinazoline

Rf value: 0.60 (silica gel, ethyl acetate) (13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- (N - [(tert-butyloxycarbonyl) methyl] -N - (R) -2-hydroxy-propyl) -amino} -ethoxy) -7cyclopropylmethoxy-quinazoline

Rf value: 0.60 (silica gel, ethyl acetate) (14) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2 {K - [(tert-butyloxycarbonyl) methyl] - N - ((S) -2-hydroxy-propyl) amino} -ethoxy) -quinazoline

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

Rf value: 0.30 (silica gel, ethyl acetate) (16) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3 {X - [(tert-butyloxy-carb) one. | N-ethyl] -L1 - ((R) -2-hydroxy-propyl) amino} -propyloxy) -quinazoline

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

Rf value: 0.35 (silica gel, ethyl acetate) (18) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {b1 - [(ethoxycarbonyl) methyl] -1H- (2-hydroxy- 2-methyl-propyl-amino} -ethoxy) -7cyclopentyloxy-quinazoline

Rf value: 0.35 (silica gel, ethyl acetate)

Mass Spectrum (ESI ⁺ ): m / z = 575, 577 [M + H] ⁺ (19) 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {M [( tert-butyloxy-carbonyl) methyl] -N - ((S) -2-hydroxy-propyl) -amino} ethoxy) -quinazoline

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

Rf value: 0.51 (silica gel, ethyl acetate) (21) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (4- {N - [(tert-butyloxycarbonyl) methyl] -1H - ((8 ) -2-hydroxy-propyl) -amino} -butyloxy) -7cyclopentyloxy-quinazoline

Rf value: 0.61 (silica gel, ethyl acetate) (22) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (4- (1 '[- [(tert-butyloxycarbonyl) methyl] -1 \ [ - ((R) -2-hydroxy-propyl) -amino} -butyloxy) -7cyclopentyloxy-quinazoles and

Rf value: 0.61 (silica gel, ethyl acetate)

W (23) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3- {T4 - [(tert-butyloxycarbonyl) methyl] -N - ((S) -2-hydroxy-propyl) - amino} -propyloxy) -7methoxy-quinazoline

Rf value: 0.46 (silica gel, ethyl acetate)

Mass Spectrum (ESP): m / z = 547, 549 [M-H] '(24) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (3- {1 \ [- [(tert- butyloxy-carbonyl) methyl] -14- (1,1-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- {T4 - [(tert-butyloxycarbonyl) ) methyl] -L1 - ((S) -2-hydroxy-propyl) -amino} -ethoxy) -7methoxy-quinazoline

Rf 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- {b [- [(ethoxy- carbonyl) methyl] -1 N- (2-hydroxy-2-methyl-propyl) -amino} -ethoxy) -7-methoxyquinazoline

Rf value: 0.44 (silica gel, ethyl acetate) (Exists as a mixture with already cyclized)

Mass Spectrum (ESI ⁺ ): m / z = 521, 523 [M + H] ⁺ (27) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {M - [(ethoxycarbonyl) ) methyl] -1H- (2-hydroxy-2-methyl-propyl) -amino} -ethoxy) -7 - ((D) tetrahydrofuran-3-yloxy) -quinazoline (Exists as a mixture with already cyclized)

Rf value: 0.30 (silica gel, methylene chloride / methanol = 9: 1) (28) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (2- {M - [(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl-propyl) -amino} -ethoxy) -7 - [(4-tetrahydrofuran-2-yl) -methoxy] -quinazoline

C Mass Spectrum (ESF): m / z = 589, 591 [M-H] '(29) 4 - [(3-chloro-4-fluorophenyl) amino] -7- (2- (M - [(ethoxycarbonyl) ) methyl] -N- (2-hydroxy-2-methyl-propyl) -amino} -ethoxy) -6 - ((8) tetrahydrofuran-3-yloxy) -quinazoline

Rf value: 0.16 (silica gel, methylene chloride / methanol = 20: 1) (30) 4 - [(3-chloro-4-fluorophenyl) amino] -7- (2- {b1 - [(ethoxycarbonyl) methyl] -X- (2-hydroxy-2-methyl-propyl) -amino} -ethoxy) -6 - [(8) tetrahydrofuran-2-yl) -methoxy] -quinazoline

Rf value: 0.68 (silica gel, ethyl acetate / methanol = 15: 1) ^{w The} following compounds can be obtained analogously to the above examples and to other known methods:

(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-oxomorpholin-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-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline (6) 4- [(3-chloro- 4-fluorophenyl) amino] -6- [2- (5,5-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7-m (7) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (3-methyl-2-oxomorpholin-4-yl) -propyl oxy] -7-methoxy-quinazoline toxin-quinazoline ( 8) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (3-methyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline (9) 4- [ (R) - (1-phenylethyl) amino] -6- [3 - ((1 H) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline (10) 4- [ (R) - (1-phenylethyl) amino] -6- [2 - ((R) -6-methyl-2-oxo-morpholine-

F * 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) -butyl oxy] -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-fluoro phenyl) amino] -6- [2- (6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7- (tetrahydropyran-4-yloxy) -quinazoline (17) 4 - [(3-chloro-4 -fluorophenyl) amino] -6- [2- (6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7- (tetrahydrofuran-2-ylmethoxy) -quinazoline (18) 4 - [(3-chloro- 4-Fluorophenyl) amino] -6- [2- (6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7- (tetrahydropyran-4-ylmethoxy) -quinazoline (19) 4 - [(3-chloro -4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-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-oxomorpholin-4-yl) -butyloxy] -7- (tetrahydrofuran-3-yloxy) -quinazoline (22) 4 - [(3 -chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -7- (tetrahydrofuran-2-ylmethoxy) -quinazoline (23) 4- [(3-chloro-4-fluoro-phenyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7- (tetrahydrofuran-2-ylmethoxy) quinazoline

D. (24) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [4- (6,6-dimethyl-2-oxomorpholin-4-yl) -butyloxy] -7- (tetrahydrofuran-2 (25) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) -ethoxy] -6- (tetrahydrofuran-3-ylmethoxy) quinazoline -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 (2S) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxomorpholin-4-yl) -ethoxy] -6- ( tetrahydrofuran-2-ylmethoxy) -quina olin (29) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2 "(6-methyl-2-oxomorpholin-4-yl) -ethoxy] -6- (tetrahydropyran-4-ylmethoxy) -quinazoline (3 O) 4- [(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) -ethoxy] -6- (tetrahydrofuran- 3-yloxy) -quinazoline (31) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -6- (tetrahydrofuran-3-yloxy) quinazoline (32) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [4- (6,6-dimethyl-2-oxomorpholin-4-yl) -butyloxy] - 6- (tetrahydrofuran-3-yloxy) -quinazoline (33) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxomorpholin-4-yl) ) -ethoxy] -6- (tetrahydrof ran-3-ylmethoxy) -quinazoline (34) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] - 6- (tetrahydrofuran-2-ylmethoxy) quinazoline (35) 4 - ((3-chloro-4-fluorophenyl) amino] -7 - [4- (6,6-dimethyl-2-oxomorpholin-4-yl) - butyloxy] -6- (tetrahydrofuran-3-ylmethoxy) quinazoline

Example 5

Dragees with 75 mg of active substance

Composition:

The core of 1 dragee contains:

active substance 75.0 mg calcium phosphate 93.0 mg cornstarch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropyl methylcellulose 15.0 mg magnesium stearate 1.5 mg 230,0 mg

Receive:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose and half of the specified amount of magnesium stearate. Tablets of about 13 mm in diameter are pressed on a tablet machine, passed to a suitable machine through a 1.5 mm mesh sieve and mixed with the remaining magnesium stearate. This granulate is compressed on a tablet machine into tablets of the desired shape. Core Weight: 230 mg

Panson: 9 mm, vaulted

The dragee cores thus obtained are coated with a film consisting essentially of hydroxypropyl methylcellulose. Finished film dragees are glossed with beeswax.

Dragee Weight: 245 mg.

Example 6

100 mg tablets of active substance

Composition:

tablet contains:

active substance 100.0 mg lactose 80.0 mg cornstarch 34,0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220,0 mg

Method of production:

The active substance, lactose and starch are mixed and moistened evenly with an aqueous solution of polyvinylpyrrolidone. After sifting the wet mass (2.0 mm light opening) and drying in an oven at 50 ° C, sift again (1.5 mm light hole) and add lubricant when mixed. The ready-to-press mixture is processed into tablets.

Tablet weight: 220 mg

Diameter: 10 mm, biplanar with two-sided veneer and dividing line on one side.

Example 7

150 mg tablets of the active substance

Composition:

tablet contains:

active substance 150.0 mg lactose powder 89.0 mg cornstarch 40,0 mg colloidal silicic acid 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300,0 mg

Receiving

The active substance, lactose, corn starch and silicic acid are mixed and moistened evenly with a 20% aqueous solution of polyvinylpyrrolidone. After sieving the wet mass through a 1.5 mm light opening and drying in an oven at 45 ° C, the dried granulate was sieved again through the same sieve and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.

Tablet weight: 300 mg

Pansons: 10 mm, flat

Example 8

Hard gelatin capsules with 150 mg of active substance 1 capsule contains:

active substance 150.0 mg cornstarch, dried, about 180,0 mg lactose powder, ca. 87,0 mg magnesium stearate 3,0 mg around 420,0 mg

Receive:

The active substance is mixed with the excipients, passed through a 0.75 mm sieve and sieve homogenized in a suitable apparatus.

The mixture is filled into hard gelatin capsules of size 1. Capsule content: about 320 mg

Capsule: a size 1 hard gelatin capsule.

Example 9

Suppositories with 150 mg of suppository active substance contains:

active substance 150.0 mg polyethylene glycol 1500 550,0 mg polyethylene glycol 6000 460,0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2000,0 mg

Receive:

After melting the candle mass, the active substance is distributed homogeneously therein and said mass is poured into pre-cooled forms.

Example 10

Suspensions with 50 mg of active substance

100 ml suspension contains:

active substance 1.00 g Carboxymethylcellulose Na-salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g cane sugar 10,00 g glycerin 5,00 g sorbitol solution 70% 20,00 g a fragrant substance 0.30 g water dest. to 100 ml

Receive:

Distilled water is heated to 70 ° C. When stirred, the methyl ester and the propyl ester of p-hydroxybenzoic acid as well as the glycerol and the sodium salt of carboxymethylcellulose are dissolved therein. It is cooled to room temperature and, with stirring, the active substance is added and dispersed homogeneously. After the sugar, the sorbitol solution and the flavoring substance have been added and dissolved, the suspension is vented by evacuation with stirring. 5 ml of suspension contains 50 mg of active substance.

Example 11 p

Ampoules with 10 mg of active substance

Composition:

active substance 10.0 mg 0.01N hydrochloric acid s.q. water distilled to 2,0 ml

Receive:

The active substance was dissolved in the required amount of 0.01 N HCl, the solution made isotonic with the cooking salt, filtered sterile and filled in 2 ml ampoules.

Example 12

Ampoules with 50 mg of active substance

Composition:

active substance 50,0 mg 0.01N hydrochloric acid s.q. water distilled to 10,0 ml

Receive:

The active substance is dissolved in the required amount of 0.01N HCl, the solution is isotonic with the cooking salt, filtered sterile and filled in 10 ml ampoules.

Example 13

Powder inhalation capsules with 5 mg active substance capsule contains:

active substance 5.0 mg lactose for inhalation purposes 15.0 mg 20,0 mg

Receive:

The active substance is mixed with lactose for inhalation purposes. The mixture was filled into a capsule machine in capsules (empty capsule weight about 50 mg).

Capsule Weight: 70.0 mg

Capsule size: 3

Example 14

Manual nebulizer solution with 2.5 mg of active ingredient pressing contains:

active substance 2,500 mg benzalkonium chloride 0,001 mg 0.01N hydrochloric acid s.q. ethanol / water (50/50) to 15,000 ml

Receive:

The active substance and benzalkonium chloride were dissolved in ethanol / water (50/50). The pH of the solution was adjusted with 1 N-hydrochloric acid. The adjusted solution is filtered and filled into a suitable tank for the hand sprayer (cartridge).

Tank filling: 4,5 g

Claims (12)

Claims 1. Bicyclic heterocycles of the general formula R _b Rc (I) in which Ra represents a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R 1 and R ₂ , wherein R 1 represents a hydrogen, fluorine, chlorine or bromine atom, methyl, trifluoromethyl, cyano or ethynyl group, and R ₂ represents a hydrogen or fluorine atom, one of the radicals R b or R c represents R 3 - (CH ₂ ) _m- O-rpyna, and the other of Rb or Rc represents methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy-, tetrahydrofuran-3yloxy-, tetrahydropyran-3-yloxy- tetrahydro-tetrahydro-tetrahydro-tetrahydro-tetrahydro-tetrahydro-tetrahydro-tetrahydro d * 'which R3 represents a N- (2-oxo-tetrahydrofuran-4-yl) -methylaminoyl-L [- (2-oxo-tetrahydrofuran-4-yl) -ethylamino group, one for methylene groups with one or two methyl or ethyl groups substituted R4- O-CO-CH ₂ -N-CH ₂ CH ₂ -OH-pyrene in which R 4 represents a hydrogen atom or a C 1-4 alkyl group or with one or two methyl or ethyl groups substituted a 2 oxo-morpholin-4-yl group and m represents the number 2, 3 or 4, provided that the compounds are excluded 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2-N- (2-hydroxy-2-methyl-prop-1-yl) -N '[- [(ethoxycarbonyl) -methyl] ] -aminoethoxy) -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6 dimethyl-2-oxo-morpholin-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- [1- (2-oxo-tetrahydrofuran-4-yl) -L-methyl-amino] -ethoxy-7-methoxy-quinazoline, their tautomers, their stereoisomers and their salts. Compounds of the general formula I according to claim 1, wherein R _a represents a gasoline or 1-phenylethyl group or a phenyl group substituted by the radicals R 1 and R ₂ , wherein R1 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group, and R ₂ represents a hydrogen or fluorine atom, one of the radicals Rb or Rc represents R ₃ - (CH ₂ ) mO-rpyna, and the other of the radicals Rb or Rc represents methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy-, cyclops ethyl methoxy, tetrahydrofuran-3yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranyl methoxy, wherein R ₃ represents a N- (2-oxo-tetrahydrofuran-4-yl) -methylaminoyl or N- (2-oxo-tetrahydrofuran-4-yl) -ethylamino group, one for methylene groups with one or two methyl or ethyl groups substituted R 4 -O -CO-CH ₂ -N-CH ₂ CH ₂ -OH-pyrene in which R 4 represents a hydrogen atom or a C 1-4 alkyl group, or with one or two methyl or ethyl groups substituted a 2 oxo-morpholin-4-yl group, and m represents the number 2, 3 or 4, provided that the compounds are excluded 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2-N- (2-hydroxy-2-methyl-prop-1-yl) -N - [(ethoxycarbonyl) -methyl] - aminoethoxy) -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclo-pentyloxy-7- [2- (6,6 dimethyl-2-oxo-morpholin-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) -methyl-amino] -ethoxy-7-methoxy-quinazoline, 4 - [(3-bromophenyl) amino] -6- (2-N- (2-hydroxy-2-methyl-prop-1-yl) -X [(ethoxycarbonyl) methyl] -amino-ethoxy) -7-methoxy -quinazoline, 4- [(3-bromophenyl) amine]] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] - 7-methoxy-quinazoline, 4 - [(3-bromophenyl) 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, ΊΟ 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- [L [- (2-oxo-tetrahydrofuran-4-yl) -1H-methyl-amino] -ethoxy-7-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6-2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy-7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6-2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -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) -propyl oxy] -7-cyclopentylmethoxy-quinazoline, (K) - 4 - [(1-phenylethyl) 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- [T4- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy-6-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7-2- [N- (2-oxo-tetrahydrofuran-4-yl) -T4-methyl-amino] -ethoxy-6-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7-2- [14- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -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-phenylethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline, their tautomers, their stereoisomers and their salts. Compounds of general formula I according to claim 1, wherein Ra represents a 1-phenylethyl group or a phenyl group substituted by the radicals Ri and R ₂ , wherein R 1 represents a fluorine, chlorine or bromine atom, a methyl or ethynyl group and R ₂ represents a hydrogen or fluorine atom, one of the radicals Rb or Rc represents R ₃ - (CH ₂ ) mO-rpyna, and the other of the radicals Rb or Rc represents methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy -, tetrahydrofuran-3yloxy-, tetrahydropyran-3-yloxy-, tetrahydropyran-4-yloxy-, tetrahydrofuranylmethoxy- or tetrahydropyranylmethoxy, wherein R ₃ represents a L- (2-oxo-tetrahydrofuran-4-yl) -methylamino group, one in methylene groups with one or two methyl groups substituted by R 4 -O-CO-CH 2 -N-CH ₂ CH ₂ -OH-pyrene, in which R4 represents a _b-4 alkyl, or with one or two methyl groups substituted 2-oxo-morpholin-4-yl group, and m represents the number 2, 3 or 4, provided that excluded are the compounds 4 - [(3- chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2-N- (2-hydroxy-2-methyl-prop-1-yl) -N - [(ethoxycarbonyl) -methyl] -aminoethoxy) -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6 dimethyl-2-oxo-morpholin-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) -L-methyl-amino] -ethoxy-7-methoxy-quinazoline, 4 - [(3-bromophenyl) amino] -6- (2-N- (2-hydroxy-2-methyl-prop-1-yl) -N [(ethoxycarbonyl) methyl] -amino-ethoxy) -7-methoxy -quinazoline, 4 - [(3-bromophenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] - 7-methoxy-quinazoline, 4- [(3-bromophenyl) 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-cyclo-butyl oxy-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 yn, 4 - [(3-chloro-4-fluorophenyl) amino] -6-2- [1- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy-7-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6-2- [1- (2-oxo-tetrahydrofuran-4-yl) -L-methyl-amino] -ethoxy-7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6-2- {N - [- (2-oxo-tetrahydrofuran-4-yl) -X-methyl-amino] -ethoxy-7-cyclopentylmethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyl oxy] -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, (K) -4 - [(1-phenylethyl) 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-methyl-amino] -ethoxy-o-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7-2-N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy-6-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7-2- [T4- (2-oxo-tetrahydrofuran-4-yl) -1H-methyl-amino] -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-morpholin-4-yl) propyloxy] -6-cyclopentyloxy-quinazoline, their tautomers, their stereoisomers and their salts. Compounds of general formula I according to claim 1, wherein Ra represents a 1-phenylethyl group or a phenyl group substituted by the radicals Ri and R ₂ , wherein R 1 represents a fluorine, chlorine or bromine atom, a R ₂ represents a hydrogen or fluorine atom, one of the radicals Rb or Rc represents R ₃ - (CH ₂ ) mO-rpyna, and the other of the radicals Rb or Rc represents methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, cyclobutylmethoxy-, cyclopentylmethoxy -, tetrahydrofuran-3-yloxy-, tetrahydropyran-3-yloxy-, tetrahydropyran-4-yloxy-, tetrahydrofuranylmethoxy- or tetrahydropyranyl methoxy, wherein R ₃ represents a 15 N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group or with one or two methyl groups substituted by a 2-oxo75 morpholin-4-yl group, am represents the number 2, 3 or 4, provided that compounds are excluded 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6 dimethyl-2-oxo-morpholin-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- [1 N- (2-oxo-tetrahydrofuran-4-yl) -methyl-amino] -ethoxy-7-methoxy-quinazoline, 4- [(3-bromophenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4 - [(3-bromophenyl) 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-cycle on butyloxy-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- [T4- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy-7-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6-2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy-7-cyclopentyl oxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6-2- N- (2-oxo-tetrahydrofuran-477 morpholin-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 their tautomers, their stereoisomers and their salts. Compounds of general formula I according to claim 1, wherein Ra represents a 1-phenylethyl, 3-bromophenyl or 3-chloro-4fluorophenyl group, with R b is R ₃ - (CH ₂ ) m O -pyrene in which R ₃ represents one with one or two methyl groups substituted 2-oxo-morpholin-4-yl-group and m represents the number 2 or 3, and Rc stands for methoxy-, cyclobutyloxy-, cyclopentyloxy-, cyclopropylmethoxy-, tetrahydropyran-3-yloxy- or tetrahydrofuranylmethoxy-group, provided that compounds excluded 4 - [(3-bromophenyl) amino] -6- [2- (6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4 - [(3-bromophenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] 7-methoxy-quinazoline, 4- [(3-bromophenyl) 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 and 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-cyclopentyl oxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxomorpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline and (R) -4 - [(1-Phenyl ethyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) propyloxy] -7-cyclopentyloxy-quinazoline their tautomers, their stereoisomers and their salts . Compounds of general formula I according to claim 1, wherein Ra is a 3-chloro-4-fluorophenyl group, Rb stands for cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydropyran-3-yloxy, or tetrahydrofuranylmethoxy, R c is R 3 - (CH ₂ ) m O -pyrene in which R3 represents one with one or two methyl groups substituted 2-oxo-morpholin-4-yl-group and m represents the number 2, provided that the compounds are excluded 4 - [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6 dimethyl-2-oxo-morpholin-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, their tautomers, their stereoisomers and salts thereof. 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- [19- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -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-oxo-morpholin-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) -14-methyl-amino] -ethoxy-quinazoline, (7) 4 - [(3- bromophenyl) amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, (S) 4 - [(3-bromophenyl) amino] -6- [2 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, (9) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (S) - 6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, (10) 4 - [(3-chloro-4-fluorophenyl) amino ] -6- [3 - ((R) -6-methyl-2-oxomorpholin-4-yl) -propyl oxy] -7-methoxy-quinazoline, (11) 4 - [(R) - (1-phenylethyl) amino] -6- [3 - ((S) -6-methyl-2-oxo-morpholin4-yl) -propyloxy] -7-methoxy-kinase olin, (12) 4- [(R) - (1-phenyl ethyl) amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy -quinazoline, (13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - ((S) -6-methyl-2-oxomorpholin-4-yl) -ethoxy] -7-methoxy -quinazoline, their tautomers, their stereoisomers and their salts. 8. Physiologically acceptable salts of the compounds of claims 1 to 7 with inorganic or organic acids or bases. A medicament comprising a compound according to claims 1 to 7 or a physiologically acceptable salt according to claim 8, optionally together with one or more inert carriers and / or diluents. Use of a compound according to claims 1 to 8 for the preparation of a medicament suitable for the treatment of benign and malignant tumors, for the prevention and treatment of diseases of the respiratory tract and lungs, for the treatment of polyps, diseases of the stomach the intestinal tract, the biliary tract and gallbladder, as well as the kidneys and skin. A method for the preparation of a medicament according to claim 9, characterized in that the non-chemical route of the compound according to claims 1 to 8 is mixed with one or more inert carriers and / or diluents. A process for the preparation of the compounds of general formula I according to claims 1 to 8, characterized in that it comprises a) reacting a compound of the general formula