KR20030024914A - Bicyclic heterocycles, medicaments containing these compounds, their use, and methods for the production thereof - Google Patents

Abstract

The present invention provides bicyclic heterocycles of formula I, tautomers thereof, stereoisomers and salts thereof, in particular inorganic acids, organic acids, inorganic bases, which exhibit useful pharmacological properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases. Or a physiologically acceptable salt thereof with an organic base. The invention also relates to the use of the bicyclic heterocycle for the treatment of diseases, in particular neoplastic and pulmonary and respiratory tract diseases, and to methods for their preparation.

Formula I

In Formula I above,

R _a to R _c are as defined in claims 1 to 7.

Description

Bicyclic heterocycles, medicaments containing these compounds, their use, and methods for the production according to the present invention.

The present invention provides bicyclic heterocycles of formula I, their tautomers, their stereoisomers and salts thereof, in particular inorganic acids, organics, which exhibit useful pharmacological properties, in particular their inhibitory effect on signal transduction mediated by tyrosine kinases. It relates to physiologically acceptable salts, diseases thereof, especially tumorous diseases and lung and respiratory tract diseases with acids, inorganic bases or organic bases, and methods for their preparation.

In Formula I above,

R _a is benzyl or 1-phenylethyl group, or a phenyl group substituted by R ₁ and R ₂ groups, wherein R ₁ is hydrogen, fluorine, chlorine or bromine or methyl, trifluoromethyl, Cyano or ethynyl group, R ₂ is a hydrogen atom or a fluorine atom),

One of the R _b and R _c groups is an R _3- (CH ₂ ) _m -O group wherein R ₃ is N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or N- (2- Oxo-tetrahydrofuran-4-yl) -ethylamino group, or a R ₄ —O—CO—CH ₂ —N—CH ₂ CH ₂ —OH group, wherein the methylene group is substituted by one or two methyl or ethyl groups Wherein R ₄ is a hydrogen atom or a C _1-4 -alkyl group or a 2-oxo-morpholin-4-yl group substituted by 1 or 2 methyl or ethyl groups, m is 2, 3 or 4], and the other of the R _b and R _c groups is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group,

Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop in the compound of formula (I) -1-yl) -N-[(ethoxycarbonyl) -methyl] -amino} -ethoxy) -quinazolin,

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

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

4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Toxy-quinazoline is excluded.

Preferred compounds of formula (I)

R _a is benzyl or 1-phenylethyl group, or a phenyl group substituted by R ₁ and R ₂ groups, wherein R ₁ is hydrogen, fluorine, chlorine or bromine or methyl, trifluoromethyl, Cyano or ethynyl group, R ₂ is a hydrogen atom or a fluorine atom),

One of the R _b and R _c groups is an R _3- (CH ₂ ) _m -O group wherein R ₃ is N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or N- (2- Oxo-tetrahydrofuran-4-yl) -ethylamino group, or a R ₄ —O—CO—CH ₂ —N—CH ₂ CH ₂ —OH group, wherein the methylene group is substituted by one or two methyl or ethyl groups Wherein R ₄ is a hydrogen atom or a C _1-4 -alkyl group or a 2-oxo-morpholin-4-yl group substituted by 1 or 2 methyl or ethyl groups, m is 2, 3 or 4], and the other of the R _b and R _c groups is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group,

Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) -methyl] -amino} -ethoxy) -quinazolin,

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

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

4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Oxy-quinazoline,

4-[(3-bromo-phenyl) amino] -6- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) methyl ] -Amino} -ethoxy) -7-methoxy-quinazolin,

4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazolin,

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

4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin,

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

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

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

4-[(3-chloro-4-fluorophenyl] amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentylme Oxy-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- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentyloxy-quinazolin,

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

4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin,

4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline,

4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentylme Oxy-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-oxo-morpholin-4-yl) -ethoxy] -6-methoxy- Quinazolin,

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-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy Quinazoline,

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

4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Oxy-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-quinazolin,

4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentylmethoxy-quinazolin,

4-[(3-Chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy- Quinazolin,

4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy Quinazoline,

4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylme Oxy-quinazolin and

(R) -4-[(1-phenyl-ethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy -Compounds other than quinazoline, tautomers thereof, stereoisomers thereof and salts thereof,

Especially

R _a is a 1-phenylethyl group or a phenyl group substituted by R ₁ and R ₂ groups, wherein R ₁ is a fluorine atom, a chlorine atom or a bromine atom, a methyl or ethynyl group, and R ₂ is a hydrogen atom or Fluorine atom),

One of the R _b and R _c groups is an R _3- (CH ₂ ) _m -O group wherein R ₃ is an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group, or the methylene group is R ₄ —O—CO—CH ₂ —N—CH ₂ CH ₂ —OH groups substituted by 1 or 2 methyl groups, wherein R ₄ is a C _1-4 -alkyl group or 1 or 2 methyl 2-oxo-morpholin-4-yl group substituted by a group, m is 2, 3 or 4], and the other of the R _b and R _c groups is methoxy, cyclobutyloxy, cyclopentyloxy, Cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydro Pyranylmethoxy group,

Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) -methyl] -amino} -ethoxy) -quinazolin,

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

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

4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Oxy-quinazoline,

4-[(3-bromo-phenyl) amino] -6- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) methyl ] -Amino} -ethoxy) -7-methoxy-quinazolin,

4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazolin,

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

4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin,

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

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

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

4-[(3-chloro-4-fluorophenyl] amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentylme Oxy-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- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentyloxy-quinazolin,

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

4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin,

4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline,

4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentylme Oxy-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-oxo-morpholin-4-yl) -ethoxy] -6-methoxy- Quinazolin,

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-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy Quinazoline,

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

4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Oxy-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-quinazolin,

4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentylmethoxy-quinazolin,

4-[(3-Chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy- Quinazolin,

4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy Quinazoline,

4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylme Oxy-quinazolin and

(R) -4-[(1-phenyl-ethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy -Compounds other than quinazoline, tautomers thereof, stereoisomers thereof and salts thereof.

Particularly preferred compounds of formula I are

R _a is a 1-phenylethyl group or is a phenyl group substituted by R ₁ and R ₂ groups, wherein R ₁ is a fluorine atom, a chlorine atom or a bromine atom, and R ₂ is a hydrogen atom or a fluorine atom,

One of the R _b and R _c groups is an R _3- (CH ₂ ) _m -O group wherein R ₃ is an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group, or 1 or 2 2-oxo-morpholin-4-yl group substituted by 2 methyl groups, m is 2, 3 or 4] and the other of the R _b and R _c groups is methoxy, cyclobutyloxy, cyclopentyl Oxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or Tetrahydropyranylmethoxy group,

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

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

4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Oxy-quinazoline,

4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazolin,

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

4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin,

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

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

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

4-[(3-chloro-4-fluorophenyl] amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentylme Oxy-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- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentyloxy-quinazolin,

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

4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin,

4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline,

4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentylme Oxy-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-oxo-morpholin-4-yl) -ethoxy] -6-methoxy- Quinazolin,

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-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy Quinazoline,

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

4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Oxy-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-quinazolin,

4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentylmethoxy-quinazolin,

4-[(3-Chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy- Quinazolin,

4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy Quinazoline,

4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylme Oxy-quinazolin and

(R) -4-[(1-phenyl-ethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy -Compounds other than quinazoline, tautomers thereof, stereoisomers thereof and salts thereof.

Most particularly preferred compounds of formula I are

R _a is 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,

R _b is a R _3- (CH ₂ ) _m -O group wherein R ₃ is a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups, m is 2 or 3 ego,

R _c is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group,

Provided that 4-[(3-bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quina Sleepy,

4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazolin,

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

4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin,

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

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

4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin,

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

4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-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 -Compounds other than quinazoline, tautomers thereof, stereoisomers thereof and salts thereof.

Most particularly preferred compounds of formula I are

R _a is a 3-chloro-4-fluorophenyl group,

R _b is cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group,

R _c is an R ₃ — (CH ₂ ) _m —O group wherein R ₃ is a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups, m is 2, and

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

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

4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropylme Oxy-quinazolin and

4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Compounds except oxy-quinazolin, tautomers thereof, stereoisomers thereof and salts thereof.

As the most particularly preferred compounds the following compounds are exemplified:

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

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

(3) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -Ethoxy] -quinazolin,

(4) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl)- Propyloxy] -quinazolin,

(5) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -Propyloxy] -quinazolin,

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

(7) 4-[(3-bromo-phenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-meth Oxy-quinazoline,

(8) 4-[(3-bromo-phenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-meth Oxy-quinazoline,

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

(10) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazoline,

(11) 4-[(R)-(1-phenyl-ethyl) amino] -6- [3-((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazoline,

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

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

Tautomers thereof, stereoisomers thereof and salts thereof.

Compounds of formula (I) can be prepared, for example, by the following methods.

(a) A method of reacting a compound of Formula II with a compound of Formula III.

In Formula II above,

R _a is as defined above,

One of the R _b 'and R _c ' groups is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, the other of the R _b 'and R _c ' groups Is a Z _1- (CH ₂ ) _m -O group wherein m is as defined above and Z ₁ is a leaving group, for example a halogen atom or a sulfonyloxy group, for example a chlorine atom, a bromine atom, Methanesulfonyloxy group or p-toluenesulfonyloxy group).

HR ₃

In Formula III above,

R ₃ is as defined above.

The reaction is carried out in a solvent or solvent mixture, for example methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, Conveniently in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (whereas these organic bases can also act as solvent at the same time) or an inorganic base such as sodium carbonate Or in the presence of potassium carbonate, optionally at a temperature of −20 to 200 ° C., preferably 0 to 150 ° C. for convenience.

(b) ring closure of the compound of formula IV optionally formed in the reaction mixture.

In Formula IV above,

R _a is as defined above,

One of the R _b "and R _c " groups is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, and the other of the R _b "and R _c " groups Is a R ₃ '-(CH ₂ ) _m -O group wherein m is as defined above and R ₃ ' is a R ₄ -O-CO-CH wherein the methylene group is substituted by one or two methyl or ethyl groups ₂ -N-CH ₂ CH ₂ -OH group wherein R ₄ is a hydrogen atom or a C _1-4 -alkyl group.

The reaction is carried out in a solvent or solvent mixture, for example methylene chloride, acetonitrile, dimethylformamide, dimethyl sulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, For convenience, in the presence of anhydrous acids such as trifluoroacetic acid, methanesulfonic acid or sulfuric acid or dehydrating agents such as isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentachloride, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexyl-carbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or Optionally in the presence of triphenylphosphine / carbon tetrachloride at a temperature of -20 to 200 ° C, preferably -10 to 160 ° C.

In the reactions described above, any reactive groups present, such as hydroxy, carboxy or imino groups, may be protected during the reaction by conventional protecting groups which decompose again after the reaction.

For example, a protecting group for a hydroxy group can be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group and the protecting group for a carboxy group is trimethyl May be silyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl groups, and the protecting group for the imino group is formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxy Carbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groups.

Any protecting group used is, for example, an acid, for example trifluoro, in an aqueous solvent such as water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water. 0 to 120 ° C., preferably in the presence of acetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium or potassium hydroxide or in the presence of an aprotic solvent such as iodotrimethylsilane It is then optionally decomposed by hydrolysis at a temperature of 10 to 100 ° C.

However, benzyl, methoxybenzyl or benzyloxycarbonyl groups can be, for example, by hydrogenolysis, for example with hydrogen, in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid. In the presence of a catalyst, for example palladium / charcoal, optionally an acid, for example hydrochloric acid, is added to a temperature of 0 to 100 ° C., preferably 20 to 60 ° C. and hydrogen of 1 to 7 bar, preferably 3 to 5 bar. Decompose at pressure. However, the 2,4-dimethoxybenzyl group is decomposed in trifluoroacetic acid, preferably in the presence of anisole.

Preferably tert-butyl or tert-butyloxycarbonyl groups are treated with iodotrimethylsilane or optionally acidic, for example using a solvent such as methylene chloride, dioxane, methanol or diethyl ether. Decompose by treating with trifluoroacetic acid or hydrochloric acid.

Preferably the trifluoroacetyl group is treated with an acid, for example hydrochloric acid, optionally in the presence of a solvent, for example acetic acid, at a temperature of 50 to 120 ° C., or optionally at a temperature of 0 to 50 ° C. For example, it is decomposed by treatment with sodium hydroxide solution in the presence of tetrahydrofuran.

In addition, the compounds of formula (I) obtained can be divided into their enantiomers and / or diastereomers as mentioned above. Thus, for example, the cis / trans mixtures can be divided into their cis and trans isomers and the compounds with one or more optically active carbon atoms can be separated into their enantiomers.

Thus, for example, the cis / trans mixtures can be chromatographically divided into their cis and trans isomers, and the compounds of formula (I) obtained as racemates can be obtained from the methods known per se by the known methods [Allinger NL and Eliel EL, "Topics inStereochemistry", Vol. 6, Wiley Interscience, 1971], wherein the compounds of formula I, which have two or more asymmetric carbon atoms, can be separated by their optical cognate, and their physicochemical properties are inherently known by methods such as chromatography and / or fractional crystallization. On the basis of the differences can be divided into their diastereomers, and if these compounds are obtained in racemic form, they can be subsequently divided into enantiomers as mentioned above.

Preferably, the enantiomers are separated by column separation for the chiral phase or recrystallization from the optically active solvent, or optically active substances, in particular, which form salts or derivatives, eg esters or amides, with racemic compounds Reactions with acids and their activating derivatives or alcohols and diastereomeric mixtures of the salts or derivatives thus obtained are separated, for example, on the basis of their solubility difference, whereas the free colon is a By action can be released from pure diastereomeric salts or derivatives. Commonly used optically active acids are, for example, tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid in the D- and L-forms. The optically active alcohol is, for example, (+) or (-)-menthol, and the optically active acyl group in the amide can be, for example, (+)-or (-)-methyloxycarbonyl.

In addition, the compounds of formula (I) can be converted into salts thereof, in particular physiologically acceptable salts thereof, for pharmaceutical use using inorganic or organic acids. Acids that can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, when the compounds of the formula (I) thus obtained contain carboxy, hydroxyphosphoryl, sulfo or 5-tetrazolyl groups, then, if desired, these are optionally used using inorganic bases or organic bases, salts thereof, in particular Conversion to physiologically acceptable salts thereof for pharmaceutical use. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanamine.

The compounds of the formulas (II) to (IV) used as starting materials can in some cases be known in the literature or obtained by methods known in the literature (see Examples I to XIV).

As already mentioned above, the compounds of formula (I) and the physiologically acceptable salts thereof according to the invention exhibit useful pharmacological properties, in particular their inhibitory effect on signal transduction mediated by epidermal growth factor receptor (EGF-R). Which can be achieved, for example, by inhibiting ligand binding, receptor dimerization or tyrosine kinase itself. It is also possible to block signal transmission for components located further down.

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

Inhibition of EGF-R-mediated signal transduction can be demonstrated using, for example, cells which express human EGF-R and whose survival and proliferation depend on palpation by EGF or TGF-alpha. We use cell lines of mouse origin that rely on interleukin-3 (IL-3) genetically modified to express functional human EGF-R. Thus, the proliferation of these cells, known as F / L-HERc, can be promoted by either mouse IL-3 or EGF. Von Ruden, T. et al., EMBO J. 7 , 2749-2756 (1988); Pierce, JH et al., Science 239 , 628-631 (1988).

The starting material used for F / L-HERc cells is cell line FDC-P ₁ and its preparation is described in the literature. Dexter, TM et al. J. Exp. Med. 152, 1036-1047 (1980). However, other growth factor-dependent cells can also be used. 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). For expressing human EGF-R cDNA (Ullrich, A. et al., Nature 309 , 418-425 (1984)), recombinant retroviruses are described in von Ruden, T. et al., EMBO J. 7 , 2749-2756 (1988), except that the retroviral vector LXSN (Miller, AD et al., BioTechniques 7 , 980-990 (1989)) was used for the expression of EGF-R cDNA. Cell line GP + E86 [Markowitz, D. et al., J. Virol. 62 , 1120-1124 (1988), are used as packaging cells.

The test is performed as follows:

F / L-HERc cells were cultured in RPMI / 1640 medium [BioWhittaker] and 10% fetal bovine serum [FCS, Boehringer Mannheim], 2 mM glutamine at 37 ° C. and 5% CO ₂ . Biobiter), standard antibiotics and 20 ng / ml of human EGF (Promega). To investigate the inhibitory activity of the compounds according to the invention, 1.5 × 10 ⁴ cells per well were cultured three times in 96-well dishes in the medium (200 μl), and cell proliferation was determined by EGF (20 ng / ml) or mouse IL −. Promote to 3. IL-3 used is obtained from the culture supernatant of cell line X63 / 0 mIL-3. Karasuyama, H. et al., Eur. J. Immunol. 18 , 97-104 (1988). The compounds according to the invention are dissolved in 100% dimethylsulfoxide (DMSO) and diluted to various concentrations (maximum DMSO concentration is 1%) and added to the culture. Cultures are incubated at 37 ° C. for 48 hours.

Relative cell numbers were measured in OD units using the Cell Titer 96 ^TM Aqueous Non-Radioactive Cell Proliferation Assay (Promega) to determine the inhibitory activity of the compounds according to the invention. Measure Relative cell number is calculated as a percentage of the control (F / LHERc cells without inhibitor) and from which results in a concentration of active substance (IC ₅₀ ) that inhibits cell proliferation 50%. The following results are obtained:

Compound (Example Number) EGF-dependent proliferation inhibitory IC ₅₀ [nM] One 59 1 (1) 29 1 (2) 29 2 (1) 36

Accordingly, the compounds of formula (I) according to the invention inhibit the signal transduction by tyrosine kinases, as demonstrated for example with human EGF receptors, to treat pathophysiological processes caused by the hyperfunction of tyrosine kinases. useful. These are, for example, benign or malignant tumors, especially tumors of epithelial and neuroepithelial origin, metastasisation and abnormal proliferation of neovascular endothelial cells (neovascularization).

The compounds according to the invention are used for airway and lung diseases, such as inflammatory diseases of the airways, for example chronic bronchitis, chronic obstructive bronchitis, asthma, bronchus, accompanied by increased or altered mucus production by stimulation by tyrosine kinases. It is also useful for preventing and treating bloat, allergic or nonallergic rhinitis or sinusitis, cystic fibrosis, α1-antitrypsin deficiency or cough, emphysema, pulmonary fibrosis, and reactive airways.

The compound also contains gastrointestinal, bile duct and gallbladder diseases associated with the disrupted activity of tyrosine kinases, such as those that may appear upon chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis and increased gastrointestinal ulcers or increased secretion. What may appear in gastrointestinal diseases associated with, for example, Mentrier's disease, secreting adenoma and protein loss syndrome, and also suitable for the treatment of nasal polyps, gastrointestinal polyps of various origins, eg For example, colonic chorionic or adenomatous polyps, as well as polyps in familial colon polyps, small intestine polyps in Gardner's syndrome, and the entire gastrointestinal tract in Peutz-Jeghers syndrome. It is also suitable for treating polyps, inflammatory pseudopolyps, combustible polyps, deep cystic colitis and barrier cystic carcinoma over time.

In addition, compounds of formula (I) and physiologically acceptable salts thereof can be used to treat kidney disease, especially in cystic changes, such as in the cysts, or to be idiopathic in nature or, for example, syndromes such as tuberculous sclerosis, Bon-Hiffel-Linda Von-Hippel-Lindau Syndrome, nephrolithiasis and other diseases caused by dysfunction of the kidney and tyrosine kinases in the cavernous kidney, such as epidermal hyperplasia (psoriasis), inflammatory processes, immune system diseases, hematopoietic cells Overgrowth can be treated.

The compounds according to the invention can be used on their own due to their biological properties, or for example in combination with other pharmacologically active compounds in tumor therapy, monotherapy, or other anti-tumor agents such as topo Isomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g. vinblastine), compounds that interact with nucleic acids (e.g. cis-platin, cyclophosphamide, adriamycin), hormonal antagonists (e.g. Tamoxifen), metabolic inhibitors (eg 5-FU), cytokines (eg interferon), antibodies, etc. To treat respiratory tract diseases, these compounds may be used on their own or in combination with other airway therapeutics, such as substances with secretolytic, broncholytic and / or anti-inflammatory activity. To treat diseases in the gastrointestinal tract, these compounds may be administered on their own or in combination with substances or anti-inflammatory substances that affect exercise or secretion. These mixtures can be administered simultaneously or sequentially.

These compounds may be administered on their own or in combination with other active substances by the intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation or percutaneously or orally, and aerosol formulations are particularly suitable for inhalation. Suitable.

For pharmaceutical use, the compounds according to the invention are generally used in warm blood vertebrates, especially humans, in dosages of 0.01 to 100 mg / kg body weight, preferably 0.1 to 15 mg / kg. For administration, they are one or more conventional inert carriers or diluents, for example corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol Conventional herbal preparations, such as water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as solid fats or suitable mixtures thereof It is formulated as a plain tablet or as a tablet, capsule, powder, suspension, solution, spray or suppository.

The following examples are intended to illustrate the invention but do not limit the invention:

Preparation of Starting Compounds:

Example I

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

4.84 g of potassium carbonate was added to 6.89 ml of 1,2-dibromoethane in 40 ml of N, N-dimethylformamide and 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyl-methoxy- To 3.50 g of 7-hydroxy-quinazoline. The reaction mixture is stirred at 80 ° C. for 1.5 h under a nitrogen atmosphere. After cooling to ambient temperature, the reaction mixture is filtered and the filtrate is evaporated in vacuo. The brown oily residue is cooled in an ice bath and triturated with a small amount of methanol, at which time a yellowish solid precipitates. The precipitate is suction filtered, washed with cold methanol and dried in a vacuum desiccator.

Yield: 2.60 g (58% of theory),

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

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

The following compounds are obtained similar to Example I.

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

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

Mass spectrum ^{(ESI -): m / z} = 464, 466, 468 [MH] -

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

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

Mass spectrum ^{(ESI -): m / z} = 478, 480, 482 [MH] -

(3) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6- (3-bromopropyloxy) -quinazolin (reaction is carried out in acetonitrile as solvent )

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

Mass spectrum ^{(ESI -): m / z} = 478, 480, 482 [MH] -

(4) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6- (3-bromopropyloxy) -quinazolin (reaction is carried out in acetonitrile as solvent do)

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

Mass spectrum ^{(ESI -): m / z} = 478, 480, 482 [MH] -

(5) 4-[(3-bromo-phenyl) amino] -6- (2-bromoethoxy) -7-methoxy-quinazoline

Melting Point: 244 ℃

Mass spectrum (ESI ⁺ ): m / z = 452, 454, 456 [M + H] ⁺

(6) 4-[(R)-(1-phenyl-ethyl) amino] -6- (3-bromopropyloxy) -7-methoxy-quinazolin (reaction with potassium tert-butoxide as base Perform using)

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

(7) 4-[(R)-(1-phenyl-ethyl) amino] -6- (2-bromoethoxy) -7-methoxy-quinazolin (reaction using potassium tert-butoxide as base To be performed)

Melting point: 255 ℃

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

(8) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxy-propyloxy) -7-cyclobutyloxy-quinazoline

R _f value: 0.50 (silica gel, methylene chloride / methanol = 90:10)

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

(9) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxy-propyloxy) -7-cyclopropylmethoxy-quinazoline

R _f value: 0.21 (silica gel, methylene chloride / methanol = 95: 5)

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

(10) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2-bromo-ethoxy) -7-cyclopentyloxy-quinazoline

R _f value: 0.67 (silica gel, methylene chloride / methanol = 90:10)

Mass spectrum (ESI ⁺ ): m / z = 480, 482, 484 [M + H] ⁺

(11) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2-bromo-ethoxy) -7-cyclopropylmethoxy-quinazoline

R _f value: 0.68 (silica gel, methylene chloride / methanol = 90:10)

Mass spectrum (ESI ⁺ ): m / z = 466, 468, 470 [M + H] ⁺

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

R _f value: 0.53 (silica gel, methylene chloride / methanol = 90:10)

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

(13) 4-[(3-chloro-4-fluorophenyl) amino] -6- (4-hydroxy-butyloxy) -7-cyclopentyloxy-quinazoline

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

(14) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2-bromo-ethoxy) -7-((R) -tetrahydrofuran-3-yloxy) -quina Sleepy

R _f value: 0.37 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum ^{(ESI -): m / z} = 480, 482, 484 [MH] -

(15) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2-bromo-ethoxy) -7-[(R)-(tetrahydrofuran-2-yl) methoxy ] -Quinazolin

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

(16) 4-[(3-chloro-4-fluorophenyl) amino] -7- (2-bromo-ethoxy) -6-[(S)-(tetrahydrofuran-2-yl) methoxy ] -Quinazolin

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

Example II

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

4.99 g of 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazolin are suspended in 80 ml of methanol and 1.80 ml of concentrated aqueous ammonia solution is added. The reaction mixture is stirred overnight at ambient temperature. For workup the reaction mixture is diluted with 500 ml of methylene chloride and washed with water and saturated sodium chloride solution, then dried over magnesium sulphate and evaporated to concentrate. 4.30 g of a brownish solid are obtained. The crude product is stirred with tert-butyl methyl ether, suction filtered, washed with a small amount of tert-butyl methyl ether and dried in vacuo at ambient temperature.

Yield: 3.59 g (80% of theory),

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

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

The following compounds are obtained similarly to Example II:

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

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

Mass spectrum ^{(ESI -): m / z} = 358, 360 [MH] -

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

R _f value: 0.53 (silica gel, methylene chloride / methanol / 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-hydroxy-quinazolin

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

Mass spectrum (ESI ⁺ ): m / z = 396, 398 [M + H] ⁺

(4) 4-[(3-bromo-phenyl) amino] -6-hydroxy-7-methoxy-quinazolin (reaction is carried out using a solution of sodium hydroxide in ethanol as solvent)

R _f value: 0.23 (silica gel, ethyl acetate)

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

(5) 4-[(3-chloro-4-fluorophenyl) amino] -7-hydroxy-6-((S) -tetrahydrofuran-3-yloxy) -quinazoline

R _f value: 0.57 (silica gel, methylene chloride / methanol = 9: 1)

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

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

R _f value: 0.42 (silica gel, methylene chloride / methanol = 9: 1)

Example III

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

4.03 g of 4-chloro-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazolin is suspended in 70 ml of isopropanol and 1.95 g of 3-chloro-4-fluoro-aniline are added. The reaction mixture is refluxed for 2 hours under a nitrogen atmosphere. After cooling to ambient temperature, the pale colored precipitate formed is suction filtered, washed with a small amount of isopropanol and dried in air.

Yield: 4.99 g (92% of theory),

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

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

The following compounds are obtained similarly to Example III:

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

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

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

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

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

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

(3) 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-methyl-carbonyloxy-quinazolin

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

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

(4) 4-[(3-bromo-phenyl) amino] -6-methylcarbonyloxy-7-methoxy-quinazoline

R _f value: 0.50 (silica gel, ethyl acetate)

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

(5) 4-[(R)-(1-phenyl-ethyl) amino] -6-hydroxy-7-methoxy-quinazolin (acetoxy protecting group has already been degraded under reaction conditions)

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

Mass spectrum (ESI ⁺ ): m / z = 296 [M + H] ⁺

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

(Pyridine is added as auxiliary base)

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

Mass spectrum (ESI ⁺ ): m / z = 464, 466 [M + H] ⁺

(7) 4-[(3-chloro-4-fluorophenyl) amino] -7-methylcarbonyloxy-6-((S) -tetrahydrofuran-3-yloxy) -quinazoline

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

Mass spectrum ^{(ESI -): m / z} = 416, 418 [MH] -

(8) 4-[(3-chloro-4-fluorophenyl) amino] -7-methylcarbonyloxy-6-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazolin- Hydrochloride

Melting Point: 274-276 ° C

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

Example IV

4-Chloro-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazolin

3.80 g of 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazolin is suspended in 90 ml of thionyl chloride and heated to boiling under nitrogen atmosphere. After adding 4 drops of N, N-dimethylformamide, the reaction mixture is refluxed for a further 2 hours. After cooling to ambient temperature, the excess thionyl chloride is distilled off under water jet vacuum. The brown residue is stirred with 30 ml of toluene. The solvent is distilled off to give 4.30 g of an off-brown solid, which is further reacted without further purification.

R _f value: 0.89 (silica gel, methylene chloride / methanol / condensed aqueous ammonia = 90: 10: 0.1)

The following compounds are obtained analogously to Example IV:

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

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

(2) 4-chloro-6-cyclopentyloxy-7-methylcarbonyloxy-quinazolin

R _f value: 0.69 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)

(3) 6-benzyloxy-4-chloro-7-methylcarbonyloxy-quinazolin

R _f value: 0.77 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)

(4) 6-benzyloxy-4-chloro-7-cyclopentyloxy-quinazolin

R _f value: 0.91 (silica gel, methylene chloride / methanol = 9: 1)

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

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

(6) 4-chloro-7-methylcarbonyloxy-6-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline

R _f value: 0.48 (silica gel, cyclohexane / ethyl acetate = 1: 1)

Example V

4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazolin

4.30 g of 4,7-dihydroxy-6-cyclopentylmethoxy-quinazolin in 100 ml of pyridine is heated to 80 ° C. under a nitrogen atmosphere. 1.80 ml of acetic anhydride are added to the dark brown suspension. The reaction mixture is stirred at 80 ° C. for 3 hours during which time the entire solution is formed. After cooling to ambient temperature, the reaction mixture is poured into about 800 ml of ice water. The formed precipitate is suction filtered and washed thoroughly with water. The light brown solid is dried in a vacuum desiccator.

Yield: 3.82 g (77% of theory),

R _f value: 0.49 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum ^{(ESI -): m / z} = 301 [MH] -

The following compounds are obtained analogously to Example V:

(1) 4-hydroxy-6-cyclopropylmethoxy-7-methylcarbonyloxy-quinazolin

R _f value: 0.53 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum ^{(ESI -): m / z} = 273 [MH] -

(2) 4-hydroxy-6-cyclopentyloxy-7-methylcarbonyloxy-quinazolin

Melting Point: 209-212 ° C

Mass spectrum ^{(ESI -): m / z} = 287 [MH] -

(3) 6-benzyloxy-4-hydroxy-7-methylcarbonyloxy-quinazolin

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

Mass spectrum ^{(ESI -): m / z} = 309 [MH] -

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

R _f value: 0.62 {commercial reverse phase TLC plate]. E. Merck], acetonitrile / water / trifluoroacetic acid = 50: 50: 1}

Mass spectrum (ESI ⁺ ): m / z = 291 [M + H] ⁺

(5) 4-hydroxy-7-methylcarbonyloxy-6-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline

R _f value: 0.50 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI ⁺ ): m / z = 305 [M + H] ⁺

Example VI

4,7-dihydroxy-6-cyclopentylmethoxy-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 are refluxed for about 3 hours. For workup the reaction mixture is evaporated to about 100 ml and 300 ml of ice water is added, whereby a gray precipitate is formed. The precipitate is suction filtered, washed with water and dried in a vacuum desiccator.

Yield: 4.57 g (77% of theory),

R _f value: 0.25 (silica gel, methylene chloride / methanol = 95: 5)

Mass spectrum ^{(ESI -): m / z} = 259 [MH] -

The following compounds are obtained analogously to Example VI:

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

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

Mass spectrum ^{(ESI -): m / z} = 231 [MH] -

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

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

Mass spectrum (EI): m / z = 246 [M] ⁺

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

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

Mass spectrum ^{(ESI -): m / z} = 267 [MH] -

(4) 6-benzyloxy-7-cyclopentyloxy-4-hydroxy-quinazolin

Melting Point: 221-223 DEG C

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

(5) 4,7-dihydroxy-6-((S) -tetrahydrofuran-3-yloxy) -quinazoline

R _f value: 0.69 [commercial reverse phase TLC plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1]

Mass spectrum ^{(ESI -): m / z} = 247 [MH] -

(6) 4,7-dihydroxy-6-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline

R _f 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

After dissolving 6.50 g of 5-cyclopentylmethoxy-4-hydroxy-2-nitro-benzoic acid in 130 ml of methanol and adding 2.00 g of Raney nickel, the mixture was hydrogenated at approximately ambient temperature under hydrogen pressure of 50 psi for about 3 hours. Absorb the calculated amount of hydrogen. The catalyst is filtered off and washed with heated methanol. The filtrate is evaporated in vacuo. A brownish solid remains, which is further reacted without further purification.

Yield: 5.79 g (100% of theory),

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

Mass spectrum ^{(ESI -): m / z} = 250 [MH] -

The following compounds are obtained similarly to Example VII:

(1) 2-Amino-5-cyclopropylmethoxy-4-hydroxy-benzoic acid

R _f value: 0.51 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)

Mass spectrum ^{(ESI -): m / z} = 222 [MH] -

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

R _f value: 0.38 (silica gel, methylene chloride / methanol / aqueous ammonia solution = 90: 10: 0.1)

Mass spectrum (ESI ⁺ ): m / z = 238 [M + H] ⁺

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

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

Mass spectrum ^{(ESI -): m / z} = 258 [MH] -

(4) cyclopentyl 2-amino-5-benzyloxy-4-cyclopentyloxy-benzoate

(The reaction is carried out in a 1: 1 mixture of methanol and tetrahydrofuran)

R _f value: 0.84 (silica gel, ethyl acetate / cyclohexane = 1: 1)

Mass spectrum (ESI ⁺ ): m / z = 396 [M + H] ⁺

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

R _f value: 0.70 [commercial reverse phase TLC plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1]

Mass spectrum ^{(ESI -): m / z} = 238 [MH] -

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

R _f value: 0.59 [commercial reverse phase TLC plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1]

Mass spectrum ^{(ESI -): m / z} = 252 [MH] -

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 are dissolved in 100 ml of dimethyl sulfoxide and cooled in an ice bath under a nitrogen atmosphere. Then, 3.90 g of sodium is added batchwise. The reaction mixture is stirred for 30 minutes while cooling in an ice bath, then briefly heated to 35-40 ° C. and then stirred for an additional 3 hours while cooling in an ice bath. The ice bath is then removed and the reaction mixture is stirred overnight at ambient temperature. Pour the reddish dark brown reaction solution into about 800 ml of acetone, at which time a dark brown precipitate is formed. The precipitate is suction filtered, washed with acetone, dissolved in 300-400 ml of water and adjusted to about pH 2 with 60 ml of 2N hydrochloric acid. The aqueous solution is extracted several times with methylene chloride. The combined extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and then evaporated to concentrate. The dark brown oily flask residue is dissolved in 800 ml of methylene chloride and purified through silica gel charge with methylene chloride / methanol (9: 1). A brown oil is obtained, which is crystallized by stirring with water while cooling in an ice bath. The brownish precipitate formed is suction filtered, washed with a small amount of water and dried in a vacuum desiccator.

Yield: 9.55 g (47% of theory),

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

Mass spectrum ^{(ESI -): m / z} = 280 [MH] -

The following compounds are obtained analogously to Example VIII:

(1) 5-cyclopropylmethoxy-4-hydroxy-2-nitro-benzoic acid

R _f value: 0.61 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6)

Mass spectrum ^{(ESI -): m / z} = 252 [MH] -

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

R _f value: 0.62 (silica gel, toluene / dioxane / ethanol / glacial acetic acid = 90: 10: 10: 6)

Mass spectrum ^{(ESI -): m / z} = 266 [MH] -

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

Melting point: 176-178 ° C

Mass spectrum ^{(ESI -): m / z} = 288 [MH] -

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

R _f value: 0.58 [commercial reverse phase TLC plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1]

Mass spectrum ^{(ESI -): m / z} = 268 [MH] -

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

R _f value: 0.53 [commercial reverse phase TLC plate (E. Merck), acetonitrile / water / trifluoroacetic acid = 50: 50: 1]

Mass spectrum ^{(ESI -): m / z} = 282 [MH] -

Example IX

Ethyl (2-hydroxy-2-methyl-propylamino) -acetate

100.00 g of sodium carbonate is added to 50.00 g of glycine ethyl ester hydrochloride in 100 ml of saturated potassium carbonate solution while cooling. The formed mass is extracted several times with a total of about 600 ml of diethyl ether. The combined ether extracts are dried over sodium sulphate and evaporated to dryness. Remains 28.60 g of glycine ethyl ester. It is mixed with 26.00 ml of isobutylene oxide and 40 ml of anhydrous ethanol and heated to 90 ° C. for 6 hours in a Roth bomb. After cooling to ambient temperature, the reaction mixture is evaporated and concentrated to leave a flowable oil.

Yield: 45.80 g (73% of theory),

Mass spectrum (ESI ⁺ ): m / z = 176 [M + H] ⁺

Example X

4-methylamino-dihydro-furan-2-one

2.00 g of 4- (N-benzyl-N-methyl-amino) -dihydro-furan-2-one in 25 ml of methanol at ambient temperature for about 2 hours at 50 psi hydrogen pressure in the presence of 250 mg of palladium (10% on activated carbon) Hydrogenation absorbs the calculated amount of hydrogen. The catalyst is filtered off and evaporated under vacuum for workup. Colorless oil remains and is reacted further without further purification.

Yield: 1.20 g

R _f value: 0.13 (silica gel, ethyl acetate)

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

Example XI

4- (N-benzyl-N-methyl-amino) -dihydro-furan-2-one

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

Yield: 19.77 g (54% of theory),

R _f 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-hydroxy-quinazolin

10 ml of trifluoroacetic acid is added dropwise to 5.60 g of 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-quinazolin with stirring. The reaction mixture is heated to about 40 ° C. After 20 hours of stirring at ambient temperature, additional 3 ml of trifluoroacetic acid is added. The reaction mixture is heated to 50 ° C., since the reaction hardly proceeds after further stirring at ambient temperature for 3 hours. After 4 hours, the reaction is complete and the excess trifluoroacetic acid is substantially distilled off using a rotary evaporator. The residue is mixed with water and made alkaline using concentrated aqueous ammonia solution. The light brown precipitate formed is suction filtered and washed with plenty of water and then dried in a desiccator. The product obtained still contains trifluoroacetic acid.

Yield: 5.82 g

R _f value: 0.61 (silica gel, methylene chloride / methanol = 9: 1)

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

The following compounds are obtained analogously to Example XII:

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

R _f value: 0.65 (silica gel, methylene chloride / methanol = 9: 1)

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

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

R _f value: 0.65 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI ⁺ ): m / z = 374, 376 [M + H] ⁺

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

R _f value: 0.32 (silica gel, methylene chloride / methanol = 9: 1)

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

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

Example XIII

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

7.50 g of potassium carbonate and 4.50 g of cyclobutyl methanesulfonate were added to 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-hydroxy-quina in 60 ml of N, N-dimethylformamide. Add 7.00 g sleepy. The reaction mixture is stirred at 80 ° C. for 2 hours. Then 2.00 g of cyclobutyl methanesulfonate and 3.00 g of potassium carbonate are added and the mixture is stirred at 60 ° C. over the weekend. Since the reaction is still incomplete, 3.50 g of cyclobutyl methanesulfonate and 5.00 g of potassium carbonate are added. After a further 20 hours of stirring at 80 ° C., the reaction is almost complete. The reaction mixture is combined with 300 ml of ethyl acetate for workup and washed with water and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated by evaporation. Stirring the residue with methanol gives a brownish precipitate. This is suction filtered, washed with methanol and dried in desiccator.

Yield: 5.10 g (64% of theory),

R _f value: 0.69 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum ^{(ESI -): m / z} = 448, 450 [MH] -

The following compounds are obtained analogously to Example XIII:

(1) 6-benzyloxy-4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-quinazolin (using bromomethylcyclopropane)

R _f value: 0.72 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum ^{(ESI -): m / z} = 448, 450 [MH] -

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

(Use bromocyclopentane)

R _f value: 0.78 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI ⁺ ): m / z = 464, 466 [M + H] ⁺

Example XIV

Tert-butyl (S)-(2-hydroxy-propylamino) -acetate

15.00 g of (S)-(+)-1-amino-2-propanol is dissolved in 100 ml of N, N-dimethylformamide and 6.97 ml of diisopropylethylamine are added. Subsequently, 5.91 ml of tert-butyl bromoacetate is added dropwise within 30 minutes, followed by cooling in an ice bath. The ice bath is removed and the reaction mixture is stirred overnight at ambient temperature. The reaction mixture is evaporated under vacuum for workup. The flask residue is dissolved in 50 ml of water and saturated with 15 g of sodium chloride. The aqueous solution is extracted several times with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated under vacuum to leave a yellowish oil.

Yield: 7.36 g (97% of theory),

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

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

The following compounds are obtained analogously to Example XIV:

(1) tert-butyl (R)-(2-hydroxy-propylamino) -acetate

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

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

(2) tert-butyl (1,1-dimethyl-2-hydroxy-ethylamino) -acetate

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

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

Example XV

4-[(3-chloro-4-fluorophenyl) amino] -6- (3-methanesulfonyloxy-propyloxy) -7-cyclobutyloxy-quinazoline

This compound is a mixture of 4-[(3-chloro-4-fluorophenyl) amino] -6- (3-hydroxy-propyloxy) -7-cyclobutyloxy-quinazolin at ambient temperature of diisopropylethylamine. Prepared by reaction with methanesulfonic acid chloride in methylene chloride in the presence.

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

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

The following compounds are obtained similar to Example XV:

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

R _f value: 0.65 (silica gel, methylene chloride / methanol = 90:10)

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

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

R _f value: 0.73 (silica gel, methylene chloride / methanol = 90:10)

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

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

R _f value: 0.76 (silica gel, methylene chloride / methanol = 90:10)

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

Example XVI

4-[(3-chloro-4-fluorophenyl) amino] -6-hydroxy-7-cyclopropyl-methoxy-quinazolin

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

Yield: 73% of theory

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

Example XVII

Cyclopentyl 5-benzyloxy-4-cyclopentyloxy-2-nitro-benzoate

The compound is obtained by reacting 5-benzyloxy-4-hydroxy-2-nitro-benzoic acid with 2.2 equivalents of bromocyclopentane at ambient temperature in the presence of potassium carbonate as an auxiliary base in dimethyl sulfoxide.

Yield: 87% of theory

R _f value: 0.92 (silica gel, ethyl acetate / cyclohexane = 1: 1)

Mass spectrum (ESI ⁺ ): m / z = 426 [M + H] ⁺

Example XVIII

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

5.03 ml of diethyl azodicarboxylate was added to 4-[(3-chloro-4-fluorophenyl) amino] -6-benzyloxy-7-hydroxy-quinazolin in 160 ml of tetrahydrofuran [see WO 0055141 A1. Arc] dropwise to a solution of 8.00 g, 2.42 ml of (S)-(+)-3-hydroxy-tetrahydrofuran and 7.95 g of triphenylphosphine. The reaction mixture is stirred at ambient temperature overnight and then evaporated using a rotary evaporator. The flask residue is purified by chromatography on a silica gel column using methylene chloride / ethyl acetate (gradient 2: 1 to 1: 2) as eluent.

Yield: 7.34 g (78% of theory),

Melting Point: 165-168 ° C.

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

The following compounds are obtained analogously to Example XVIII:

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

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

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

(2) 4-[(3-chloro-4-fluorophenyl) amino] -7- (2-bromo-ethoxy) -6-((S) -tetrahydrofuran-3-yloxy) -quina Sleepy

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

Preparation of the final compound:

Example 1

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

250 mg of 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentylmethoxy-7- (2-bromoethoxy) -quinazolin and ethyl (2-hydroxy-2-methyl-propyl 341 mg of amino) -acetate is dissolved in 20 ml of acetonitrile and combined with 50 mg of sodium iodide, 275 mg of potassium carbonate and 0.70 ml of diisopropylethylamine. The reaction mixture is refluxed for about 90 hours. After cooling to ambient temperature, the reaction mixture is filtered and the filtrate is evaporated in vacuo. The flask residue is chromatographed on a silica gel column using petroleum ether / ethyl acetate (50:50, then 0: 100) as eluent. The ring closure product is obtained as a beige solid.

Yield: 62 mg (23% of theory),

R _f value: 0.29 (silica gel, ethyl acetate)

Mass spectrum ^{(ESI -): m / z} = 541, 543 [MH] -

The following compounds are obtained similarly to Example 1:

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

R _f value: 0.58 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum ^{(ESI -): m / z} = 513, 515 [MH] -

(2) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl)- Propyloxy] -quinazolin

Melting Point: 212-214 ° C

Mass Spectrum ^{(ESI -): m / z} = 527, 529 [MH] -

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

Melting point: 200-202 ° C

Mass Spectrum ^{(ESI -): m / z} = 527, 529 [MH] -

(4) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -propyloxy] -7- Methoxy-Quinazoline

Melting Point: 222-224 ° C

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

Example 2

4-[(3-Chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl- Amino] -ethoxy} -quinazoline

300 mg of 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2-bromoethoxy) -quinazolin in 20 ml of acetonitrile and 4-methylamino-dihydro- 400 mg of furan-2-one are mixed with 240 mg of potassium carbonate and 70 mg of sodium iodide and refluxed for 24 hours. After cooling to ambient temperature, the reaction mixture is filtered and the filtrate is evaporated in vacuo. The flask residue is chromatographed on a silica gel column using methylene chloride / methanol / rich aqueous ammonia solution (97: 3: 0.05) as eluent. The title compound is obtained as a light beige solid.

Yield: 70 mg (22% of theory),

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

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

The following compounds are obtained similarly 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

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

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

(2) 4-[(3-chloro-4-fluorophenyl) amino] -6- {3- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -propyl Oxy} -7-cyclobutyloxy-quinazoline

Melting Point: 147.5-151 ° C

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

Example 3

4-[(3-Bromo-phenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quina Sleepy

90 μl of methanesulfonic acid was added to 4-[(3-bromo-phenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) methyl] -N-((S in 8 ml of acetonitrile. To 380 mg) -2-hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazolin. After the reaction mixture is refluxed for about 3 hours, an additional equivalent of methanesulfonic acid is added and the reflux is continued to terminate the reaction. For workup the reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and evaporated in vacuo. The flask residue is stirred with diethyl ether and suction filtered. The title compound is obtained as a white solid.

Yield: 280 mg (85% of theory),

Melting point: 190 ℃

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

The following compounds are obtained similarly to Example 3:

(1) 4-[(3-bromo-phenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-meth Toxy-Quinazoline

Melting point: 193 ℃

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

(2) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)

Melting point: 208 ℃

Mass spectrum ^{(ESI -): m / z} = 459, 461 [MH] -

(3) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)

R _f value: 0.33 (silica gel, ethyl acetate)

Mass spectrum ^{(ESI -): m / z} = 473, 475 [MH] -

(4) 4-[(R)-(1-phenyl-ethyl) amino] -6- [3-((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)

R _f value: 0.41 (silica gel, ethyl acetate / methanol = 9: 1)

Mass spectrum ^{(ESI -): m / z} = 449 [MH] -

(5) 4-[(R)-(1-phenyl-ethyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)

R _f value: 0.49 (silica gel, ethyl acetate / methanol / condensed aqueous ammonia = 9: 1: 0.1)

Mass spectrum ^{(ESI -): m / z} = 435 [MH] -

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

Melting Point: 185.5-189.5 ° C

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

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

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

Melting Point: 214-216 ° C

Mass Spectrum ^{(ESI -): m / z} = 527, 529 [MH] -

(8) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-cyclopropylmethoxy-quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

Melting point: 160.5 to 163 ° C

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

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

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

Melting point: 160-162 ° C

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

(10) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-cyclopentyloxy-quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

R _f value: 0.31 (silica gel, ethyl acetate)

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

(11) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-cyclopentyloxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)

Melting point: 176-178 ° C

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

(12) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-cyclopropylmethoxy-quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)

R _f value: 0.37 (silica gel, ethyl acetate)

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

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

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

R _f value: 0.37 (silica gel, ethyl acetate)

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

(14) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2-((S) -6-methyl-2-oxo-morpholine-4- Yl) -ethoxy] -quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

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

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

(15) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2-((R) -6-methyl-2-oxo-morpholine-4- Yl) -ethoxy] -quinazolin (reaction is carried out using trifluoroacetic acid in acetonitrile)

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

(16) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [3-((R) -6-methyl-2-oxo-morpholine-4- Yl) -propyloxy] -quinazolin

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

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

Mass spectrum ^{(ESI -): m / z} = 513, 515 [MH] -

(17) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [3-((S) -6-methyl-2-oxo-morpholine-4- Yl) -propyloxy] -quinazolin

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

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

Mass spectrum ^{(ESI -): m / z} = 513, 515 [MH] -

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

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

R _f value: 0.56 (silica gel, ethyl acetate)

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

(19) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2-((S) -6-methyl-2-oxo-morpholin-4-yl ) -Ethoxy] -quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

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

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

(20) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2-((R) -6-methyl-2-oxo-morpholin-4-yl ) -Ethoxy] -quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

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

(21) 4-[(3-chloro-4-fluorophenyl) amino] -6- [4-((S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy]- 7-cyclopentyloxy-quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

R _f value: 0.51 (silica gel, ethyl acetate)

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

(22) 4-[(3-chloro-4-fluorophenyl) amino] -6- [4-((R) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy]- 7-cyclopentyloxy-quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

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

(23) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

Melting point: 183-186 ° C

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

(24) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (5,5-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7- Methoxy-Quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

R _f value: 0.43 (silica gel, ethyl acetate)

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

(25) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

Melting Point: 212-213 ° C

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

(26) 4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (carboxymethyl) -N-((S) -2-hydroxy-propyl) -amino] -Ethoxy} -7-methoxy-quinazoline

[By-products in the manufacture of 3 (25)]

Melting Point: 187 to 190 ° C

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

(27) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7- Methoxy-Quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

Melting Point: 229-232 ° C

Mass spectrum ^{(ESI -): m / z} = 473, 475 [MH] -

(28) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7- ((R) -tetrahydrofuran-3-yloxy) -quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

Melting point: 195-196 ° C

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

(29) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -7- [(R)-(tetrahydrofuran-2-yl) methoxy] -quinazoline

(Reaction is carried out using trifluoroacetic acid in acetonitrile)

Melting Point: 184 ℃

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

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

Melting Point: 202-205 ° C

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

(31) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -6- [(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline

Melting Point: 182 ℃

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

Example 4

4-[(3-Bromo-phenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2-hydroxy-propyl)- Amino} -ethoxy) -7-methoxy-quinazoline

0.25 ml of diisopropylethylamine was added to 650 mg of 4-[(3-bromo-phenyl) amino] -6- (2-bromoethoxy) -7-methoxy-quinazolin in 15 ml of acetonitrile and tert-butyl ( To 1.10 g of S)-(2-hydroxy-propylamino) -acetate. The reaction mixture is stirred at 50 ° C. overnight. No reaction is detected so the reaction mixture is concentrated in vacuo, combined with 20 ml of N, N-dimethylformamide and stirred at 60 ° C. for 8 hours. The temperature is then raised to 80 ° C. After an additional 8 hours, the reaction is terminated. The reaction mixture is concentrated by evaporation and chromatography is performed on a silica gel column using ethyl acetate as eluent. The desired product is obtained as a white solid.

Yield: 410 mg (51% of theory),

R _f value: 0.27 (silica gel, ethyl acetate)

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

The following compounds are obtained similarly to Example 4:

(1) 4-[(3-bromo-phenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) -methyl] -N-((R) -2-hydroxy -Propyl) -amino} -ethoxy) -7-methoxy-quinazoline

Melting point: 130 ℃

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

(2) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(tert-butyloxy-carbonyl) methyl] -N-((R) -2 -Hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazolin (reaction is carried out in N, N-dimethylformamide)

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

(3) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxy-carbonyl) methyl] -N-((R) -2 -Hydroxy-propyl) -amino} -propyloxy) -7-methoxy-quinazolin (reaction is carried out in N, N-dimethylformamide)

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

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

(4) 4-[(R)-(1-phenyl-ethyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -propyloxy) -7-methoxy-quinazolin (reaction is carried out in N, N-dimethylformamide)

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

Mass spectrum (EI): m / z = 524 [M] ⁺

(5) 4-[(R)-(1-phenyl-ethyl) amino] -6- (2- {N-[(tert-butyloxy-carbonyl) methyl] -N-((S) -2 -Hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazolin (reaction is carried out in N, N-dimethylformamide)

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

(6) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N-((R) -2- Hydroxy-propyl) -amino} -propyloxy) -7-cyclobutyloxy-quinazoline

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

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

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

Mass spectrum (ESI ⁺ ): m / z = 603, 605 [M + H] ⁺

(8) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N-((R) -2- Hydroxy-propyl) -amino} -propyloxy) -7-cyclopropylmethoxy-quinazoline

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

(9) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -propyloxy) -7-cyclopropylmethoxy-quinazoline

R _f value: 0.50 (silica gel, ethyl acetate)

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

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

(11) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) methyl] -N-((R) -2- Hydroxy-propyl) -amino} -ethoxy) -7-cyclopentyloxy-quinazoline

R _f value: 0.66 (silica gel, ethyl acetate)

(12) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -ethoxy) -7-cyclopropylmethoxy-quinazoline

R _f 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) -7-cyclopropylmethoxy-quinazoline

R _f value: 0.60 (silica gel, ethyl acetate)

(14) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2- {N-[(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxy-propyl) -amino} -ethoxy) -quinazoline

R _f value: 0.30 (silica gel, ethyl acetate)

(15) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (2- {N-[(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxy-propyl) -amino} -ethoxy) -quinazoline

R _f value: 0.30 (silica gel, ethyl acetate)

(16) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3- {N-[(tert-butyloxycarbonyl) methyl] -N- ((R) -2-hydroxy-propyl) -amino} -propyloxy) -quinazoline

R _f value: 0.35 (silica gel, ethyl acetate)

(17) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- (3- {N-[(tert-butyloxycarbonyl) methyl] -N- ((S) -2-hydroxy-propyl) -amino} -propyloxy])-quinazoline

R _f value: 0.35 (silica gel, ethyl acetate)

(18) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -7-cyclopentyloxy-quinazoline

R _f value: 0.64 (silica gel, methylene chloride / methanol = 9: 1)

Mass spectrum (ESI ⁺ ): m / z = 575, 577 [M + H] ⁺

(19) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N-[(tert-butyloxycarbonyl) methyl] -N- ( (S) -2-hydroxy-propyl) -amino} -ethoxy) -quinazoline

R _f value: 0.51 (silica gel, ethyl acetate)

(20) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N-[(tert-butyloxycarbonyl) methyl] -N- ( (R) -2-hydroxy-propyl) -amino} -ethoxy) -quinazoline

R _f value: 0.51 (silica gel, ethyl acetate)

(21) 4-[(3-chloro-4-fluorophenyl) amino] -6- (4- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -butyloxy) -7-cyclopentyloxy-quinazolin

R _f value: 0.61 (silica gel, ethyl acetate)

(22) 4-[(3-chloro-4-fluorophenyl) amino] -6- (4- {N-[(tert-butyloxycarbonyl) methyl] -N-((R) -2- Hydroxy-propyl) -amino} -butyloxy) -7-cyclopentyloxy-quinazolin

R _f value: 0.61 (silica gel, ethyl acetate)

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

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

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

(24) 4-[(3-chloro-4-fluorophenyl) amino] -6- (3- {N-[(tert-butyloxycarbonyl) methyl] -N- (1,1-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- {N-[(tert-butyloxycarbonyl) methyl] -N-((S) -2- Hydroxy-propyl) -amino} -ethoxy) -7-methoxy-quinazoline

R _f value: 0.66 (silica gel, ethyl acetate / methanol = 9: 1)

Mass spectrum (ESI ⁺ ): m / z = 535, 537 [M + H] ⁺

(26) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -7-methoxy-quinazoline

(Appears as a mixture with already closed substances)

R _f value: 0.44 (silica gel, ethyl acetate)

Mass spectrum (ESI ⁺ ): m / z = 521, 523 [M + H] ⁺

(27) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -7-((R) -tetrahydrofuran-3-yloxy) -quinazoline

(Appears as a mixture with already closed substances)

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

(28) 4-[(3-chloro-4-fluorophenyl) amino] -6- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -7-[(R)-(tetrahydrofuran-2-yl) methoxy] -quinazoline

Mass spectrum ^{(ESI -): m / z} = 589, 591 [MH] -

(29) 4-[(3-chloro-4-fluorophenyl) amino] -7- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -6-((S) -tetrahydrofuran-3-yloxy) -quinazoline

R _f value: 0.16 (silica gel, methylene chloride / methanol = 20: 1)

(30) 4-[(3-chloro-4-fluorophenyl) amino] -7- (2- {N-[(ethoxycarbonyl) methyl] -N- (2-hydroxy-2-methyl- Propyl) -amino} -ethoxy) -6-[(S)-(tetrahydrofuran-2-yl) methoxy] -quinazoline

R _f value: 0.68 (silica gel, ethyl acetate / methanol = 15: 1)

The following compounds can be prepared analogously to the examples described above and other methods known in the literature:

(1) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6-methoxy Quinazoline

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

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

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

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

(6) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7- Methoxy-Quinazoline

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

(8) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy Quinazoline

(9) 4-[(R)-(1-phenyl-ethyl) amino] -6- [3-((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazoline

(10) 4-[(R)-(1-phenyl-ethyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazoline

(11) 4-[(3-chloro-4-fluorophenyl) amino] -7- [4- (6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -6-methoxy Quinazoline

(12) 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6-methyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy Quinazoline

(13) 4-[(3-chloro-4-fluorophenyl) amino] -6- [4- (6-methyl-2-oxo-morpholin-4-yl) -butyloxy] -7-methoxy Quinazoline

(14) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetra Hydrofuran-3-yloxy) -quinazolin

(15) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetra Hydropyran-3-yloxy) -quinazolin

(16) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetra Hydropyran-4-yloxy) -quinazolin

(17) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetra Hydrofuran-2-ylmethoxy) -quinazolin

(18) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (tetra Hydropyran-4-ylmethoxy) -quinazolin

(19) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7- (Tetrahydrofuran-3-yloxy) -quinazoline

(20) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7- (Tetrahydrofuran-3-yloxy) -quinazoline

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

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

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

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

(25) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetra Hydrofuran-3-yloxy) -quinazolin

(26) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetra Hydropyran-3-yloxy) -quinazolin

(27) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetra Hydropyran-4-yloxy) -quinazolin

(28) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetra Hydrofuran-2-ylmethoxy) -quinazolin

(29) 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -6- (tetra Hydropyran-4-ylmethoxy) -quinazolin

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

(31) 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6- (Tetrahydrofuran-3-yloxy) -quinazoline

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

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

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

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

Example 5

Tablets containing 75 mg of active substance

One tablet core contains:

Active substance 75.0 mg

Calcium Phosphate 93.0mg

Corn Starch 35.5mg

Polyvinylpyrrolidone 10.0mg

Hydroxypropylmethylcellulose 15.0mg

Magnesium Stearate 1.5mg

230.0mg

Produce:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the amount of magnesium stearate in the specified amount. After the blanks with a diameter of 13 mm are produced in a tablet press, they are rubbed through a sieve having a mesh size of 1.5 mm using a suitable machine and mixed with the remaining amount of magnesium stearate. The granules are pressed in a tablet press to form tablets of the desired shape.

Core weight: 230 mg

Die: 9 mm, convex

The tablets thus obtained are coated with a film consisting essentially of hydroxypropylmethylcellulose. The final film coated tablets are polished using beeswax.

Coating weight: 245 mg.

Example 6

Tablets containing 100 mg of active substance

Furtherance:

One tablet contains:

100.0 mg of active substance

Lactose 80.0mg

Corn Starch 34.0mg

Polyvinylpyrrolidone 4.0mg

Magnesium Stearate 2.0mg

220.0mg

Manufacturing Method:

The active substance, lactose and starch are mixed together and uniformly wetted with aqueous polyvinylpyrrolidone. The wet composition is sieved (mesh size: 2.0 mm), dried in a shelf dryer at 50 ° C., then sieved again (mesh size: 1.5 mm) and lubricant is added. The final mixture is compressed to form tablets.

Tablet weight: 220 mg

Diameter: 10 mm, double planes, with cut faces on both sides and notches on one side.

Example 7

Tablets containing 150 mg of active substance

Furtherance:

One tablet contains:

50.0 mg of active substance

Lactose Powder 89.0mg

Corn Starch 40.0mg

10.0 mg colloidal silica

Polyvinylpyrrolidone 10.0mg

Magnesium Stearate 1.0mg

300.0mg

Produce:

The active material is mixed with lactose, corn starch and silica and then wetted with 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a mesh size of 1.5 mm. The granules are dried at 45 ° C. and passed again through the same sieve and then mixed with the specified amount of magnesium stearate. The tablet is compressed from the mixture.

Tablet weight: 300 mg

Die: 10 mm, flat

Example 8

Hard gelatin capsules containing 150 mg of active substance

One capsule contains:

50.0 mg of active substance

Corn starch (dried) approx. 80.0 mg

Lactose (powder) approx. 87.0 mg

Magnesium Stearate 3.0mg

420.0 mg

Produce:

The active material is mixed with excipients and passed through a sieve with a mesh size of 0.75 mm, followed by homogeneous mixing using a suitable apparatus. The final mixture is filled into size 1 hard gelatin capsules.

Capsule Filling Capacity: Approximately 320mg

Capsule Shell: Size 1, Hard Gelatin Capsules

Example 9

Suppositories containing 150 mg of active substance

One suppository contains:

150.0 mg of active substance

Polyethylene glycol 1500 550.0mg

Polyethylene Glycol 6000 460.0mg

Polyoxyethylene Sorbitan Monostearate 840.0mg

2,000.0mg

Produce:

After the suppository mass is melted, the active substance is distributed homogeneously therein and the melt is poured into a cooled mold.

Example 10

Suspension containing 50 mg of active substance

100 ml of the suspension contains:

1.00 g of active substance

0.10 g of carboxymethylcellulose-Na salt

0.05 g of methyl p-hydroxybenzoate

0.01 g of propyl p-hydroxybenzoate

Glucose 10.00 g

5.00 g of glycerol

20.00 g of 70% sorbitol solution

Flavor 0.30g

Volume to make 100 ml of distilled water

Produce:

Distilled water is heated to 70 ° C. Methyl and propyl p-hydroxybenzoate are dissolved with stirring in the distilled water together with the sodium salts of glycerol and carboxymethylcellulose. After cooling the solution to ambient temperature, the active substance is added thereto and dispersed homogeneously with stirring. After sugar, sorbitol solution and flavoring agent are added to dissolve, the suspension is degassed while stirring to remove air.

5 ml of suspension contains 50 mg of active substance.

Example 11

Ampoule with 10 mg of active substance

Furtherance:

10.0 mg active substance

0.01N hydrochloric acid

Amount to make 2.0 ml of total distilled water

Produce:

The active material is dissolved in the required amount of 0.01 N HCl, isotonic with conventional salts, filtered sterilized and placed in a 2 ml ampoule.

Example 12

Ampoule with 50 mg of active substance

Furtherance:

50.0 mg of active substance

0.01N hydrochloric acid

Amount of 10.0 ml of secondary distilled water

Produce:

The active material is dissolved in the required amount of 0.01 N HCl, isotonic with conventional salts, filtered sterilized and placed in a 10 ml ampoule.

Example 13

Powder inhalation capsule containing 5 mg of active substance

One capsule contains:

5.0 mg of active substance

Inhalation Lactose 15.0mg

20.0 mg

Produce:

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

Capsule Weight: 70.0mg

Capsule size = 3

Example 14

Inhalation solution for hand-held nebulisers containing 2.5 mg of active substance

The single spray solution contains:

2.500 mg active substance

Benzalkonium Chloride 0.001mg

1N hydrochloric acid

Ethanol / water (50/50) for a total of 15.000 mg

Produce:

The active substance and benzalkonium chloride are dissolved in ethanol / water (50/50). The pH of the solution is adjusted with 1N hydrochloric acid. The resulting solution is filtered and placed in a container (cartridge) suitable for hand held sprayers.

Container Content: 4.5g

Claims (12)

Bicyclic heterocycles of formula (I), tautomers thereof, stereoisomers thereof and salts thereof. Formula I In Formula I above, R _a is benzyl or 1-phenylethyl group, or a phenyl group substituted by R ₁ and R ₂ groups, wherein R ₁ is hydrogen, fluorine, chlorine or bromine or methyl, trifluoromethyl, Cyano or ethynyl group, R ₂ is a hydrogen atom or a fluorine atom), One of the R _b and R _c groups is an R _3- (CH ₂ ) _m -O group wherein R ₃ is N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or N- (2- Oxo-tetrahydrofuran-4-yl) -ethylamino group, or a R ₄ —O—CO—CH ₂ —N—CH ₂ CH ₂ —OH group, wherein the methylene group is substituted by one or two methyl or ethyl groups Wherein R ₄ is a hydrogen atom or a C _1-4 -alkyl group or a 2-oxo-morpholin-4-yl group substituted by one or two methyl or ethyl groups, and m is 2, 3 or 4], and the other of the R _b and R _c groups is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop in the compound of formula (I) -1-yl) -N-[(ethoxycarbonyl) -methyl] -amino} -ethoxy) -quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] Quinazoline, 4-[(3-Bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline and 4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Toxy-quinazoline is excluded. The method of claim 1, R _a is benzyl or 1-phenylethyl group, or a phenyl group substituted by R ₁ and R ₂ groups, wherein R ₁ is hydrogen, fluorine, chlorine or bromine or methyl, trifluoromethyl, Cyano or ethynyl group, R ₂ is a hydrogen atom or a fluorine atom), One of the R _b and R _c groups is an R _3- (CH ₂ ) _m -O group wherein R ₃ is N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or N- (2- Oxo-tetrahydrofuran-4-yl) -ethylamino group, or a R ₄ —O—CO—CH ₂ —N—CH ₂ CH ₂ —OH group, wherein the methylene group is substituted by one or two methyl or ethyl groups Wherein R ₄ is a hydrogen atom or a C _1-4 -alkyl group or a 2-oxo-morpholin-4-yl group substituted by 1 or 2 methyl or ethyl groups, m is 2, 3 or 4], and the other of the R _b and R _c groups is methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, Tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) -methyl] -amino} -ethoxy) -quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] Quinazoline, 4-[(3-bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Oxy-quinazoline, 4-[(3-bromo-phenyl) amino] -6- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) methyl ] -Amino} -ethoxy) -7-methoxy-quinazolin, 4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazolin, 4-[(3-bromo-phenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclobutyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylme Oxy-quinazoline, 4-[(3-chloro-4-fluorophenyl] amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentylme Oxy-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- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentyloxy-quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentylmethoxy-quinazolin, 4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentylme Oxy-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-oxo-morpholin-4-yl) -ethoxy] -6-methoxy- Quinazolin, 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-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropylme Oxy-quinazoline, 4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Oxy-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-quinazolin, 4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentylmethoxy-quinazolin, 4-[(3-Chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy- Quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylme Oxy-quinazolin and (R) -4-[(1-phenyl-ethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy -Compounds of formula (I), tautomers, stereoisomers thereof and salts thereof, except quinazoline. The method of claim 1, R _a is a 1-phenylethyl group or a phenyl group substituted by R ₁ and R ₂ groups, wherein R ₁ is a fluorine atom, a chlorine atom or a bromine atom, a methyl or ethynyl group, and R ₂ is a hydrogen atom or Fluorine atom), One of the R _b and R _c groups is an R _3- (CH ₂ ) _m -O group wherein R ₃ is an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group, or the methylene group is R ₄ —O—CO—CH ₂ —N—CH ₂ CH ₂ —OH groups substituted by 1 or 2 methyl groups, wherein R ₄ is a C _1-4 -alkyl group or 1 or 2 methyl 2-oxo-morpholin-4-yl group substituted by a group, m is 2, 3 or 4], and the other of the R _b and R _c groups is methoxy, cyclobutyloxy, cyclopentyloxy, Cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydro Pyranylmethoxy group, Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) -methyl] -amino} -ethoxy) -quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] Quinazoline, 4-[(3-bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Oxy-quinazoline, 4-[(3-bromo-phenyl) amino] -6- (2- {N- (2-hydroxy-2-methyl-prop-1-yl) -N-[(ethoxycarbonyl) methyl ] -Amino} -ethoxy) -7-methoxy-quinazolin, 4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazolin, 4-[(3-bromo-phenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclobutyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylme Oxy-quinazoline, 4-[(3-chloro-4-fluorophenyl] amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentylme Oxy-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- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentyloxy-quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentylmethoxy-quinazolin, 4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentylme Oxy-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-oxo-morpholin-4-yl) -ethoxy] -6-methoxy- Quinazolin, 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-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropylme Oxy-quinazoline, 4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Oxy-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-quinazolin, 4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentylmethoxy-quinazolin, 4-[(3-Chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy- Quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylme Oxy-quinazolin and (R) -4-[(1-phenyl-ethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy -Compounds of formula (I), tautomers, stereoisomers thereof and salts thereof, except quinazoline. The method of claim 1, R _a is a 1-phenylethyl group or is a phenyl group substituted by R ₁ and R ₂ groups, wherein R ₁ is a fluorine atom, a chlorine atom or a bromine atom, and R ₂ is a hydrogen atom or a fluorine atom, One of the R _b and R _c groups is an R _3- (CH ₂ ) _m -O group wherein R ₃ is an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino group, or 1 or 2 2-oxo-morpholin-4-yl group substituted by 2 methyl groups, m is 2, 3 or 4] and the other of the R _b and R _c groups is methoxy, cyclobutyloxy, cyclopentyl Oxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or Tetrahydropyranylmethoxy group, Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl)- Oxy] -quinazoline, 4-[(3-bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4-[(3-Bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-meth Oxy-quinazoline, 4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazolin, 4-[(3-bromo-phenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclobutyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylme Oxy-quinazoline, 4-[(3-chloro-4-fluorophenyl] amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentylme Oxy-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- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentyloxy-quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 7-cyclopentylmethoxy-quinazolin, 4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentylme Oxy-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-oxo-morpholin-4-yl) -ethoxy] -6-methoxy- Quinazolin, 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-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropylme Oxy-quinazoline, 4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Oxy-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-quinazolin, 4-[(3-Chloro-4-fluorophenyl) amino] -7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- 6-cyclopentylmethoxy-quinazolin, 4-[(3-Chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy- Quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylme Oxy-quinazolin and (R) -4-[(1-phenyl-ethyl) amino] -7- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy -Compounds of formula (I), tautomers, stereoisomers thereof and salts thereof, except quinazoline. The method of claim 1, R _a is 1-phenylethyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group, R _b is a R _3- (CH ₂ ) _m -O group wherein R ₃ is a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups, m is 2 or 3 ego, R _c is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group, Provided that 4-[(3-bromo-phenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quina Sleepy, 4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazolin, 4-[(3-bromo-phenyl) amino] -6- [2- (5,5-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline, 4-[(3-Chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy- Quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclobutyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylme Oxy-quinazoline, 4-[(3-Chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy- Quinazolin, 4-[(3-chloro-4-fluorophenyl) amino] -6- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (6,6-dimethyl-2-oxo-morpholin-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 -Compounds of formula (I), tautomers, stereoisomers thereof and salts thereof, except quinazoline. The method of claim 1, R _a is a 3-chloro-4-fluorophenyl group, R _b is cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group, R _c is an R ₃ — (CH ₂ ) _m —O group wherein R ₃ is a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups, m is 2, and Provided that 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl)- Oxy] -quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy Quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropylme Oxy-quinazolin and 4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmeth Compounds of formula I, tautomers thereof, stereoisomers thereof and salts thereof, except oxy-quinazolin. A compound of 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] -quinazolin, (2) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N- Methyl-amino] -ethoxy} -quinazolin, (3) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -Ethoxy] -quinazolin, (4) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl)- Propyloxy] -quinazolin, (5) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclopropylmethoxy-6- [3- (2,2-dimethyl-6-oxo-morpholin-4-yl) -Propyloxy] -quinazolin, (6) 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy-7- {2- [N- (2-oxo-tetrahydrofuran-4-yl) -N -Methyl-amino] -ethoxy} -quinazolin, (7) 4-[(3-bromo-phenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-meth Oxy-quinazoline, (8) 4-[(3-bromo-phenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-meth Oxy-quinazoline, (9) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((R) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazoline, (10) 4-[(3-chloro-4-fluorophenyl) amino] -6- [3-((R) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazoline, (11) 4-[(R)-(1-phenyl-ethyl) amino] -6- [3-((S) -6-methyl-2-oxo-morpholin-4-yl) -propyloxy]- 7-methoxy-quinazoline, (12) 4-[(R)-(1-phenyl-ethyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]- 7-methoxy-quinazoline and (13) 4-[(3-chloro-4-fluorophenyl) amino] -6- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) ethoxy] -7 Methoxy-quinazoline, and Tautomers thereof, stereoisomers thereof and salts thereof. The physiologically acceptable salt with an inorganic acid, an organic acid, an inorganic base or an organic base according to any one of claims 1 to 7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a physiologically acceptable salt according to claim 8 optionally together with one or more inert carriers and / or diluents. Any one of claims 1 to 8 for the manufacture of pharmaceutical compositions suitable for the treatment of benign or malignant tumors, the prevention and treatment of airway and lung diseases, and the treatment of polyps, gastrointestinal tract, bile ducts, gallbladder, kidney and skin diseases. Use of a compound according to claim 1. A process for preparing a pharmaceutical composition according to claim 9, characterized in that the compound according to claim 1 is incorporated into one or more inert carriers and / or diluents by non-chemical means. (a) reacting a compound of formula II with a compound of formula III, or (b) closing the compound of formula IV optionally formed in the reaction mixture, If desired, the protective group used during the above reaction is decomposed again and / or if desired, the compound of formula I thus obtained is divided into its stereoisomer and / or the compound of formula I thus obtained A process for preparing a compound of formula (I) according to any one of claims 1 to 8, characterized in that it is converted to its salt, more particularly its physiologically acceptable salt for pharmaceutical use. Formula II In Formula II above, R _a is as defined in claim 1, One of the R _b 'and R _c ' groups is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, the other of the R _b 'and R _c ' groups Is a Z _1- (CH ₂ ) _m -O group wherein m is as defined in claims 1 to 7 and Z ₁ is a leaving group. Formula III HR ₃ In Formula III above, R ₃ is as defined in claim 1. Formula IV In Formula IV above, R _a is as defined in claim 1, One of the R _b "and R _c " groups is a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group, and the other of the R _b "and R _c " groups Is a R ₃ '-(CH ₂ ) _m -O group, wherein m is as defined in claims 1 to 7, wherein R ₃ ' is R in which the methylene group is substituted by one or two methyl or ethyl groups ₄ -O-CO-CH ₂ -N-CH ₂ CH ₂ -OH group wherein R ₄ is a hydrogen atom or a C _1-4 -alkyl group.