ZA200300991B - Bicyclic heterocycles, medicaments containing these compounds, their use, and methods for the production thereof. - Google Patents

Bicyclic heterocycles, medicaments containing these compounds, their use, and methods for the production thereof. Download PDF

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ZA200300991B
ZA200300991B ZA200300991A ZA200300991A ZA200300991B ZA 200300991 B ZA200300991 B ZA 200300991B ZA 200300991 A ZA200300991 A ZA 200300991A ZA 200300991 A ZA200300991 A ZA 200300991A ZA 200300991 B ZA200300991 B ZA 200300991B
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amino
oxo
quinazoline
morpholin
chloro
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ZA200300991A
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Frank Himmelsbach
Elke Langkopf
Birgit Jung
Stefan Blech
Flavio Solca
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Boehringer Ingelheim Pharma
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Description

YAY, TRA ) . Boehringer Ingelheim Pharma KG | Case 5/1304-FL i : @® D-55216 @-ein/rhein Foreign filing text 73890fft2.204
Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them -
The present invention relates to bicyclic heterocycles of general formula
EN
N ral Rp “IX , (1)
N Re the tautomers, the stereoisomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.
In the above general formula I
R, denotes a benzyl or l-phenylethyl group or a phenyl group substituted by the groups R, and R,, where
R, denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and
R, denotes a hydrogen or fluorine atom, : one of the groups R, or R. denotes an R,- (CH,) _-O group and the other group R, or R, denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran- 3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
. Co
R, denotes an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or
N- (2-oxo-tetrahydrofuran-4-yl) -ethylamino group, an R,-0-CO-CH,-N-CH,CH,-OH group substituted at the methylene groups by one or two methyl or ethyl groups, wherein
R, represents a hydrogen atom or a C,,~alkyl group, :
Or a 2-oxo-morpholin-4-yl group substituted by one or two methyl or ethyl groups and m denotes the number 2, 3 or 4, with the proviso that the compounds 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7-(2-{N- (2-hydroxy-2-methyl-prop-1-yl) -N- [ (ethoxycarbonyl) - methyl] -amino}-ethoxy) -quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl)-ethoxy] -quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2-(6,6-dimethyl-2-oxo-morpholin- 4-yl) -ethoxyl] -7-methoxy-quinazoline and 4-[(3-bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran- 4-yl) -N-methyl-amino] -ethoxy}-7-methoxy-quinazoline are excluded, the tautomers, the stereoisomers and the salts thereof.
Preferred compounds of the above general formula I are those wherein
Ca
R, denotes a benzyl or l-phenylethyl group or a phenyl group substituted by the groups R, and R,, where
R, denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and
R, denotes a hydrogen or fluorine atom, one of the groups R, or R, denotes a R,- (CH,),-O group and the other group R, or R. denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyolopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran- 3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
R, denotes an N- (2-oxo-tetrahydrofuran-4-yl)-methylamino or
N- (2-oxo-tetrahydrofuran-4-yl) -ethylamino group, an R,-0-CO-CH,-N-CH,CH,-OH group substituted at the methylene groups by one or two methyl or ethyl groups wherein
R, represents a hydrogen atom or a C, ,-alkyl group, , or a 2-oxo-morpholin-4-yl group substituted by one or two methyl or ethyl groups and m represents the number 2, 3 or 4, with the proviso that the compounds 4-[(3-chloro-4-fluorophenyl)amino] -6-cyclopentyloxy- 7- (2-{N- (2-hydroxy-2-methyl-prop-1-yl) -N- [ (ethoxycarbonyl) - methyl] -amino}-ethoxy) -quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-cyclopentyloxy- 7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline,
. C4 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-methoxy-quinazoline, 4-[(3-bromo-phenyl) amino] -6- (2- {N- (2-hydroxy-2-methyl -prop- 1-yl) -N- [ (ethoxycarbonyl) methyl] -amino} -ethoxy) - 7-methoxy- quinazoline,
/ 4- [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin- 4-yl)ethoxy] -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6-[2- (5,5-dimethyl-2-oxo-morpholin-
4-yl)ethoxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6-[2- (6, 6-dimethyl-2-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-cyclobutyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl)amino] -6-[2- (6,6~dimethyl-2-oxo-
oo 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-cyclopropylmethoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl] amino] -6- [2- (6, 6-dimethyl-2-oxo-
morpholin-4-yl)-ethoxyl]-7-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl -amino] -ethoxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -6-{2- [N- (2-oxo-tetrahydro-
furan-4-yl) -N-methyl -amino] -ethoxy}-7-cyclopentyloxy- quinazoline,
. Cs 4-[(3-chloro-4-fluorophenyl)amino] -6-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy} -7-cyclopentylmethoxy- quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6- [3- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] - 7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6- [3- (6, 6-dimethyl-2-oxo- morpholin-4-yl)-propyloxyl-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-[3- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -7-cyclopentylmethoxy-quinazoline, (R) -4- [(1-phenyl-ethyl)amino] -6- [3- (6, 6-dimethyl-2-oxo-morpho- lin-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-quinazoline, 4- [(3-chloro-4-fluorophenyl)amino] -7-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -6-cyeclobutyloxy-quinazoline,
Co 4-[(3-chloro-4-fluorophenyl)amino] -7- [2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxyl -6-cyclopentyloxy-quinazoline, 4- [(3-chloro-4-fluorophenyl)amino] -7-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -6-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyllamino] -7-[2-(6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-6-methoxy-quinazoline,
Ce 4-[(3-chloro-4-fluorophenyl) amino] -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy)} -6-cyclopentyloxy- quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl -amino] -ethoxy}-6-cyclopentylmethoxy- quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7- [3-(6,6-dimethyl-2-oxo- morpholin-4-yl)-propyloxyl-6-methoxy-quinazoline, 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)aminol-7-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -6-cyclopentylmethoxy-quinazoline and (R) -4-[(1-phenyl-ethyl)amino] -7-[3-(6,6-dimethyl-2-oxo-morpho- lin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline are excluded, : particularly those wherein
R, represents a 1l-phenylethyl group or a phenyl group substituted by the groups R, and R,, where
R, represents a fluorine, chlorine or bromine atom, a methyl or ethynyl group and
R, denotes a hydrogen or fluorine atom, one of the groups R, or R, represents a R,- (CH,),-O group and the other group R, or R, represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-
; Co 3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
R;, represents an N- (2-oxo-tetrahydrofuran-4-yl)-methylamino group, an R,-0-CO-CH,-N-CH,CH,-OH group substituted at the methylene groups by one or two methyl groups, wherein
R, represents.a C,_,-alkyl group, or a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and m represents the number 2, 3 or 4, with the proviso that the compounds 4-[(3-chloro-4-fluorophenyl)amino] -6-cyclopentyloxy- 7-(2-{N- (2-hydroxy-2-methyl-prop-1-yl) -N- [ (ethoxycarbonyl) - methyl] -amino}-ethoxy) -quinazoline, . | 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline, 4-[(3-bromo-phenyl) amino] -6-[2- (6,6-dimethyl-2-oxo-morpholin- 4-yl) -ethoxyl] -7-methoxy-quinazoline, 4-[(3-bromo-phenyl)amino]-6-{2-[N- (2-oxo-tetrahydrofuran- 4-yl) -N-methyl-amino] -ethoxy}-7-methoxy-quinazoline, 4-[(3-bromo-phenyl) amino] -6- (2- {N- (2-hydroxy-2-methyl-prop- 1-yl) -N-[ (ethoxycarbonyl) methyl] -~amino} -ethoxy) -7-methoxy- qguinazoline,
4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin- 4-yl) ethoxy] -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin- 4-yl)ethoxyl] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)aminol -6-[2-(6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -7-methoxy-guinazoline,
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-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl] amino] -6- [2- (6, 6-dimethyl-2-oxo-
morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl) amino] -6-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-7-cyclopentyloxy- quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6-{2- [N- (2-oxo-tetrahydro-
furan-4-yl) -N-methyl-amino] -ethoxy} -7-cyclopentylmethoxy- quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6- [3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxyl] -7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl) amino] -6-[3- (6, 6-dimethyl-2 -oxo- : morpholin-4-yl) -propyloxyl -7-cyclopentyloxy-quinazoline,
. Cs 4-[(3-chloro-4-fluorophenyl)aminel -6- [3- (6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxyl -7-cyclopentylmethoxy-quinazoline,
(R) -4-[(1-phenyl-ethyl)aminol -6-[3- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -propyloxyl -7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-[2- (6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -6-methoxy-quinazoline,
‘ 4-[(3-chloro-4-fluorophenyl)aminol -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-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl]amino]-7-[2-(6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-{2- [N- (2-oxo-tetrahydro-
) furan-4-yl) -N-methyl-amino] -ethoxy}-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl) amino] -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-6-cyclopentyloxy- guinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-{2- [N-(2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-6-cyclopentylmethoxy- quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7- [3- (6, 6-dimethyl-2-oxo-
morpholin-4-yl)-propyloxy] -6-methoxy-quinazoline,
- 10 -~ 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-cyclopentylmethoxy-quinazoline and (R) -4- [(1-phenyl-ethyl)amino] -7~-[3- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline , are excluded, the tautomers, the stereoisomers and the salts thereof. i5 Particularly preferred compounds of general formula I are those wherein
R, represents a l-phenylethyl group or a phenyl group substituted by the groups R, and R,, where
R, denotes a fluorine, chlorine or bromine atom and
R, denotes a hydrogen or fluorine atom, oo one of the groups R, or R, denotes a R,-(CH,),-O group and the other group R, or R, denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclo- pentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3- yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
R, denotes an N- (2-oxo-tetrahydrofuran-4-yl)-methylamino group Or a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and m represents the number 2, 3 or 4, with the proviso that the compounds
4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7-12-(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-methoxy-quinazoline, k 4- [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) - ethoxy] -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin- 4-yl)ethoxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)aminol -6-[2- (6,6-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-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)aminol -6-[2-(6,6-dimethyl-2-oxo-
K morpholin-4-yl) -ethoxyl] -7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl] amino] -6-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy]-7-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy} -7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{2- [N- (2-oxo-tetrahydro- furan-4-yl)-N-methyl-amino] -ethoxy}-7-cyclopentyloxy- guinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -6-{2- [N- (2-0ox0- tetrahydrofuran-4-yl)-N-methyl-amino] -ethoxy}-7- cyclopentylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -6- [3- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline, 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)aminol -6- [3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -7-cyclopentylmethoxy-quinazoline,
(R) -4-[(1-phenyl-ethyl)amino] -6-[3-(6,6-dimethyl-2-oxo-mor- pholin-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-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -7- [2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxyl] -6-cyclobutyloxy-quinazoline,
oo 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) -ethoxyl -6-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl] amino] -7-[2- (6, 6-dimethyl-2-0oxo- morpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy} -6-cyclopentyloxy- guinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-6-cyclopentylmethoxy- quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl)-propyloxy] -6-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxyl] -6-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxyl] -6-cyclopentylmethoxy-quinazoline and (R) -4- [(1-phenyl-ethyl)amino] -7-[3- (6, 6-dimethyl-2-oxo- morpholin-4-yl)-propyloxy] -6-cyclopentyloxy-quinazoline are excluded, ) the tautomers, the stereoisomers and the salts thereof.
Most particularly preferred compounds of general formula I are those wherein
R, denotes a 1-phenylethyl, 3-bromophenyl or 3-chloro- 4-fluorophenyl group,
R, denotes a R,-(CH,),-O group, wherein
R, denotes a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and m denotes the number 2 or 3,
and R. denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group, with the proviso that the compounds
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- (3-methyl-2-oxo-morpholin-
4-yl)ethoxy]-7-methoxy-quinazecline,
4- [(3-bromo-phenyl) amino] -6-[2- (5, 5-dimethyl-2-oxo-morpholin- 4-yl)ethoxy] -7-methoxy-guinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -6-[2-(6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxyl] -7-methoxy-quinazoline, 4-[(3-chloro-4-flucrophenyl)aminol -6-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxyl] -7-cyclobutyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -6-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxyl] -7-cyclopropylmethoxy-quinazoline,
oo 4-[(3-chloro-4-fluorophenyl)amino] -6-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -7-methoxy-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-[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-quinazoline are excluded,

Claims (12)

Patent Claims
1. Bicyclic heterocycles of general formula R a oH N N~ l\ , (I) SN N R, wherein R, denotes a benzyl or l-phenylethyl group or a phenyl group substituted by the groups R, and R,, where R, denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and R, denotes a hydrogen or fluorine atom, one of the groups R, or R, denotes an R,- (CH,),-O group and the other group R, or R, denotes a methoxy, cyclobutyloxy,
."20 cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran- 3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where R, denotes an N- (2-oxo-tetrahydrofuran-4-yl)-methylamino or N- (2-oxo-tetrahydrofuran-4-yl)-ethylamino group, an R,-0-CO-CH,-N-CH,CH,-OH group substituted at the methylene groups by one or two methyl or ethyl groups, wherein R, represents a hydrogen atom or a C,,-alkyl group,
Or a 2-oxo-morpholin-4-yl group substituted by one or two methyl or ethyl groups and m denotes the number 2, 3 or 4, with the proviso that the compounds 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7- (2-{N- (2-hydroxy-2-methyl-prop-1-yl) -N- [ (ethoxycarbonyl) - methyl] -amino}-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-cyclopentyloxy- 7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline, 4-[(3-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-methoxy-quinazoline are excluded, the tautomers, the stereoisomers and the salts thereof.
2. Compounds of general formula I according to claim 1, wherein R, denotes a benzyl or l-phenylethyl group or a phenyl group substituted by the groups R, and R,, where R, denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and R, denotes a hydrogen or fluorine atom, one of the groups R, or R, denotes a R,-(CH,),-O group and the other group R, or R, denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy,
cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-
3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where
R, denotes an N- (2-oxo-tetrahydrofuran-4-yl) -methylamino or
N- (2-oxo-tetrahydrofuran-4-yl) -ethylamino group, an R,-0-CO-CH,-N-CH,CH,-OH group substituted at the methylene groups by one or two methyl or ethyl groups wherein '
R, represents a hydrogen atom or a C, ,-alkyl group, or a 2-oxo-morpholin-4-yl group substituted by one or two methyl or ethyl groups and m represents the number 2, 3 or 4, with the proviso that the compounds
4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy-
7-(2-{N- (2-hydroxy-2-methyl-prop-1-yl) -N- [ (ethoxycarbonyl) - methyl] -amino}-ethoxy) -quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -6-cyclopentyloxy- 7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxy] -quinazoline, 4-[(3-bromo-phenyl)amino] -6-[2-(6,6-dimethyl-2-oxo-morpholin- 4-yl) -ethoxyl -7-methoxy-quinazoline,
4-[(3-bromo-phenyl)amino] -6-{2- [N- (2-oxo-tetrahydrofuran- 4-yl)-N-methyl-amino] -ethoxy}-7-methoxy-quinazoline, 4-[(3-bromo-phenyl)amino] -6- (2-{N- (2-hydroxy-2-methyl-prop-
1-yl)-N-[(ethoxycarbonyl)methyl] -amino}-ethoxy) -7-methoxy- guinazoline,
4- [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin- 4-yl) ethoxy] -7-methoxy-quinazoline, 4-[(3-bromo-phenyl) amino] -6-[2- (5, 5~-dimethyl-2-oxo-morpholin- 4-yl)ethoxyl -7-methoxy-gquinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-[2- (6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4-[(3-chloro-4-flucrophenyl)amino] -6-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)aminol-6-[{2-(6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)aminol -6-[2- (6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl]amino] -6-[2~-(6,6-dimethyl-2-oxo-
morpholin-4-yl)-ethoxyl] -7-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] ethoxy} -7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -6-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy} -7-cyclopentyloxy- quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-{2- [N- (2-oxo-tetrahydro-
furan-4-yl) -N-methyl-amino] -ethoxy}-7-cyclopentylmethoxy- guinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-[3-(6,6-dimethyl-2-0ox0- morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline,
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-cyclopentylmethoxy-quinazoline,
(R) -4-[(1-phenyl-ethyl)amino] -6- [3- (6, 6-dimethyl-2-oxo-morpho- lin-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-quinazoline,
4-[(3-chloro-4-fluorophenyl) amino] -7- [2- (6, 6-dimethyl-2 -oxo- morpholin-4-yl) -ethoxy] -6-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-[2-(6,6-dimethyl-2 -oxo-
morpholin-4-yl)-ethoxy]-6-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7- [2- (6, 6-dimethyl-2 -oxo- morphelin-4-yl) -ethoxy] -6-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl]lamino] -7-[2-(6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxyl] -6-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7-{2- [N- (2-oxo-tetrahydro-
oo furan-4-yl) -N-methyl-amino] -ethoxy}-6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)aminol -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-6-cyclopentyloxy- quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-6-cyclopentylmethoxy- guinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -7-[3- (6, 6-dimethyl-2-oxo-
morpholin-4-yl)-propyloxy] -6-methoxy-quinazoline,
‘ ~ 80 - 4-[(3-chloro-4-fluorophenyl)amino] -7- [3- (6, 6-dimethyl -2-oxo- morpholin-4-yl) -propyloxyl] -6-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-[3- (6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxyl -6-cyclopentylmethoxy-quinazoline and (R) -4-[(1-phenyl-ethyl)amino] -7- [3- (6, 6-dimethyl-2-oxo-morpho- lin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline : are excluded, ) the tautomers, the stereoisomers and the salts thereof.
3. Compounds of general formula I according to claim 1, wherein R, represents a l-phenylethyl group or a phenyl group substituted by the groups R, and R,, where R, represents a fluorine, chlorine or bromine atom, a methyl or ethynyl group and R, denotes a hydrogen or fluorine atom, one of the groups R, or R, represents a R,-(CH,),-O group and the other group R, or R. represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran- 3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where R, represents an N- (2-oxo-tetrahydrofuran-4-yl)-methylamino group, an R,-O0-CO-CH,-N-CH,CH,-OH group substituted at the methylene groups by one or two methyl groups, wherein
R, represents a C, ,-alkyl group, Or a Z-oxo-morpholin-4-yl group substituted by one or two methyl groups and m represents the number 2, 3 or 4, with the proviso that the compounds : 4-[(3-chloro-4-fluorophenyl) amino] -6-cyclopentyloxy- 7-(2-{N- (2-hydroxy-2-methyl-prop-1-yl) -N- [ (ethoxycarbonyl) - methyl] -amino}-ethoxy) -quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-cyclopentyloxy- 7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl) -ethoxyl -quinazoline, 4- [ (3-bromo-phenyl) amino) -6- [2- (6, 6-dimethyl -2-oxo-morpholin- 4-yl) -ethoxyl -7-methoxy-quinazoline,
4- [(3-bromo-phenyl) amino] -6-{2- [N- (2-oxo-tetrahydrofuran- 4-yl) -N-methyl-amino] -ethoxy}-7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6- (2- {N- (2-hydroxy-2-methyl-prop- 1-yl)-N-[(ethoxycarbonyl) methyl] -amino}-ethoxy) -7-methoxy- quinazoline, 4-[(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin- 4-yl) ethoxy] -7-methoxy-quinazoline,
4-[(3-bromo-phenyl) amino] -6- [2-(5,5-dimethyl-2-oxo-morpholin- 4-yl) ethoxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)aminol -6-[2- (6, 6-dimethyl-2-0xo- 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-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-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl]amino] -6-[2-(6,6-dimethyl-2-oxo- morpholin-4-yl) ethoxy] -7-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorcphenyl)amino] -6-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy} -7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)aminol -6-{2-[N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] ethoxy} -7-cyclopentyloxy- quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -6-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy} -7-cyclopentylmethoxy- quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluorophenyl)amino] -6-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxyl -7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -6-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -7-cyclopentylmethoxy-quinazoline, (R) -4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl) amino] -7-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -7-[2- (6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy]-6-cyclobutyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-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-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl] amino] -7- [2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-{2- [N- (2-oxo-tetrahydro-
furan-4-yl)-N-methyl-amino] -ethoxy}-6-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-aminc] -ethoxy}-6-cyclopentyloxy- guinazoline,
4-[(3-chloro-4-fluorophenyl) amino] -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-6-cyclopentylmethoxy- quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -7-[3- (6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -6-methoxy-quinazoline, 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-cyclopentylmethoxy-quinazoline and
(R) -4-[(1-phenyl-ethyl)amino] -7-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline are excluded, the tautomers, the stereoisomers and the salts thereof.
4. Compounds of general formula I according to claim 1, wherein R, represents a l-phenylethyl group or a phenyl group substituted by the groups R, and R,, where ‘ R, denotes a fluorine, chlorine or bromine atom and R, denotes a hydrogen or fluorine atom, one of the groups R, or R, denotes a R,- (CH,)_,-O group and the other group R, or R, denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclo- pentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3- yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group, where R; denotes an N- (2-oxo-tetrahydrofuran-4-yl)-methylamino group or a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and m represents the number 2, 3 or 4, with the proviso that the compounds 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) -ethoxyl] -7-methoxy-quinazoline, 4-[(3-bromo-phenyl)amino]-6-{2-[N- (2-oxo-tetrahydrofuran- 4-yl) -N-methyl-amino] -ethoxy}-7-methoxy-quinazoline,
4- [(3-bromo-phenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin-4-yl) - ethoxy] -7-methoxy-quinazoline, 4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morphol in- 4-yl)ethoxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)aminol -6-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
4- [(3-chloro-4-fluorophenyl)aminol -6- [2- (6, 6-dimethyl-2 -oxo- morpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline,
4- [(3-chloro-4-fluorophenyl)aminol -6-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)aminol -6-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl] amino] -6-[2- (6, 6-dimethyl-2-oxo-
morpholin-4-yl)-ethoxy]-7-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl) amino] -6-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy} -7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -6-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-7-cyclopentyloxy- qguinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-{2- [N- (2-0oxo-
tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}-7- cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)aminol -6- [3- (6, 6-dimethyl-2 -oxo- morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)aminol -6- [3- (6, 6-dimethyl-2 -oxo- morpholin-4-yl) -propyloxyl -7-cyclopentyloxy-quinazoline,
4- [(3-chloro-4-fluorophenyl)amino] -6-[3- (6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxyl-7-cyclopentylmethoxy-quinazoline, (R) -4-[(1-phenyl-ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-mor- pholin-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-quinazoline,
, 4-[(3-chloro-4-fluorophenyl)amino] -7- [2- (6, 6-dimethyl-2 -oxo- morpholin-4-yl) -ethoxyl -6-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-[2- (6, 6-dimethyl-2-oxo-
morpholin-4-yl)-ethoxyl -6-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-[2- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -ethoxyl] -6-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl]aminol-7-[2-(6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-{2- [N- (2-oxo-tetrahydro-
~~ furan-4-yl)-N-methyl-amino] -ethoxy} -6-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -7-{2- [N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-6-cyclopentyloxy- guinazoline,
4-[(3-chloro-4-fluorophenyl)amino] -7-{2-[N- (2-oxo-tetrahydro- furan-4-yl) -N-methyl-amino] -ethoxy}-6-cyclopentylmethoxy- guinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -7-[3-(6,6-dimethyl-2-oxo-
morpholin-4-yl)-propyloxy] -6-methoxy-quinazoline,
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)aminol -7- [3- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -6-cyclopentylmethoxy-quinazoline and (R) -4- [(1-phenyl-ethyl)amino] -7-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline i are excluded, the tautomers, the stereoisomers and the salts thereof.
5. Compounds of general formula I according to claim 1, wherein R, denotes a l-phenylethyl, 3-bromophenyl or 3-chloro- 4-fluorophenyl group, R, denotes a R,-(CH,),-O group, wherein R, denotes a 2-oxo-morpholin-4-yl group substituted by one oo or two methyl groups and m denotes the number 2 or 3, and R, denotes a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group, with the proviso that the compounds 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-(3-methyl-2-oxo-morpholin- 4-yl)ethoxyl] -7-methoxy-quinazoline,
4- [(3-bromo-phenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpholin- 4-yl) ethoxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-[2-(6,6-dimethyl-2-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-cyclobutyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amineo] -6-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)aminol -6-[2- (6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)aminol-6-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxyl-7-cyclopentyloxy-quinazoline and (R)-4-[(1-phenyl-ethyl)aminol -6-[3-(6,6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline are excluded, the tautomers, the stereoisomers and the salts thereof.
6. Compounds of general formula I according to claim 1, wherein R, denotes a 3-chloro-4-fluorophenyl group, R, denotes a cyclopentyloxy, cyclopropylmethoxy, cyclopentyl- methoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy group and i - 89 -
R. denotes a R,- (CH,) _,-O group, wherein R, denotes a 2-oxo-morpholin-4-yl group substituted by one or two methyl groups and m denotes the number 2, with the proviso that the compounds 4-[(3-chloro-4-fluorophenyl)amino] -6-cyclopentyloxy- 7-[2-(6,6-dimethyl-2-oxo-morpholin-4-yl) ethoxy] -quinazoline, 4-[(3~chloro-4-fluorophenyl) amino] -7-[2- (6, 6~dimethyl-2-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-cyclopropylmethoxy-quinazoline and 4-[(3-chloro-4-fluorophenyl]amino] -7-[2- (6,6-dimethyl-2-oxo- morpholin-4-yl) -ethoxyl -6-cyclopentylmethoxy-quinazoline, are excluded, the tautomers, the stereoisomers and the salts thereof.
7. The following compounds of general formula I according to claim 1: (1) 4-[(3-chloro-4-fluorophenyl)amino] -6-cyclopentylmethoxy- 7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxyl] -quinazoline, (2) 4-[(3-chloro-4-fluorophenyl)amino] -6-cyclopentyloxy- 7-{2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy}- quinazoline, (3) 4-[(3-chloro-4-fluorophenyl)amino] -6-cyclopropylmethoxy- 7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -quinazoline,
Y - 90 - (4) 4-[(3-chloro-4-fluorophenyl) amino] -7-cyclobutyloxy- 6-13-(2,2-dimethyl-6-oxo-morpholin-4-yl) -propyloxy] - quinazoline,
(5) 4-1 (3-chloro-4-fluorophenyl) amino] - 7-cyclopropylmethoxy- 6-13-(2,2-dimethyl-6-oxo-morpholin-4-yl) -propyloxy] - quinazoline,
(6) 4- [(3-chloro-4-fluorophenyl) amino] -6-cyclopropylmethoxy- 7-{2- [N- (2-oxo-tetrahydrofuran-4-yl) -N-methyl-amino] ethoxy) - guinazoline,
(7) 4-[(3-bromo-phenyl) amino] -6- [2- ( (S$) -6-methyl-2-oxo-
morpholin-4-yl)-ethoxy] -7-methoxy-quinazoline,
(8) 4- [(3-bromo-phenyl) amino] -6-[2- ( (R) -6-methyl-2-oxo- morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline,
(9) 4-[(3-chloro-4-fluorophenyl)aminol -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) -propyloxyl] -7-methoxy-quinazoline,
(12) 4-1(R)-(l-phenyl-ethyl)aminol-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-gquinazoline,
the tautomers, the stereoisomers and the salts thereof.
x
8. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 7 with inorganic or organic acids or bases.
9. Pharmaceutical compositions containing a compound according to at least 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.
10. Use of a compound according to at least one of claims 1 to 8 for preparing a pharmaceutical composition which is suitable for treating benign or malignant tumours, for preventing and treating diseases of the airways and lungs, for treating polyps, diseases of the gastrointestinal tract, the bile duct and gall bladder as well as the kidneys and skin.
11. Process for preparing a pharmaceutical composition according to claim 9, characterised in that a compound according to at least one of claims 1 to 8 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
12. Process for preparing the compounds of general formula I according to claims 1 to 8, characterised in that a) a compound of general formula R a AA N R 1 N~ ° § , (IT) NS N R,' wherein R, is defined as in claims 1 to 7,
one of the groups R,' or R,' represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and the other group R,' or R,' represents a Z,- (CH,),-O group, wherein m is defined as in claims 1 to 7 and Z, denotes a leaving group, 1s reacted with a compound of general formula - H - R, , (III) wherein R, is defined as in claims 1 to 7, or b) a compound of general formula R ANZ
N
R. " N~ ° NR , (IV) x
N R." optionally formed in the reaction mixture wherein R, 1s defined as in claims 1 to 7, one of the groups R," or R.," represents a methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group and ‘the other group R," or R." represents a R,'-(CH,),~-O group wherein m is defined as in claims 1 to 7 and R;' denotes an R,-0-CO-CH,-N-CH,CH,-OH group substituted at the methylene groups by one or two methyl or ethyl groups, wherein
&
R, represents a hydrogen atom or a C, ,-alkyl group, is cyclised and if necessary any protecting group used during the above reactions is cleaved again and/or if desired a compound of general formula I thus obtained is resolved into its stereoisomers and/or a compound of general formula I thus obtained is converted into the salts thereof, more particularly, for pharmaceutical use, into the physiologically acceptable salts thereof.
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