NO329271B1 - 4- (N-Phenylamino) quinazolines / quinolines, the preparation thereof, pharmaceutical preparations containing them and the use thereof for the manufacture of medicaments for the treatment of disease - Google Patents

4- (N-Phenylamino) quinazolines / quinolines, the preparation thereof, pharmaceutical preparations containing them and the use thereof for the manufacture of medicaments for the treatment of disease Download PDF

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NO329271B1
NO329271B1 NO20043997A NO20043997A NO329271B1 NO 329271 B1 NO329271 B1 NO 329271B1 NO 20043997 A NO20043997 A NO 20043997A NO 20043997 A NO20043997 A NO 20043997A NO 329271 B1 NO329271 B1 NO 329271B1
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amino
morpholin
phenyl
chloro
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NO20043997L (en
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Frank Himmelsbach
Flavio Solca
Birgit Jung
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Boehringer Ingelheim Pharma
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Priority claimed from DE2002131711 external-priority patent/DE10231711A1/en
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Publication of NO20043997L publication Critical patent/NO20043997L/en
Publication of NO329271B1 publication Critical patent/NO329271B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen 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
    • 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
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Description

Foreliggende oppfinnelse angår bicykliske, heterocykliske forbindelser med den generelle formel The present invention relates to bicyclic, heterocyclic compounds with the general formula

tautomerer, stereoisomerer og salter derav, spesielt de fysiologisk akseptable salter derav med uorganiske eller organiske syrer eller baser som har verdifulle farmakologiske egenskaper, spesielt en hemmende effekt på signaltransduksjon mediert av tyrosinkinaser, anvendelse derav for fremstilling av medikamenter for behandling av sykdommer, spesielt tumor-sykdommer, så vel som godartet prostata-hyperplasi (BPH), sykdommer i lungene og luftveiene og fremstilling derav. tautomers, stereoisomers and salts thereof, in particular the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases, use thereof for the preparation of drugs for the treatment of diseases, in particular tumor- diseases, as well as benign prostatic hyperplasia (BPH), diseases of the lungs and respiratory tract and manufacture thereof.

I den generelle formel I ovenfor betyr In the general formula I above means

Ra betyr et hydrogenatom, Ra means a hydrogen atom,

R<b> betyr en 3-etynylfenyl-, 3-bromfenyl-, 3,4-difluorfenyl- eller 3-klor-4-fluor-fenylgruppe, R<b> means a 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chloro-4-fluorophenyl group,

en 3-klor-4-benzyloksy-fenyl-, 3-klor-4-[(3-fluor-benzyl)oksy]-fenyl-, 4-(pyridin-3-yloksy)-fenyl-, 4-[(6-metyl-pyridin-3-yl)oksy]-fenyl-, 3-metyl-4-(pyridin-3-yloksy)-fenyl-, 3-metyl-4-[(6-metyl-pyridin-3-yl)oksy]-fenyl-, 3-klor-4-(pyridin-3-yloksy)-fenyl- eller 3-klor-4-[(6-metyl-pyridin-3-yl)oksy]-fenylgruppe, a 3-chloro-4-benzyloxy-phenyl-, 3-chloro-4-[(3-fluoro-benzyl)oxy]-phenyl-, 4-(pyridin-3-yloxy)-phenyl-, 4-[(6 -methyl-pyridin-3-yl)oxy]-phenyl-, 3-methyl-4-(pyridin-3-yloxy)-phenyl-, 3-methyl-4-[(6-methyl-pyridin-3-yl) oxy]-phenyl-, 3-chloro-4-(pyridin-3-yloxy)-phenyl- or 3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group,

R<c> betyr en cykloheksylgruppe som er substituert i 3-stillingen eller i 4-stillingen med en gruppe R<4->N-R<5>, hvor R<c> means a cyclohexyl group which is substituted in the 3-position or in the 4-position with a group R<4->N-R<5>, where

R<4> betyr et hydrogenatom, en metyl- eller etylgruppe og R<4> means a hydrogen atom, a methyl or ethyl group and

R<5> betyr et hydrogenatom, en metyl-, aminokarbonylmetyl-, metylamino-karbonylmetyl-, dimetylaminokarbonylmetyl-, pyrrolidin-1-ylkarbonylmetyl-, piperidin-1-ylkarbonylmetyl-, piperazin-1-ylkarbonylmetyl-, 4-metylpiperazin-1 -ylkarbonylmetyl-, morfolin-4-ylkarbonylmetyl-, 2-(morfolin-4-yl-karbonyl)etyl- eller 3-(morfolin-4-ylkarbonyl)propylgruppe, R<5> means a hydrogen atom, a methyl-, aminocarbonylmethyl-, methylamino-carbonylmethyl-, dimethylaminocarbonylmethyl-, pyrrolidin-1-ylcarbonylmethyl-, piperidin-1-ylcarbonylmethyl-, piperazin-1-ylcarbonylmethyl-, 4-methylpiperazin-1 - ylcarbonylmethyl, morpholin-4-ylcarbonylmethyl, 2-(morpholin-4-ylcarbonyl)ethyl or 3-(morpholin-4-ylcarbonyl)propyl group,

en etyl-, propyl-, 2-hydroksyetyl-, 3-hydroksypropyl-, 2-metoksyetyl-, 3-metoksypropyl-, 2-(butyloksykarbonylamino)-etyl-, 2-aminoetyl-, 3-aminopropyl-, 2-(acetylamino)etyl-, 3-(acetylamino)propyl-, 2-(etylkarbonylamino)etyl-, 3-(etylkarbonylamino)propyl-, 2-(propylkarbonylamino)etyl-, 3-(propylkarbonylamino)propyl-, 2-(etylaminokarbonylamino)etyl-, 3-(etylaminokarbonylamino)propyl-, 2-(dimetylaminokarbonylamino)etyl-, 3-(dimetylaminokarbonylamino)-propyl-, 2-(morfolin-4-ylkarbonylamino)etyl-, 3-(morfolin-4-ylkarbonylamino)propyl-, 2-(metylsulfonyl)etyl-, 3-(metylsulfonyl)propyl-, 2-(metylsulfonylamino)etyl- eller en 3-(metylsulfonylamino)propylgruppe, an ethyl-, propyl-, 2-hydroxyethyl-, 3-hydroxypropyl-, 2-methoxyethyl-, 3-methoxypropyl-, 2-(butyloxycarbonylamino)-ethyl-, 2-aminoethyl-, 3-aminopropyl-, 2-(acetylamino )ethyl-, 3-(acetylamino)propyl-, 2-(ethylcarbonylamino)ethyl-, 3-(ethylcarbonylamino)propyl-, 2-(propylcarbonylamino)ethyl-, 3-(propylcarbonylamino)propyl-, 2-(ethylaminocarbonylamino)ethyl -, 3-(ethylaminocarbonylamino)propyl-, 2-(dimethylaminocarbonylamino)ethyl-, 3-(dimethylaminocarbonylamino)-propyl-, 2-(morpholin-4-ylcarbonylamino)ethyl-, 3-(morpholin-4-ylcarbonylamino)propyl- , 2-(methylsulfonyl)ethyl-, 3-(methylsulfonyl)propyl-, 2-(methylsulfonylamino)ethyl- or a 3-(methylsulfonylamino)propyl group,

en 2-(2-okso-pyrrolidin-1-yl)etyl-, 2-(2-oksopiperidin-1-yl)etyl-, 2-(3-okso-morfolin^-yljetyl-, 2-(2-okso-imidazolidin-1 -yl)etyl-, 2-(2-okso-3-metyl-imidazolidin-1-yl)etyl-, 2-(2-okso-heksahydropyrimidin-1-yl)etyl- eller en 2- (2-okso-3-metyl-heksahydropyrimidin-1-yl)etylgruppe, a 2-(2-oxo-pyrrolidin-1-yl)ethyl-, 2-(2-oxopiperidin-1-yl)ethyl-, 2-(3-oxo-morpholin^-ylethyl-, 2-(2-oxo -imidazolidin-1 -yl)ethyl-, 2-(2-oxo-3-methyl-imidazolidin-1-yl)ethyl-, 2-(2-oxo-hexahydropyrimidin-1-yl)ethyl- or a 2-( 2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl group,

en 3-(2-okso-pyrrolidin-1-yl)propyl-, 3-(2-oksopiperidin-1-yl)propyl-, 3-(3-okso-morfolin-4-yl)propyl-, 3-(2-okso-imidazolidin-1 -yl)propyl-, 3-(2-okso-3- metyl-imidazolidin-1 -yl)propyl-, 3-(2-okso-heksahydropyrimidin-1 - yl)propyl- eller en 3-(2-okso-3-metyl-heksahydropyrimidin-1-yl)propylgruppe, a 3-(2-oxo-pyrrolidin-1-yl)propyl-, 3-(2-oxopiperidin-1-yl)propyl-, 3-(3-oxo-morpholin-4-yl)propyl-, 3-( 2-oxo-imidazolidin-1 -yl)propyl-, 3-(2-oxo-3-methyl-imidazolidin-1 -yl)propyl-, 3-(2-oxo-hexahydropyrimidin-1 -yl)propyl- or a 3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)propyl group,

en metylsulfonyl-, etylsulfonyl-, 3-klorpropylsulfonyl-, 2-(morfolin-4-yl)-etylsulfonyl- eller en 3-(morfolin-4-yl)-propylsulfonylgruppe, a methylsulfonyl, ethylsulfonyl, 3-chloropropylsulfonyl, 2-(morpholin-4-yl)ethylsulfonyl or a 3-(morpholin-4-yl)propylsulfonyl group,

en propyloksykarbonyl- eller butyloksykarbonylgruppe, a propyloxycarbonyl or butyloxycarbonyl group,

en formyl-, acetyl-, etylkarbonyl-, propylkarbonyl-, metoksyacetyl-, (2-metoksyetyl)karbonyl-, (3-metoksypropyl)karbonyl-, tetrahydrofuran-2- a formyl-, acetyl-, ethylcarbonyl-, propylcarbonyl-, methoxyacetyl-, (2-methoxyethyl)carbonyl-, (3-methoxypropyl)carbonyl-, tetrahydrofuran-2-

ylkarbonyl-, tetrahydropyran-4-ylkarbonyl-, aminoacetyl-, metylaminoacetyl-, dimetylaminoacetyl-, morfolin-4-ylacetyl-, [2-(morfolin-4-yl)etyl]karbonyl-, [3-(morfolin-4-yl)propyl]karbonyl- eller en metylsulfonylacetylgruppe, ylcarbonyl-, tetrahydropyran-4-ylcarbonyl-, aminoacetyl-, methylaminoacetyl-, dimethylaminoacetyl-, morpholin-4-ylacetyl-, [2-(morpholin-4-yl)ethyl]carbonyl-, [3-(morpholin-4-yl )propyl]carbonyl or a methylsulfonylacetyl group,

en cyano-, aminokarbonyl-, metylaminokarbonyl-, dimetylaminokarbonyl-, etylaminokarbonyl-, dietylaminokarbonyl-, propylaminokarbonyl-, (2-metoksyetyl)aminokarbonyl-, N-metyl-N-(2-metoksyetyl)-aminokarbonyl-, (3-metoksypropyl)aminokarbonyl-, N-metyl-N-(3-metoksypropyl)-aminokarbonyl-, fenylaminokarbonyl-, pyrrolidin-1-ylkarbonyl-, piperidin-1-ylkarbonyl-, morfolin-4-ylkarbonyl-, 2-metylmorfolin-4-ylkarbonyl-, 2,6-dimetylmorfolin-4-ylkarbonyl-, homomorfolin-4-ylkarbonyl-, 2-oksa-5-aza-bicyklo[2.2.1]hept-5-ylkarbonyl-, 3-oksa-8-aza-bicyklo[3.2.1]okt-8-ylkarbonyl-, 8-oksa-3-aza-bicyklo[3.2.1]okt-3-ylkarbonyl-, 4-metylpiperazin-1 -ylkarbonyl-, aminosulfonyl-, metylaminosulfonyl-, dimetylaminosulfonyl- eller en morfolin-4-ylsulfonylgruppe, a cyano-, aminocarbonyl-, methylaminocarbonyl-, dimethylaminocarbonyl-, ethylaminocarbonyl-, diethylaminocarbonyl-, propylaminocarbonyl-, (2-methoxyethyl)aminocarbonyl-, N-methyl-N-(2-methoxyethyl)aminocarbonyl-, (3-methoxypropyl) aminocarbonyl-, N-methyl-N-(3-methoxypropyl)-aminocarbonyl-, phenylaminocarbonyl-, pyrrolidin-1-ylcarbonyl-, piperidin-1-ylcarbonyl-, morpholin-4-ylcarbonyl-, 2-methylmorpholin-4-ylcarbonyl- , 2,6-dimethylmorpholin-4-ylcarbonyl-, homomorpholin-4-ylcarbonyl-, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl-, 3-oxa-8-aza-bicyclo[ 3.2.1]oct-8-ylcarbonyl-, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl-, 4-methylpiperazin-1-ylcarbonyl-, aminosulfonyl-, methylaminosulfonyl-, dimethylaminosulfonyl- or a morpholin-4-ylsulfonyl group,

en cykloheksylgruppe som er substituert i 3-stillingen eller i 4-stillingen med en gruppe R<6>, hvor a cyclohexyl group which is substituted in the 3-position or in the 4-position with a group R<6>, where

R<6> betyr en 2-okso-pyrrolidin-1-yl-, 2-oksopiperidin-1-yl-, 3-okso-morfolin-4-yl-, 2-okso-imidazolidin-1-yl-, 2-okso-3-metyl-imidazolidin-1-yl-, 2-okso-heksahydropyrimidin-1-yl- eller en 2-okso-3-metyl-heksahydropyrimidin-1-ylgruppe, R<6> means a 2-oxo-pyrrolidin-1-yl-, 2-oxopiperidin-1-yl-, 3-oxo-morpholin-4-yl-, 2-oxo-imidazolidin-1-yl-, 2- oxo-3-methyl-imidazolidin-1-yl-, 2-oxo-hexahydropyrimidin-1-yl- or a 2-oxo-3-methyl-hexahydropyrimidin-1-yl group,

en pyrrolidin-3-ylgruppe som er substituert i 1-stillingen med gruppen R<5>, hvor R<5> er som ovenfor definert, a pyrrolidin-3-yl group which is substituted in the 1-position with the group R<5>, where R<5> is as defined above,

en piperidin-3-ylgruppe som er substituert i 1-stillingen med gruppen R<5>, hvor R<5 >er som ovenfor definert, a piperidin-3-yl group which is substituted in the 1-position with the group R<5>, where R<5> is as defined above,

en piperidin-4-ylgruppe som er substituert i 1-stillingen med gruppen R<5>, hvor R<5 >er som ovenfor definert, a piperidin-4-yl group which is substituted in the 1-position with the group R<5>, where R<5> is as defined above,

en tetrahydrofuran-3-yl-, tetrahydropyran-3-yl- eller tetrahydropyran-4-ylgruppe, a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

Rd betyr et hydrogenatom, Rd means a hydrogen atom,

en metoksy-, difluormetoksy- eller etyloksygruppe, a methoxy, difluoromethoxy or ethyloxy group,

en etyloksygruppe som er substituert i 2-stillingen med en gruppe R<6> eller R<7>, hvor R<6> er som ovenfor definert og an ethyloxy group which is substituted in the 2-position with a group R<6> or R<7>, where R<6> is as defined above and

R<7> betyr en hydroksy-, metoksy-, etoksy-, amino-, dimetylamino-, dietylamino-, bis-(2-metoksyetyl)-amino-, pyrrolidin-1-yl-, piperidin-1-yl-, morfolin-4-yl-, homomorfolin-4-yl-, 2-oksa-5-aza-bicyklo[2.2.1]hept-5-yl-, 3-oksa-8-aza-bicyklo[3.2.1 ]okt-8-yl-, 8-oksa-3-aza-bicyklo[3.2.1 ]okt-3-yl-, piperazin-1-yl-, 4-metylpiperazin-1-yl- eller 4-etylpiperazin-1-ylgruppe, eller R<7> means a hydroxy-, methoxy-, ethoxy-, amino-, dimethylamino-, diethylamino-, bis-(2-methoxyethyl)-amino-, pyrrolidin-1-yl-, piperidin-1-yl-, morpholine -4-yl-, homomorpholin-4-yl-, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-, 3-oxa-8-aza-bicyclo[3.2.1 ]oct- 8-yl-, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-, piperazin-1-yl-, 4-methylpiperazin-1-yl- or 4-ethylpiperazin-1-yl group, or

en acetylamino-, etylkarbonylamino-, propylkarbonylamino-, butylkarbonylamino-, metoksyacetylamino-, butyloksykarbonylamino-, etylaminokarbonylamino-, dimetylaminokarbonylamino-, pyrrolidin-1 - ylkarbonylamino-, piperidin-1-ylkarbonylamino-, morfolin-4-ylkarbonylamino-, metylsulfonylamino-, etylsulfonylamino- eller butylsulfonylaminogruppe, an acetylamino-, ethylcarbonylamino-, propylcarbonylamino-, butylcarbonylamino-, methoxyacetylamino-, butyloxycarbonylamino-, ethylaminocarbonylamino-, dimethylaminocarbonylamino-, pyrrolidin-1-ylcarbonylamino-, piperidin-1-ylcarbonylamino-, morpholin-4-ylcarbonylamino-, methylsulfonylamino-, ethylsulfonylamino - or butylsulfonylamino group,

en propyloksygruppe som er substituert i 3-stillingen med en gruppe R<6> eller R<7>, hvor R6 og R<7> er som ovenfor definert eller a propyloxy group which is substituted in the 3-position by a group R<6> or R<7>, where R6 and R<7> are as defined above or

en butyloksygruppe som er substituert i 4-stillingen med en gruppe R<6> eller R<7>, hvor R6 og R<7> er som ovenfor definert og a butyloxy group which is substituted in the 4-position with a group R<6> or R<7>, where R6 and R<7> are as defined above and

X betyr et nitrogenatom, X means a nitrogen atom,

idet, hvis ikke angitt på annen måte, de ovennevnte alkylgrupper kan være lineære eller forgrenede, wherein, unless otherwise indicated, the above alkyl groups may be linear or branched,

tautomerer, stereoisomerer og salter derav. tautomers, stereoisomers and salts thereof.

Mest spesielt foretrukne forbindelser med den generelle formel I er de hvor Most particularly preferred compounds of the general formula I are those wherein

Ra betyr et hydrogenatom, Ra means a hydrogen atom,

Rb betyr en 3-bromfenyl-, 3,4-difluorfenyl-, 3-klor-4-fluor-fenyl- eller en 3-etynylfenylgruppe, eller Rb means a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl or a 3-ethynylphenyl group, or

en 3-klor-4-benzyloksy-fenyl-, 3-klor-4-[(3-fluorbenzyl)oksy]-fenyl-, 4-(pyridin-3-yloksy)-fenyl-, 4-[(6-metyl-pyridin-3-yl)oksy]-fenyl-, 3-metyl-4-(pyridin-3-yloksy)-fenyl-, 3-metyl-4-[(6-metyl-pyridin-3-yl)oksy]-fenyl-, 3-klor-4-(pyridin-3-yloksy)-fenyl- eller 3-klor-4-[(6-metyl-pyridin-3-yl)oksy]-fenylgruppe, a 3-chloro-4-benzyloxy-phenyl-, 3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl-, 4-(pyridin-3-yloxy)-phenyl-, 4-[(6-methyl -pyridin-3-yl)oxy]-phenyl-, 3-methyl-4-(pyridin-3-yloxy)-phenyl-, 3-methyl-4-[(6-methyl-pyridin-3-yl)oxy] -phenyl-, 3-chloro-4-(pyridin-3-yloxy)-phenyl- or 3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group,

R<c> betyr en cykloheksylgruppe som er substituert i 3-stillingen med en amino-, acetylamino-, tert.-butyloksykarbonylamino- eller metylsulfonylaminogruppe, R<c> means a cyclohexyl group which is substituted in the 3-position with an amino-, acetylamino-, tert-butyloxycarbonylamino- or methylsulfonylamino group,

en cykloheksylgruppe som er substituert i 4-stillingen med en amino-, metylamino-, etylamino-, dimetylamino-, aminokarbonylmetylamino-, metylaminokarbonylmetylamino-, dimetylaminokarbonylmetylamino-, morfolin-4-ylkarbonylmetylamino-, [3-(morfolin-4-ylkarbonyl)propyl]amino-, [2-(metylsulfonyl)etyl]amino-, [3-(metylsulfonyl)propyl]amino- eller [2-(metylsulfonylamino)etyl]aminogruppe, a cyclohexyl group which is substituted in the 4-position with an amino-, methylamino-, ethylamino-, dimethylamino-, aminocarbonylmethylamino-, methylaminocarbonylmethylamino-, dimethylaminocarbonylmethylamino-, morpholin-4-ylcarbonylmethylamino-, [3-(morpholin-4-ylcarbonyl)propyl ]amino-, [2-(methylsulfonyl)ethyl]amino-, [3-(methylsulfonyl)propyl]amino- or [2-(methylsulfonylamino)ethyl]amino group,

en cykloheksylgruppe som er substituert i 4-stillingen med en [2-(2-okso-pyrrolidin-1 -yl)etyl]amino-, [2-(2-oksopiperidin-1 -yl)etyl]amino-, [2-(2-okso-imidazolidin-1 -yl)etyl]amino-, [2-(2-okso-3-metyl-imidazolidin-1 -yl)etyl]amino-, [2-(2-okso-heksahydropyrimidin-1 -yl)etyl]amino- eller [2-(2-okso-3-metyl-heksahydropyrimidin-1-yl)etyl]aminogruppe, a cyclohexyl group which is substituted in the 4-position with a [2-(2-oxo-pyrrolidin-1-yl)ethyl]amino-, [2-(2-oxopiperidin-1-yl)ethyl]amino-, [2- (2-oxo-imidazolidin-1 -yl)ethyl]amino-, [2-(2-oxo-3-methyl-imidazolidin-1 -yl)ethyl]amino-, [2-(2-oxo-hexahydropyrimidine-1 -yl)ethyl]amino or [2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl]amino group,

en cykloheksylgruppe som er substituert i 4-stillingen med en [3-(2-okso-pyrrolidin-1 -yl)propyl]amino-, [3-(2-oksopiperidin-1 -yl)propyl]amino-, [3-(2-okso-imidazolidin-1 -yl)propyl]amino-, [3-(2-okso-3-metyl-imidazolidin-1 - yl)propyl]amino-, [3-(2-okso-heksahydropyrimidin-1-yl)propyl]amino- eller [3-(2-okso-3-metyl-heksahydropyrimidin-1-yl)propyl]aminogruppe, a cyclohexyl group substituted in the 4-position by a [3-(2-oxo-pyrrolidin-1-yl)propyl]amino-, [3-(2-oxopiperidin-1-yl)propyl]amino-, [3- (2-oxo-imidazolidin-1 -yl)propyl]amino-, [3-(2-oxo-3-methyl-imidazolidin-1 -yl)propyl]amino-, [3-(2-oxo-hexahydropyrimidine-1 -yl)propyl]amino- or [3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)propyl]amino group,

en cykloheksylgruppe som er substituert i 4-stillingen med en acetylamino-, N-(acetyl)-metylamino-, aminometylkarbonylamino-, a cyclohexyl group which is substituted in the 4-position with an acetylamino-, N-(acetyl)-methylamino-, aminomethylcarbonylamino-,

metylaminometylkarbonylamino-, dimetylaminometylkarbonylamino-, morfolin-4- methylaminomethylcarbonylamino-, dimethylaminomethylcarbonylamino-, morpholine-4-

ylmetylkarbonylamino-, metoksyacetylamino-, N-(metoksyacetyl)-metylamino-, tetrahydropyran-4-ylkarbonylamino-, N-(tetrahydropyran-4-ylkarbonyl)-metylamino-, tert.-butyloksykarbonylamino-, N-(tert.-butyloksykarbonyl)-metylamino-, aminokarbonylamino-, metylaminokarbonylamino-, N-(etylaminokarbonyl)-metylamino-, dimetylaminokarbonylamino-, N-(dimetylaminokarbonyl)-metylamino-, N-(piperidin-1-ylkarbonyl)-metylamino-, morfolin-4-ylkarbonylamino-, N-(morfolin-4-ylkarbonyl)-metylamino- eller N-(4-metylpiperazin-1-ylkarbonyl)-metylaminogruppe, ylmethylcarbonylamino-, methoxyacetylamino-, N-(methoxyacetyl)-methylamino-, tetrahydropyran-4-ylcarbonylamino-, N-(tetrahydropyran-4-ylcarbonyl)-methylamino-, tert-butyloxycarbonylamino-, N-(tert-butyloxycarbonyl)- methylamino-, aminocarbonylamino-, methylaminocarbonylamino-, N-(ethylaminocarbonyl)-methylamino-, dimethylaminocarbonylamino-, N-(dimethylaminocarbonyl)-methylamino-, N-(piperidin-1-ylcarbonyl)-methylamino-, morpholin-4-ylcarbonylamino-, N-(morpholin-4-ylcarbonyl)-methylamino- or N-(4-methylpiperazin-1-ylcarbonyl)-methylamino group,

en cykloheksylgruppe som er substituert i 4-stillingen med en 2-okso-pyrrolidin-1 -yl-, 2-oksopiperidin-1-yl-, 3-okso-morfolin-4-yl-, 2-okso-imidazolidin-1-yl-, 2-okso-3-metyl-imidazolidin-1-yl-, 2-okso-heksahydropyrimidin-1-yl- eller en 2-okso-3-metyl-heksahydropyrimidin-1-ylgruppe, a cyclohexyl group substituted in the 4-position by a 2-oxo-pyrrolidin-1-yl-, 2-oxopiperidin-1-yl-, 3-oxo-morpholin-4-yl-, 2-oxo-imidazolidin-1- yl-, 2-oxo-3-methyl-imidazolidin-1-yl-, 2-oxo-hexahydropyrimidin-1-yl- or a 2-oxo-3-methyl-hexahydropyrimidin-1-yl group,

en cykloheksylgruppe som er substituert i 4-stillingen med en metylsulfonylamino-, N-(metylsulfonyl)-metylamino-, etylsulfonylamino-, N-(etylsulfonyl)-metylamino-, dimetylaminosulfonylamino-, N-(dimetylaminosulfonyl)-metylamino-, morfolin-4-ylsulfonylamino-, N-(morfolin-4-ylsulfonyl)-metylamino- 3-klorpropylsulfonylamino-, [2-(morfolin-4-yl)-etyl]sulfonylamino- eller [3-(morfolin-4-yl)-propyl]sulfonylamino-gruppe, a cyclohexyl group which is substituted in the 4-position with a methylsulfonylamino-, N-(methylsulfonyl)-methylamino-, ethylsulfonylamino-, N-(ethylsulfonyl)-methylamino-, dimethylaminosulfonylamino-, N-(dimethylaminosulfonyl)-methylamino-, morpholine-4 -ylsulfonylamino-, N-(morpholin-4-ylsulfonyl)-methylamino- 3-chloropropylsulfonylamino-, [2-(morpholin-4-yl)-ethyl]sulfonylamino- or [3-(morpholin-4-yl)-propyl] sulfonylamino group,

en pyrrolidin-3-ylgruppe, a pyrrolidin-3-yl group,

en pyrrolidin-3-ylgruppe som er substituert i 1-stillingen med en metyl-, acetyl-, metoksyacetyl-, tert.-butyloksykarbonyl-, morfolin-4-ylkarbonyl- eller metylsulfonylgruppe, a pyrrolidin-3-yl group which is substituted in the 1-position with a methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl group,

en piperidin-3-ylgruppe, a piperidin-3-yl group,

en piperidin-3-ylgruppe som er substituert i 1-stillingen med en metyl-, acetyl-, metoksyacetyl-, tert.-butyloksykarbonyl-, morfolin-4-ylkarbonyl- eller metylsulfonylgruppe, a piperidin-3-yl group which is substituted in the 1-position with a methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl group,

en piperidin-4-ylgruppe som er substituert i 1-stillingen med en metyl-, etyl-, propyl-, isopropyl-, 2-hydroksyetyl-, 2-metoksyetyl-, 3-metoksypropyl-, 2- a piperidin-4-yl group which is substituted in the 1-position with a methyl-, ethyl-, propyl-, isopropyl-, 2-hydroxyethyl-, 2-methoxyethyl-, 3-methoxypropyl-, 2-

(metylsulfonyl)-etyl-, 3-(metylsulfonyl)-propyl-, 2-(tert.-butyloksykarbonylamino)-etyl-, 2-aminoetyl-, 2-(acetylamino)-etyl-, 2-(etylkarbonylamino)-etyl-, 2-(propylkarbonylamino)-etyl-, 2-(etylaminokarbonylamino)-etyl-, 2-(dimetylaminokarbonylamino)-etyl-, 2-(morfolin-4-ylkarbonylamino)-etyl-, 3-(acetylamino)-propyl-, 3-(etylkarbonylamino)-propyl-, 3-(propylkarbonylamino)-propyl-, 3-(etylaminokarbonylamino)-propyl-, 3-(dimetylaminokarbonylamino)-propyl-, 3-(morfolin-4-ylkarbonylamino)-propyl-, 2-(metylsulfonylamino)-etyl-, 3-(metylsulfonylamino)-propyl-, (aminokarbonyl)metyl-, (methylsulfonyl)-ethyl-, 3-(methylsulfonyl)-propyl-, 2-(tert-butyloxycarbonylamino)-ethyl-, 2-aminoethyl-, 2-(acetylamino)-ethyl-, 2-(ethylcarbonylamino)-ethyl- , 2-(propylcarbonylamino)-ethyl-, 2-(ethylaminocarbonylamino)-ethyl-, 2-(dimethylaminocarbonylamino)-ethyl-, 2-(morpholin-4-ylcarbonylamino)-ethyl-, 3-(acetylamino)-propyl-, 3-(ethylcarbonylamino)-propyl-, 3-(propylcarbonylamino)-propyl-, 3-(ethylaminocarbonylamino)-propyl-, 3-(dimethylaminocarbonylamino)-propyl-, 3-(morpholin-4-ylcarbonylamino)-propyl-, 2 -(methylsulfonylamino)-ethyl-, 3-(methylsulfonylamino)-propyl-, (aminocarbonyl)methyl-,

(metylaminokarbonyl)metyl-, (dimetylaminokarbonyl)metyl-, (pyrrolidin-1 - ylkarbonyl)metyl-, (morfolin-4-ylkarbonyl)metyl-T 2-(morfolin-4-ylkarbonyl)-etyl-eller 3-(morfolin-4-ylkarbonyl)-propylgruppe, (methylaminocarbonyl)methyl-, (dimethylaminocarbonyl)methyl-, (pyrrolidin-1 - ylcarbonyl)methyl-, (morpholin-4-ylcarbonyl)methyl-T 2-(morpholin-4-ylcarbonyl)-ethyl-or 3-(morpholin- 4-ylcarbonyl)-propyl group,

en piperidin-4-ylgruppe som er substituert i 1-stillingen med en 2-(2-okso-pyrrolidin-1 -yl)-etyl-, 2-(2-oksopiperidin-1 -yl)-etyl-, 2-(3-oksomorfolin-4-yl)-etyl-, 2-(2-okso-imidazolidin-1 -yl)-etyl-, 2-(2-okso-3-metyl-imidazolidin-1 -yl)-etyl-, 2-(2-okso-heksahydropyrimidin-1-yl)-etyl- eller 2-(2-okso-3-metyl-heksahydropyrimidin-1-yl)-etylgruppe, a piperidin-4-yl group which is substituted in the 1-position with a 2-(2-oxo-pyrrolidin-1-yl)-ethyl-, 2-(2-oxopiperidin-1-yl)-ethyl-, 2-( 3-oxomorpholin-4-yl)-ethyl-, 2-(2-oxo-imidazolidin-1 -yl)-ethyl-, 2-(2-oxo-3-methyl-imidazolidin-1 -yl)-ethyl-, 2-(2-oxo-hexahydropyrimidin-1-yl)-ethyl or 2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyl group,

en piperidin-4-ylgruppe som er substituert i 1-stillingen med en 3-(2-okso-pyrrolidin-1 -yl)-propyl-, 3-(2-oksopiperidin-1 -yl)-propyl-, 3-(3-oksomorfolin-4-yl)-propyl-, 3-(2-okso-imidazolidin-1 -yl)-propyl-, 3-(2-okso-3-metyl-imidazolidin-1 - yl)-propyl-, 3-(2-okso-heksahydropyrimidin-1-yl)-propyl- eller 3-(2-okso-3-metyl-heksahydropyrimidin-1-yl)-propylgruppe, a piperidin-4-yl group which is substituted in the 1-position with a 3-(2-oxo-pyrrolidin-1-yl)-propyl-, 3-(2-oxopiperidin-1-yl)-propyl-, 3-( 3-oxomorpholin-4-yl)-propyl-, 3-(2-oxo-imidazolidin-1 -yl)-propyl-, 3-(2-oxo-3-methyl-imidazolidin-1 -yl)-propyl-, 3-(2-oxo-hexahydropyrimidin-1-yl)-propyl or 3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyl group,

en piperidin-4-ylgruppe som er substituert i 1-stillingen med en formyl-, acetyl-, metoksyacetyl-, (2-metoksyetyl)karbonyl-, (3-metoksypropyl)karbonyl-, metylsulfonylacetyl-, aminoacetyl-, metylaminoacetyl-, (dimetylamino)acetyl-, (morfolin-4-yl)acetyl-, [2-(morfolin-4-yl)-etyl]karbonyl-, [3-(morfolin-4-yl)-propyl]karbonyl-, tetrahydrofuran-2-ylkarbonyl- eller tetrahydropyran-4-ylkarbonylgruppe, a piperidin-4-yl group which is substituted in the 1-position with a formyl-, acetyl-, methoxyacetyl-, (2-methoxyethyl)carbonyl-, (3-methoxypropyl)carbonyl-, methylsulfonylacetyl-, aminoacetyl-, methylaminoacetyl-, ( dimethylamino)acetyl-, (morpholin-4-yl)acetyl-, [2-(morpholin-4-yl)-ethyl]carbonyl-, [3-(morpholin-4-yl)-propyl]carbonyl-, tetrahydrofuran-2 -ylcarbonyl or tetrahydropyran-4-ylcarbonyl group,

en piperidin-4-ylgruppe som er substituert i 1-stillingen med en cyano-, aminokarbonyl-, metylaminokarbonyl-, etylaminokarbonyl-, (2-metoksyetyl)aminokarbonyl-, N-metyl-N-(2-metoksyetyl)-aminokarbonyl-, (3-metoksypropyl)aminokarbonyl-, N-metyl-N-(3-metoksypropyl)-aminokarbonyl-, a piperidin-4-yl group which is substituted in the 1-position with a cyano-, aminocarbonyl-, methylaminocarbonyl-, ethylaminocarbonyl-, (2-methoxyethyl)aminocarbonyl-, N-methyl-N-(2-methoxyethyl)aminocarbonyl-, (3-methoxypropyl)aminocarbonyl-, N-methyl-N-(3-methoxypropyl)aminocarbonyl-,

isopropylaminokarbonyl-, fenylaminokarbonyl-, dimetylaminokarbonyl-, dietylaminokarbonyl-, pyrrolidin-1-ylkarbonyl-, piperidin-1-ylkarbonyl-, morfolin-4-ylkarbonyl-, 2-metylmorfolin-4-ylkarbonyl-, 2,6-dimetylmorfolin-4-ylkarbonyl-, homomorfolin-4-ylkarbonyl-, 2-oksa-5-aza-bicyklo[2.2.1 ]hept-5-ylkarbonyl-, 3-oksa-8-aza-bicyklo[3.2.1]okt-8-ylkarbonyl-, 8-oksa-3-aza-bicyklo[3.2.1]okt-3-ylkarbonyl-, 4-metylpiperazin-1-ylkarbonyl-, isopropyloksykarbonyl- eller tert.-butyloksykarbonylgruppe, isopropylaminocarbonyl-, phenylaminocarbonyl-, dimethylaminocarbonyl-, diethylaminocarbonyl-, pyrrolidin-1-ylcarbonyl-, piperidin-1-ylcarbonyl-, morpholin-4-ylcarbonyl-, 2-methylmorpholin-4-ylcarbonyl-, 2,6-dimethylmorpholin-4- ylcarbonyl-, homomorpholin-4-ylcarbonyl-, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl-, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl -, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl-, 4-methylpiperazin-1-ylcarbonyl-, isopropyloxycarbonyl- or tert-butyloxycarbonyl group,

en piperidin-4-ylgruppe som er substituert i 1-stillingen med en metylsulfonyl-, etylsulfonyl-, [2-(morfolin-4-yl)-etyl]sulfonyl-, [3-(morfolin-4-yl)-propyl]sulfonyl-, aminosulfonyl-, metylaminosulfonyl-, dimetylaminosulfonyl- eller morfolin-4-ylsulfonylgruppe, eller a piperidin-4-yl group which is substituted in the 1-position with a methylsulfonyl-, ethylsulfonyl-, [2-(morpholin-4-yl)-ethyl]sulfonyl-, [3-(morpholin-4-yl)-propyl] sulfonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl group, or

en tetrahydrofuran-3-yl-, tetrahydropyran-3-yl- eller tetrahydropyran-4-ylgruppe, a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

Rd betyr et hydrogenatom, Rd means a hydrogen atom,

en metoksy-, difluormetoksy- eller etyloksygruppe, a methoxy, difluoromethoxy or ethyloxy group,

en 2-(morfolin-4-yl)etyloksy-, 3-(morfolin-4-yl)propyloksy- eller 4-(morfolin-4-yl )buty loksyg ru ppe, a 2-(morpholin-4-yl)ethyloxy-, 3-(morpholin-4-yl)propyloxy- or 4-(morpholin-4-yl)butyloxy group,

en 3-(dimetylamino)propyloksy-, 3-(dietylamino)propyloksy-, 3-[bis-(2-metoksyetyl)-amino]propyloksy-, 3-(piperazin-1 -yl)propyloksy-, 3-(4-metylpiperazin-1-yl)propyloksy- eller 3-(4-etylpiperazin-1-yl)propyloksygruppe, a 3-(dimethylamino)propyloxy-, 3-(diethylamino)propyloxy-, 3-[bis-(2-methoxyethyl)amino]propyloxy-, 3-(piperazin-1 -yl)propyloxy-, 3-(4- methylpiperazin-1-yl)propyloxy or 3-(4-ethylpiperazin-1-yl)propyloxy group,

en 3-(homomorfolin-4-yl)-propyloksy-, 3-(2-oksa-5-aza-bicyklo[2.2.1 ]hept-5-yl)-propyloksy-, 3-(3-oksa-8-aza-bicyklo[3.2.1]okt-8-yl)-propyloksy- eller 3-(8-oksa-3-aza-bicyklo[3.2.1]okt-3-yl)-propyloksygruppe, a 3-(homomorpholin-4-yl)-propyloxy-, 3-(2-oxa-5-aza-bicyclo[2.2.1 ]hept-5-yl)-propyloxy-, 3-(3-oxa-8- aza-bicyclo[3.2.1]oct-8-yl)-propyloxy- or 3-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-propyloxy group,

en 2-(2-okso-pyrrolidin-1-yl)-etyloksy-, 2-(2-oksopiperidin-1-yl)-etyloksy-, 2-(3-oksomorfolin-4-yl)-etyloksy-, 2-(2-okso-imidazolidin-1 -yl)-etyloksy-, 2-(2-okso-3-metyl-imidazolidin-1 -yl)-etyloksy-, 2-(2-okso-heksahydropyrimidin-1 -yl)-etyloksy-eller 2-(2-okso-3-metyl-heksahydropyrimidin-1-yl)-etyloksygruppe, a 2-(2-oxo-pyrrolidin-1-yl)-ethyloxy-, 2-(2-oxopiperidin-1-yl)-ethyloxy-, 2-(3-oxomorpholin-4-yl)-ethyloxy-, 2- (2-oxo-imidazolidin-1 -yl)-ethyloxy-, 2-(2-oxo-3-methyl-imidazolidin-1 -yl)-ethyloxy-, 2-(2-oxo-hexahydropyrimidin-1 -yl)- ethyloxy or 2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyloxy group,

en 3-(2-okso-pyrrolidin-1 -yl)-propyloksy-, 3-(2-oksopiperidin-1-yl)-propyloksy-, 3-(3-oksomorfolin-4-yl)-propyloksy-, 3-(2-okso-imidazolidin-1 -yl)-propyloksy-, 3-(2-okso-3-metyl-imidazolidin-1-yl)-propyloksy-, 3-(2-okso-heksahydropyrimidin-1 -yl)-propyloksy- eller 3-(2-okso-3-metyl-heksahydropyrimidin-1 -yl)-propyloksygruppe, a 3-(2-oxo-pyrrolidin-1-yl)-propyloxy-, 3-(2-oxopiperidin-1-yl)-propyloxy-, 3-(3-oxomorpholin-4-yl)-propyloxy-, 3- (2-oxo-imidazolidin-1 -yl)-propyloxy-, 3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyloxy-, 3-(2-oxo-hexahydropyrimidin-1 -yl)- propyloxy or 3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyloxy group,

en 2-(metoksy)-etyloksy-, 2-(tert.-butyloksykarbonylamino)-etyloksy-, 2-(amino)-etyloksy-, 2-(acetylamino)-etyloksy-, 2-(etylkarbonylamino)-etyloksy-, 2-(propylkarbonylamino)-etyloksy-, 2-(isobutylkarbonylamino)-etyloksy-, 2-(metoksyacetylamino)-etyloksy-, 2-(etylaminokarbonylamino)-etyloksy-, 2-(dimetylaminokarbonylamino)-etyloksy-, 2-(pyrrolidin-1-ylkarbonylamino)-etyloksy-, 2-(piperidin-1 -ylkarbonylamino)-etyloksy-, 2-(morfolin-4-ylkarbonylamino)-etyloksy-, 2-(metylsulfonylamino)-etyloksygruppe, 2-(etylsulfonylamino)-etyloksy- eller 2-(butylsulfonylamino)-etyloksygruppe, eller a 2-(Methoxy)-ethyloxy-, 2-(tert-butyloxycarbonylamino)-ethyloxy-, 2-(amino)-ethyloxy-, 2-(acetylamino)-ethyloxy-, 2-(ethylcarbonylamino)-ethyloxy-, 2 -(propylcarbonylamino)-ethyloxy-, 2-(isobutylcarbonylamino)-ethyloxy-, 2-(methoxyacetylamino)-ethyloxy-, 2-(ethylaminocarbonylamino)-ethyloxy-, 2-(dimethylaminocarbonylamino)-ethyloxy-, 2-(pyrrolidine-1 -ylcarbonylamino)-ethyloxy-, 2-(piperidin-1-ylcarbonylamino)-ethyloxy-, 2-(morpholin-4-ylcarbonylamino)-ethyloxy-, 2-(methylsulfonylamino)-ethyloxy group, 2-(ethylsulfonylamino)-ethyloxy- or 2-(butylsulfonylamino)-ethyloxy group, or

en 3-(tert.-butyloksykarbonylamino)-propyloksy-, 3-(amino)-propyloksy-, 3-(acetylamino)-propyloksy- eller 3-(metylsulfonylamino)-propyloksygruppe, a 3-(tert-butyloxycarbonylamino)-propyloxy-, 3-(amino)-propyloxy-, 3-(acetylamino)-propyloxy- or 3-(methylsulfonylamino)-propyloxy group,

og and

X betyr et nitrogenatom, X means a nitrogen atom,

tautomerer, stereoisomerer og salter derav. tautomers, stereoisomers and salts thereof.

Spesielt foretrukne forbindelser med den generelle formel I er de hvor Particularly preferred compounds of the general formula I are those where

Ra betyr et hydrogenatom, Ra means a hydrogen atom,

Rb fortrinnsvis betyr en 3-klor-4-fluor-fenylgruppe eller også en 3-etynylfenylgruppe, Rb preferably means a 3-chloro-4-fluoro-phenyl group or also a 3-ethynylphenyl group,

R<c> betyr en cykloheksylgruppe som er substituert i 3-stillingen med en amino-, acetylamino-, tert.-butyloksykarbonylamino- eller metylsulfonylaminogruppe, R<c> means a cyclohexyl group which is substituted in the 3-position with an amino-, acetylamino-, tert-butyloxycarbonylamino- or methylsulfonylamino group,

en cykloheksylgruppe som er substituert i 4-stillingen med en amino-, a cyclohexyl group which is substituted in the 4-position with an amino,

metylamino-, dimetylamino-, acetylamino-, N-(acetyl)-metylamino-, metoksyacetylamino-, N-(metoksyacetyl)-metylamino-, tetrahydropyran-4-ylkarbonylamino-, N-(tetrahydropyran-4-ylkarbonyl)-metylamino-, tert-butyloksykarbonylamino-, N-(tert.-butyloksykarbonyl)-metylamino-, N-(etylaminokarbonyl)-metylamino-, dimetylaminokarbonylamino-, N-(dimetylaminokarbonyl)-metylamino-, N-(piperidin-1-ylkarbonyl)-metylamino-, morfolin-4-ylkarbonylamino-, N-(morfolin-4-ylkarbonyl)-metylamino-, N-(4-metylpiperazin-1 -ylkarbonyl)-metylamino-, metylsulfonylamino-, N-(metylsulfonyl)-metylamino-, etylsulfonylamino-, N-(etylsulfonyl)-metylamino-, dimetylaminosulfonylamino-, N-(dimetylaminosulfonyl)-metylamino-, morfolin-4-ylsulfonylamino-, N-(morfolin-4-ylsulfonyl)-metylamino-, 3-klorpropylsulfonylamino- eller [3-(morfolin-4-yl)-propyl]sulfonylaminogruppe, methylamino-, dimethylamino-, acetylamino-, N-(acetyl)-methylamino-, methoxyacetylamino-, N-(methoxyacetyl)-methylamino-, tetrahydropyran-4-ylcarbonylamino-, N-(tetrahydropyran-4-ylcarbonyl)-methylamino-, tert-butyloxycarbonylamino-, N-(tert-butyloxycarbonyl)-methylamino-, N-(ethylaminocarbonyl)-methylamino-, dimethylaminocarbonylamino-, N-(dimethylaminocarbonyl)-methylamino-, N-(piperidin-1-ylcarbonyl)-methylamino- , morpholin-4-ylcarbonylamino-, N-(morpholin-4-ylcarbonyl)-methylamino-, N-(4-methylpiperazin-1 -ylcarbonyl)-methylamino-, methylsulfonylamino-, N-(methylsulfonyl)-methylamino-, ethylsulfonylamino- , N-(ethylsulfonyl)-methylamino-, dimethylaminosulfonylamino-, N-(dimethylaminosulfonyl)-methylamino-, morpholin-4-ylsulfonylamino-, N-(morpholin-4-ylsulfonyl)-methylamino-, 3-chloropropylsulfonylamino- or [3- (morpholin-4-yl)-propyl]sulfonylamino group,

en pyrrolidin-3-ylgruppe, a pyrrolidin-3-yl group,

en pyrrolidin-3-ylgruppe som er substituert i 1-stillingen med en tert.-butyloksykarbonyl- eller metylsulfonylgruppe, a pyrrolidin-3-yl group which is substituted in the 1-position with a tert-butyloxycarbonyl or methylsulfonyl group,

en piperidin-3-ylgruppe, a piperidin-3-yl group,

en piperidin-3-ylgruppe som er substituert i 1-stillingen med en tert.-butyloksykarbonyl- eller metylsulfonylgruppe, a piperidin-3-yl group which is substituted in the 1-position with a tert-butyloxycarbonyl or methylsulfonyl group,

en piperidin-4-ylgruppe, a piperidin-4-yl group,

en piperidin-4-ylgruppe som er substituert i 1-stillingen med en metyl-, (aminokarbonyl)metyl-, (dimetylaminokarbonyl)metyl-, (morfolin-4-ylkarbonyl)metyl-, 2-(tert.-butyloksykarbonylamino)etyl-, 2-aminoetyl-, 2-(acetylamino)etyl-, 2-(metylsulfonylamino)etyl-, cyano-, acetyl-, metoksyacetyl-, (dimetylamino)acetyl-, (morfolin-4-yl)acetyl-, tetrahydropyran-4-ylkarbonyl-, etylaminokarbonyl-, isopropylaminokarbonyl-, fenylaminokarbonyl-, dimetylaminokarbonyl-, dietylaminokarbonyl-, pyrrolidin-1-ylkarbonyl-, piperidin-1-ylkarbonyl-, morfolin-4-ylkarbonyl-, 2-metylmorfolin-4-ylkarbonyl-, 2,6-dimetylmorfolin-4-ylkarbonyl-, homomorfolin-4-ylkarbonyl-, 4-metylpiperazin-1 - ylkarbonyl-, isopropyloksykarbonyl-, tert.-butyloksykarbonyl-, metylsulfonyl-, a piperidin-4-yl group which is substituted in the 1-position with a methyl-, (aminocarbonyl)methyl-, (dimethylaminocarbonyl)methyl-, (morpholin-4-ylcarbonyl)methyl-, 2-(tert-butyloxycarbonylamino)ethyl- , 2-aminoethyl-, 2-(acetylamino)ethyl-, 2-(methylsulfonylamino)ethyl-, cyano-, acetyl-, methoxyacetyl-, (dimethylamino)acetyl-, (morpholin-4-yl)acetyl-, tetrahydropyran-4 -ylcarbonyl-, ethylaminocarbonyl-, isopropylaminocarbonyl-, phenylaminocarbonyl-, dimethylaminocarbonyl-, diethylaminocarbonyl-, pyrrolidin-1-ylcarbonyl-, piperidin-1-ylcarbonyl-, morpholin-4-ylcarbonyl-, 2-methylmorpholin-4-ylcarbonyl-, 2 ,6-dimethylmorpholin-4-ylcarbonyl-, homomorpholin-4-ylcarbonyl-, 4-methylpiperazin-1 - ylcarbonyl-, isopropyloxycarbonyl-, tert-butyloxycarbonyl-, methylsulfonyl-,

dimetylaminosulfonyl- eller morfolin-4-ylsulfonylgruppe, eller en tetrahydrofuran-3-yl-, tetrahydropyran-3-yl- eller tetrahydropyran-4-ylgruppe, dimethylaminosulfonyl or morpholin-4-ylsulfonyl group, or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

Rd betyr et hydrogenatom, Rd means a hydrogen atom,

en metoksy- eller etyloksygruppe, a methoxy or ethyloxy group,

en 2-(morfolin-4-yl)etyloksy-, 3-(morfolin-4-yl)propyloksy- eller 4-(morfolin-4-yl )buty loksyg ru ppe, a 2-(morpholin-4-yl)ethyloxy-, 3-(morpholin-4-yl)propyloxy- or 4-(morpholin-4-yl)butyloxy group,

en 2-(3-metyl-2-okso-heksahydropyrimidin-1 -yl)-etyloksygruppe, a 2-(3-methyl-2-oxo-hexahydropyrimidin-1-yl)-ethyloxy group,

en 2-(metoksy)-etyloksy-, 2-(tert.-butyloksykarbonylamino)-etyloksy-, 2-amino-etyloksy-, 2-(acetylamino)-etyloksy- eller 2-(metylsulfonylamino)-etyloksygruppe eller a 2-(methoxy)-ethyloxy-, 2-(tert-butyloxycarbonylamino)-ethyloxy-, 2-amino-ethyloxy-, 2-(acetylamino)-ethyloxy- or 2-(methylsulfonylamino)-ethyloxy group or

en 3-(tert.-butyloksykarbonylamino)-propyloksy-, 3-amino-propyloksy-, 3-(acetylamino)-propyloksy- eller 3-(metylsulfonylamino)-propyloksygruppe, a 3-(tert-butyloxycarbonylamino)-propyloxy-, 3-amino-propyloxy-, 3-(acetylamino)-propyloxy- or 3-(methylsulfonylamino)-propyloxy group,

og and

X betyr et nitrogenatom, X means a nitrogen atom,

tautomerer, stereoisomerer og salter derav. tautomers, stereoisomers and salts thereof.

Av de bicykliske, heterocykliske forbindelser med den generelle formel I som beskrevet ovenfor så vel som undergruppene spesifisert som foretrukne, spesielt foretrukne, mest spesielt foretrukne og særlig foretrukne, skal spesielt nevnes de forbindelser hvor Of the bicyclic, heterocyclic compounds of the general formula I as described above as well as the subgroups specified as preferred, particularly preferred, most particularly preferred and particularly preferred, particular mention must be made of the compounds where

(a) R<c> betyr en cykloheksylgruppe substituert i 4-stillingen, (a) R<c> means a cyclohexyl group substituted in the 4-position,

(b) R<c> betyr en pyrrolidin-3-ylgruppe eventuelt substituert i 1-stillingen, (b) R<c> means a pyrrolidin-3-yl group optionally substituted in the 1-position,

(c) R<c> betyr en piperidin-3-ylgruppe eventuelt substituert i 1-stillingen, (c) R<c> means a piperidin-3-yl group optionally substituted in the 1-position,

(d) R<c> betyr en piperidin-4-ylgruppe eventuelt substituert i 1-stillingen, (d) R<c> means a piperidin-4-yl group optionally substituted in the 1-position,

(e) R<c> betyr en tetrahydrofuran-3-ylgruppe, (e) R<c> means a tetrahydrofuran-3-yl group,

(f) R<c> betyr en tetrahydropyran-3-ylgruppe, eller (f) R<c> means a tetrahydropyran-3-yl group, or

(g) R<c> betyr en tetrahydropyran-4-ylgruppe, (g) R<c> means a tetrahydropyran-4-yl group,

hvor Ra, R<b>, Rd og X i hvert tilfelle er som ovenfor definert. where Ra, R<b>, Rd and X in each case are as defined above.

De følgende er nevnt som eksempler på spesielt foretrukne forbindelser med den generelle formel I: (1) 4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-tetrahydrofuran-3-yloksy)-7-metoksy-kinazolin, (2) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-metoksy-kinazolin, (3) 4-[(3-klor-4-fluor-fenyl)amino]-6-((R)-tetrahydrofuran-3-yloksy)-7-metoksy-kinazolin, (4) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-amino-cykloheksan-1-yloksy)-7-metoksy-kinazolin, (5) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-metansulfonylamino-cykloheksan-1-yloksy)-7-metoksy-kinazolin, (6) 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-metoksy-kinazolin, (7) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-metansulfonyl-piperidin-4-yloksy)-7-metoksy-kinazolin, (8) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-{[3-(morfolin-4-yl)-propyl]sulfonyl-amino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin, (9) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-3-yloksy)-7-metoksy-kinazolin, (10) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-{[3-(morfolin-4-yl)-propyl]sulfonylamino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin, (11) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1 -metyl-piperidin-4-yloksy)-7-metoksy-kinazolin, (12) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1 -[(morfolin-4-yl)karbonyl]-piperidin-4-yl-oksy}-7-metoksy-kinazolin, (13) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1 -[(metoksymetyl)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin, (14) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1 -cyano-piperidin-4-yloksy)-7-metoksy-kinazolin, (15) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1 -[(morfolin-4-yl)sulfonyl]-piperidin-4-yl-oksy}-7-metoksy-kinazolin, (16) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1 -(2-acetylamino-etyl)-piperidin-4-yloksy]-7-metoksy-kinazolin, (17) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(dimetylamino)sulfonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin, (18) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(morfolin-4-yl)karbonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin, (19) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(morfolin-4-yl)sulfonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin, (20) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(2-acetylamino-etoksy)-kinazolin, (21) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(2-metansulfonylamino-etoksy)-kinazolin og (22) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(2-metoksy-etoksy)-kinazolin, The following are mentioned as examples of particularly preferred compounds of the general formula I: (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)- 7-Methoxy-quinazoline, (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline, (3) 4-[(3 -chloro-4-fluoro-phenyl)amino]-6-((R)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline, (4) 4-[(3-chloro-4-fluoro-phenyl)amino ]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4 -methanesulfonylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline, (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy- quinazoline, (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (8) 4-[(3 -chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)-propyl]sulfonyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline , (9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, (10) 4-[(3-chloro-4- fluoro-phenyl)amino]- 6-(trans-4-{[3-(morpholin-4-yl)-propyl]sulfonylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (11) 4-[(3-chloro-4- fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1 -[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline, (13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {1 -[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (14) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1 -cyano- piperidin-4-yloxy)-7-methoxy-quinazoline, (15) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1 -[(morpholin-4-yl)sulfonyl]-piperidine -4-yl-oxy}-7-methoxy-quinazoline, (16) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidine-4 -yloxy]-7-methoxy-quinazoline, (17) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexane-1-yloxy} -7-methoxy-quinazoline, (18) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy }-7-methoxy-quinazoline, (19) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans -4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (20) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-( tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline, (21) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7 -(2-methanesulfonylamino-ethoxy)-quinazoline and (22) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy) -quinazoline,

så vel som deres salter. as well as their salts.

Forbindelsene med den generelle formel I kan fremstilles ved for eksempel de følgende metoder: The compounds with the general formula I can be prepared by, for example, the following methods:

a) omsetning av en forbindelse med den generelle formel a) turnover of a compound with the general formula

hvor where

Ra, Rb, Rd og X er som ovenfor definert, med en forbindelse med den generelle formel Ra, Rb, Rd and X are as above defined, with a compound of the general formula

hvor where

R<c> er som ovenfor definert og Z<1> betyr en utgående gruppe så som et halogenatom, f.eks. et klor- eller bromatom, en sulfonyloksygruppe så som en metan su Ifonyloksy- eller p-toluensulfonyloksygruppe eller en hydroksygruppe. Med en forbindelse med den generelle formel III hvor Z<1> betyr en hydroksygruppe, blir reaksjonen utført i nærvær av et dehydratiseringsmiddel, fortrinnsvis i nærvær av et fosfin og et azodikarboksylsyrederivat så som f.eks. trifenylfosfin/dietyl-azodikarboksylat, hensiktsmessig i et løsningsmiddel så som metylenklorid, acetonitril, tetrahydrofuran, dioksan, toluen eller etylenglykoldietyleter ved temperaturer mellom -50 og 150°C, men fortrinnsvis ved temperaturer mellom -20 og 80°C. b) For å fremstille forbindelser med den generelle formel I hvor Rd betyr én av de eventuelt substituerte alkyloksygrupper nevnt ovenfor: R<c> is defined as above and Z<1> means a leaving group such as a halogen atom, e.g. a chlorine or bromine atom, a sulfonyloxy group such as a methane su Ifonyloxy or p-toluenesulfonyloxy group or a hydroxy group. With a compound of the general formula III where Z<1> means a hydroxy group, the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as e.g. triphenylphosphine/diethyl azodicarboxylate, suitably in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or ethylene glycol diethyl ether at temperatures between -50 and 150°C, but preferably at temperatures between -20 and 80°C. b) To prepare compounds of the general formula I where Rd means one of the optionally substituted alkyloxy groups mentioned above:

omsetning av en forbindelse med den generelle formel turnover of a compound with the general formula

hvor Ra, R<b>, R<c> og X er som ovenfor definert, med en forbindelse med den generelle formel where Ra, R<b>, R<c> and X are as defined above, with a compound of the general formula

hvor Rd betyr en d^-alkylgruppe, en metylgruppe substituert med 1 til 3 fluoratomer, en etylgruppe substituert med 1 til 5 fluoratomer, en C2-4-alkylgruppe substituert med en gruppe R<6> eller R<7>, hvor R6 og R7 er som ovenfor definert, en Ci^-alkylgruppe som er substituert med en pyrrolidinyl-, piperidinyl- eller homopiperidinylgruppe substituert i 1-stillingen med gruppen R<8 >eller en Ci-4-alkylgruppe som er substituert med en morfolinylgruppe substituert i 4-stillingen med gruppen R<8>, hvor R8 i hvert tilfelle er som ovenfor definert og where Rd means a C 1 -alkyl group, a methyl group substituted with 1 to 3 fluorine atoms, an ethyl group substituted with 1 to 5 fluorine atoms, a C 2-4 alkyl group substituted with a group R<6> or R<7>, where R 6 and R7 is, as defined above, a C1-4 alkyl group which is substituted with a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1-position with the group R<8 >or a C1-4 alkyl group which is substituted with a morpholinyl group substituted in 4 -position with the group R<8>, where R8 in each case is as defined above and

Z<2> betyr en utgående gruppe så som et halogenatom, en alkylsulfonyloksy-, arylsulfonyloksy- eller en hydroksygruppe. Z<2> means a leaving group such as a halogen atom, an alkylsulfonyloxy, arylsulfonyloxy or a hydroxy group.

Hvis den utgående gruppen er et halogenatom så som et klor-, brom- eller jodatom eller en alkylsulfonyloksy- eller arylsulfonyloksygruppe så som metan su Ifonyloksy- eller p-toluensulfonyloksygruppe, blir reaksjonen fortrinnsvis utført i nærvær av en organisk eller uorganisk base så som kaliumkarbonat, natriumhydrid eller N-etyl-diisopropylamin. Hvis den utgående gruppen er en hydroksygruppe blir reaksjonen utført i nærvær av et dehydratiseringsmiddel, fortrinnsvis i nærvær av et fosfin og et azodikarboksylsyrederivat så som f.eks. trifenylfosfin/dietyl-azodikarboksylat. If the leaving group is a halogen atom such as a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group such as methane su Ifonyloxy or p-toluenesulfonyloxy group, the reaction is preferably carried out in the presence of an organic or inorganic base such as potassium carbonate, sodium hydride or N-ethyl-diisopropylamine. If the leaving group is a hydroxy group, the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as e.g. triphenylphosphine/diethyl azodicarboxylate.

c) For å fremstille forbindelser med den generelle formel I hvor Rd betyr én av de ovennevnte alkyloksygrupper som er substituert med en eventuelt substituert c) To prepare compounds of the general formula I where Rd denotes one of the above-mentioned alkyloxy groups which is substituted with an optionally substituted

amino-, alkylamino- eller dialkylaminogruppe eller med en eventuelt substituert heterocyklisk gruppe bundet via et imino-nitrogenatom: amino, alkylamino or dialkylamino group or with an optionally substituted heterocyclic group attached via an imino nitrogen atom:

omsetning av en forbindelse med den generelle formel turnover of a compound with the general formula

hvor Ra, R<b>, R<c> og X er som ovenfor definert og Z<3> betyr en utgående gruppe så som et halogenatom, f.eks. et klor- eller bromatom eller en sulfonyloksygruppe så som en metansulfonyloksy- eller p-toluensulfonyloksygruppe, med ammoniakk, en tilsvarende, eventuelt substituert alkylamin-, dialkylamin-eller en imino-forbindelse eller egnede salter eller derivater derav, så som for eksempel morfolin. d) For å fremstille forbindelser med den generelle formel I hvor Rd betyr en hydroksygruppe: Spaltning av en beskyttelsesgruppe fra en forbindelse med den generelle formel where Ra, R<b>, R<c> and X are as defined above and Z<3> means a leaving group such as a halogen atom, e.g. a chlorine or bromine atom or a sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group, with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or suitable salts or derivatives thereof, such as for example morpholine. d) To prepare compounds of the general formula I where Rd means a hydroxy group: Cleavage of a protecting group from a compound of the general formula

hvor Ra, R<b>, R<c> og X er som ovenfor definert og Rd betyr en gruppe som kan omdannes til en hydroksygruppe, for eksempel en eventuelt substituert benzyloksygruppe, en trimetylsilyloksy-, acetyloksy-, benzoyloksy-, metoksy-, etoksy-, tert-butoksy- eller trityloksygruppe. where Ra, R<b>, R<c> and X are as defined above and Rd means a group that can be converted into a hydroxy group, for example an optionally substituted benzyloxy group, a trimethylsilyloxy-, acetyloxy-, benzoyloxy-, methoxy-, ethoxy, tert-butoxy or trityloxy group.

Beskyttelsesgruppen blir spaltet ved for eksempel hydrolyse i et vandig løsningsmiddel, f.eks. i vann, isopropanol/vann, eddiksyre/vann, tetrahydrofuran/vann eller dioksan/vann, i nærvær av en syre så som trifluoreddiksyre, saltsyre eller svovelsyre eller i nærvær av en alkalimetall-base så som natriumhydroksyd eller kaliumhydroksyd eller aprotisk, f.eks. i nærvær av jodtrimetylsilan, ved temperaturer mellom 0 og 120°C, fortrinnsvis ved temperaturer mellom 10 og 100°C. The protecting group is cleaved by, for example, hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. . in the presence of iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C.

Imidlertid blir en benzyl- eller metoksybenzylgruppe spaltet, for eksempel hydrogenolytisk, f.eks. med hydrogen i nærvær av en katalysator så som palladium/trekull i et egnet løsningsmiddel så som metanol, etanol, etylacetat eller iseddik, eventuelt med tilsetning av en syre så som saltsyre ved temperaturer mellom 0 og 100°C, men fortrinnsvis ved omgivelsestemperaturer mellom 20 og 60°C og ved et hydrogentrykk på 1 til 7 bar, men fortrinnsvis 3 til 5 bar. En 2,4-dimetoksybenzylgruppe blir imidlertid fortrinnsvis spaltet i trifluoreddiksyre i nærvær av anisol. However, a benzyl or methoxybenzyl group is cleaved, for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, but preferably at ambient temperatures between 20 and 60°C and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.

En tert.butyl- eller benzylgruppe blir spaltet ved for eksempel behandling med en syre så som trifluoreddiksyre, saltsyre eller bromhydrogensyre eller ved behandling med jodtrimetylsilan, eventuelt ved anvendelse av et løsningsmiddel så som metylenklorid, dioksan, metanol eller dietyleter. e) For å fremstille forbindelser med den generelle formel I hvor R<c> inneholder en -NH- gruppe: spaltning av en beskyttelsesgruppe fra en forbindelse med den generelle formel A tert.butyl or benzyl group is cleaved by, for example, treatment with an acid such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid or by treatment with iodotrimethylsilane, optionally by using a solvent such as methylene chloride, dioxane, methanol or diethyl ether. e) To prepare compounds of the general formula I where R<c> contains an -NH- group: cleavage of a protecting group from a compound of the general formula

hvor Ra, R<b>, Rd og X er som ovenfor definert og R<c> har betydningene gitt for Rc ovenfor, med det forbehold at R<c> inneholder et beskyttet nitrogenatom. where Ra, R<b>, Rd and X are as defined above and R<c> has the meanings given for Rc above, with the proviso that R<c> contains a protected nitrogen atom.

Konvensjonelle beskyttelsesgrupper for en amino-, alkylamino- eller imino-gruppe er for eksempel en formyl-, acetyl-, trifluoracetyl-, etoksykarbonyl-, tert.-butoksykarbonyl-, benzyloksykarbonyl-, benzyl-, metoksybenzyl- eller 2,4-dimetoksybenzylgruppe, mens for aminogruppen en ftalylgruppe er en ytterligere mulighet. Conventional protecting groups for an amino, alkylamino or imino group are, for example, a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, while for the amino group a phthalyl group is a further possibility.

Beskyttelsesgruppen blir spaltet ved for eksempel hydrolyse i et vandig løsningsmiddel, f.eks. i vann, isopropanol/vann, eddiksyre/vann, tetrahydrofuran/vann eller dioksan/vann, i nærvær av en syre så som trifluoreddiksyre, saltsyre eller svovelsyre eller i nærvær av en alkalimetall-base så som natriumhydroksyd eller kaliumhydroksyd eller aprotisk, f.eks. i nærvær av jodtrimetylsilan, ved temperaturer mellom 0 og 120°C, fortrinnsvis ved temperaturer mellom 10 og 100°C. The protecting group is cleaved by, for example, hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. . in the presence of iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C.

Imidlertid blir en benzyl-, metoksybenzyl- eller benzyloksykarbonylgruppe spaltet, for eksempel hydrogenolytisk, f.eks. med hydrogen i nærvær av en katalysator så som palladium/trekull i et egnet løsningsmiddel så som metanol, etanol, etylacetat eller iseddik, eventuelt med tilsetning av en syre så som saltsyre ved temperaturer mellom 0 og 100°C, men fortrinnsvis ved omgivelsestemperaturer mellom 20 og 60°C og ved et hydrogentrykk på 1 til 7 bar, men fortrinnsvis 3 til 5 bar. En 2,4-dimetoksybenzylgruppe blir imidlertid fortrinnsvis spaltet i trifluoreddiksyre i nærvær av anisol. However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, but preferably at ambient temperatures between 20 and 60°C and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.

En tert.butyl- eller tert.butyloksykarbonylgruppe blir fortrinnsvis spaltet ved behandling med en syre så som trifluoreddiksyre eller saltsyre eller ved behandling med jodtrimetylsilan eventuelt ved anvendelse av et løsningsmiddel så som metylenklorid, dioksan, metanol eller dietyleter. A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally by using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

En trifluoracetylgruppe blir fortrinnsvis spaltet ved behandling med en syre så som saltsyre, eventuelt i nærvær av et løsningsmiddel så som eddiksyre ved temperaturer mellom 50 og 120°C eller ved behandling med natriumhydroksyd-løsning, eventuelt i nærvær av et løsningsmiddel så som tetrahydrofuran ved temperaturer mellom 0 og 50°C. A trifluoroacetyl group is preferably cleaved by treatment with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120°C or by treatment with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50°C.

En ftalylgruppe blir fortrinnsvis spaltet i nærvær av hydrazin eller et primært amin så som metylamin, etylamin eller n-butylamin i et løsningsmiddel så som metanol, etanol, isopropanol, toluen/vann eller dioksan ved temperaturer mellom 20 og 50°C. A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50°C.

f) For å fremstille forbindelser med den generelle formel I hvor R<c> inneholder en alkylgruppe substituert med en eventuelt substituert amino-, alkylamino- eller f) To prepare compounds of the general formula I where R<c> contains an alkyl group substituted with an optionally substituted amino-, alkylamino- or

dialkyaminogruppe eller med en eventuelt substituert heterocyklisk gruppe bundet via et nitrogenatom: dialkylamino group or with an optionally substituted heterocyclic group attached via a nitrogen atom:

omsetning av en forbindelse med den generelle formel turnover of a compound with the general formula

hvor Ra, R<b>, Rd og X er som ovenfor definert, Z<3> betyr en utgående gruppe, for eksempel et halogenatom så som et klor- eller bromatom eller en sulfonyloksygruppe så som en metansulfonyloksy- eller p-toluensulfonyloksygruppe og R<c> har betydningene gitt for R<c> ovenfor med det forbehold at et hydrogenatom bundet til et alifatisk karbonatom er erstattet med gruppen Z<3>, where Ra, R<b>, Rd and X are as defined above, Z<3> means a leaving group, for example a halogen atom such as a chlorine or bromine atom or a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group and R <c> has the meanings given for R<c> above with the proviso that a hydrogen atom bonded to an aliphatic carbon atom is replaced by the group Z<3>,

med ammoniakk, en tilsvarende, eventuelt substituert alkylamin-, dialkylamin-eller en imino-forbindelse eller de passende salter eller derivater derav, så som with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or the appropriate salts or derivatives thereof, such as

for eksempel morfolin. for example, morpholine.

Hvis det ifølge oppfinnelsen blir oppnådd en forbindelse med den generelle formel I som inneholder en amino-, alkylamino- eller imino-gruppe, kan denne omdannes ved acylering, cyanering eller sulfonylering til en tilsvarende acyl-, cyano- eller sulfonylforbindelse med den generelle formel I, idet acyleringsmidler for eksempel kan være isocyanat, karbamoylklorid, karboksylsyrehalogenid, karboksylsyreanhydrid og karboksylsyrer med aktiverende midler så som N,N'-karbonyldiimidazol, N,N'-dicykloheksylkarbodiimid eller 0-(benzotriazol-1-yl)-N,N,N'N'-tetrametyluronium-tetrafluorborat, idet sulfonyleringsmidler kan være sulfonylhalogenider og cyaneringsmidler kan være klor eller bromcyanogen og/eller If, according to the invention, a compound of the general formula I is obtained which contains an amino, alkylamino or imino group, this can be converted by acylation, cyanation or sulfonylation into a corresponding acyl, cyano or sulfonyl compound of the general formula I , as acylating agents can for example be isocyanate, carbamoyl chloride, carboxylic acid halide, carboxylic anhydride and carboxylic acids with activating agents such as N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide or 0-(benzotriazol-1-yl)-N,N,N 'N'-tetramethyluronium tetrafluoroborate, the sulfonylating agents can be sulfonyl halides and the cyanating agents can be chlorine or bromocyanogen and/or

hvis det blir oppnådd en forbindelse med den generelle formel I som inneholder en amino-, alkylamino- eller iminogruppe, kan denne omdannes ved alkylering eller reduktiv alkylering til en tilsvarende alkylforbindelse med den generelle formel I og/eller if a compound of the general formula I containing an amino, alkylamino or imino group is obtained, this can be converted by alkylation or reductive alkylation into a corresponding alkyl compound of the general formula I and/or

hvis det blir oppnådd en forbindelse med den generelle formel I som inneholder en klor-Ci-4-alkylsulfonyl- eller brom-Ci-4-alkylsulfonylgruppe, kan denne omdannes ved omsetning med et amin til en tilsvarende amino-Ci^-alkylsulfonylforbindelse if a compound of the general formula I containing a chloro-C1-4-alkylsulfonyl or bromo-C1-4-alkylsulfonyl group is obtained, this can be converted by reaction with an amine into a corresponding amino-C1-4-alkylsulfonyl compound

og/eller and or

hvis det blir oppnådd en forbindelse med den generelle formel I som inneholder en tert.-butyloksykarbonylamino-, N-alkyl-N-(tert.-butyloksykarbonyl)amino- eller en N-tert.-butyloksykarbonylimino-gruppe, kan denne omdannes til en tilsvarende amino-, alkylamino- eller imino-forbindelse med den generelle formel I ved behandling med en syre så som saltsyre eller trifluoreddiksyre. if a compound of the general formula I containing a tert-butyloxycarbonylamino, N-alkyl-N-(tert-butyloxycarbonyl)amino or an N-tert-butyloxycarbonylimino group is obtained, this can be converted into a corresponding amino, alkylamino or imino compound of the general formula I by treatment with an acid such as hydrochloric acid or trifluoroacetic acid.

I reaksjonene beskrevet ovenfor kan hvilke som helst reaktive grupper til stede så som hydroksy-, karboksy- eller iminogrupper beskyttes under reaksjonen med konvensjonelle beskyttelsesgrupper som blir avspaltet igjen etter reaksjonen. In the reactions described above, any reactive groups present such as hydroxy, carboxy or imino groups can be protected during the reaction with conventional protecting groups which are cleaved off again after the reaction.

For eksempel kan en beskyttelsesgruppe for en hydroksygruppe være en trimetylsilyl-, acetyl-, trityl-, benzyl- eller tetrahydropyranylgruppe. For example, a protecting group for a hydroxy group can be a trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

Beskyttelsesgrupper for en amino-, alkylamino- eller imino-gruppe kan for eksempel være en formyl-, acetyl-, trifluoracetyl-, etoksykarbonyl-, tert.butoksykarbonyl-, benzyloksykarbonyl-, benzyl-, metoksybenzyl- eller 2,4-dimetoksybenzylgruppe. Protecting groups for an amino, alkylamino or imino group can for example be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.

Hvilken som helst beskyttelsesgruppe anvendt blir eventuelt deretter avspaltet for eksempel ved hydrolyse i et vandig løsningsmiddel, f.eks. i vann, isopropanol/vann, eddiksyre/vann, tetrahydrofuran/vann eller dioksan/vann, i nærvær av en syre så som trifluoreddiksyre, saltsyre eller svovelsyre eller i nærvær av en alkalimetallbase så som natriumhydroksyd eller kaliumhydroksyd eller aprotisk, f.eks. i nærvær av jodtrimetylsilan, ved temperaturer mellom 0 og 120°C, fortrinnsvis ved temperaturer mellom 10 og 100°C. Any protective group used is optionally then cleaved off, for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C.

Imidlertid blir en benzyl-, metoksybenzyl- eller benzyloksykarbonylgruppe spaltet, for eksempel hydrogenolytisk, f.eks. med hydrogen i nærvær av en katalysator så som palladium/trekull i et egnet løsningsmiddel så som metanol, etanol, etylacetat eller iseddik, eventuelt med tilsetning av en syre så som saltsyre ved temperaturer mellom 0 og 100°C, men fortrinnsvis ved omgivelsestemperaturer mellom 20 og 60°C og ved et hydrogentrykk på 1 til 7 bar, men fortrinnsvis 3 til 5 bar. En 2,4-dimetoksybenzylgruppe blir imidlertid fortrinnsvis spaltet i trifluoreddiksyre i nærvær av anisol. However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, but preferably at ambient temperatures between 20 and 60°C and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.

En tert.butyl- eller tert.butyloksykarbonylgruppe blir fortrinnsvis avspaltet ved behandling med en syre så som trifluoreddiksyre eller saltsyre eller ved behandling med jodtrimetylsilan eventuelt ved anvendelse av et løsningsmiddel så som metylenklorid, dioksan, metanol eller dietyleter. A tert.butyl or tert.butyloxycarbonyl group is preferably split off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally by using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

En trifluoracetylgruppe blir fortrinnsvis avspaltet ved behandling med en syre så som saltsyre, eventuelt i nærvær av et løsningsmiddel så som eddiksyre ved temperaturer mellom 50 og 120°C eller ved behandling med natriumhydroksyd-løsning, eventuelt i nærvær av et løsningsmiddel så som tetrahydrofuran ved temperaturer mellom 0 og 50°C. A trifluoroacetyl group is preferably cleaved by treatment with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120°C or by treatment with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50°C.

Videre kan de oppnådde forbindelsene med den generelle formel I spaltes i deres enantiomerer og/eller diastereomerer, som nevnt ovenfor. Således kan for eksempel cis/trans-blandinger spaltes i deres cis- og trans-isomerer og forbindelser med minst ett optisk aktivt karbonatom kan separeres i deres enantiomerer. Furthermore, the obtained compounds of the general formula I can be resolved into their enantiomers and/or diastereomers, as mentioned above. Thus, for example, cis/trans mixtures can be resolved into their cis and trans isomers and compounds with at least one optically active carbon atom can be separated into their enantiomers.

Således kan for eksempel cis/trans-blandingene spaltes ved kromatografi til cis-og trans-isomerer derav, forbindelsene med den generelle formel I oppnådd som racemater kan separeres ved metoder kjent per se (kfr. Allinger N. L. og Eliel E. L. i "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) i deres optiske antipoder og forbindelser med den generelle formel I med minst 2 asymmetriske karbonatomer kan spaltes i deres diastereomerer på basis av deres fysisk-kjemiske forskjeller ved anvendelse av metoder kjent per se, f.eks. ved kromatografi og/eller fraksjonert krystallisasjon og, hvis disse forbindelser blir oppnådd i racemisk form, kan de deretter spaltes til enantiomerene som nevnt ovenfor. Thus, for example, the cis/trans mixtures can be resolved by chromatography into their cis- and trans-isomers, the compounds of the general formula I obtained as racemates can be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of the general formula I with at least 2 asymmetric carbon atoms can be resolved into their diastereomers on the basis of their physicochemical differences using methods known per se, e.g. e.g. by chromatography and/or fractional crystallization and, if these compounds are obtained in racemic form, they can then be resolved into the enantiomers as mentioned above.

Enantiomerene blir fortrinnsvis separert ved kolonne-separering på chirale faser eller ved omkrystallisering fra et optisk aktivt løsningsmiddel eller ved omsetning med en optisk aktiv substans som danner salter eller derivater så som f.eks. estere eller amider med den racemiske forbindelse, spesielt syrer og de aktiverte derivater eller alkoholer derav og separering av diastereomer-blandingen av salter eller derivater således oppnådd, f.eks. på basis av deres forskjeller i oppløselighet, mens de frie antipoder kan frigjøres fra de rene diastereomere salter eller derivater ved virkningen av egnede midler. Optisk aktive syrer i vanlig anvendelse er f.eks. D- og L-formene av vinsyre eller dibenzoylvinsyre, di-o-tolylvinsyre, eplesyre, mandelsyre, kamfersulfonsyre, glutaminsyre, asparaginsyre eller kininsyre. En optisk aktiv alkohol kan for eksempel være (+)- eller (-)-mentol og en optisk aktiv acylgruppe i amider kan for eksempel være (+)- eller (-)-mentyloksykarbonyl. The enantiomers are preferably separated by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance that forms salts or derivatives such as e.g. esters or amides with the racemic compound, especially acids and the activated derivatives or alcohols thereof and separation of the diastereomer mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, while the free antipodes may be liberated from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. The D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol can, for example, be (+)- or (-)-menthol and an optically active acyl group in amides can, for example, be (+)- or (-)-menthyloxycarbonyl.

Videre kan forbindelsene med formel I omdannes til saltene derav, spesielt for farmasøytisk anvendelse til de fysiologisk akseptable salter med uorganiske eller organiske syrer. Syrer som kan anvendes for dette formål omfatter for eksempel saltsyre, bromhydrogensyre, svovelsyre, metansulfonsyre, fosforsyre, fumarsyre, ravsyre, melkesyre, sitronsyre, vinsyre eller maleinsyre. Furthermore, the compounds of formula I can be converted into their salts, especially for pharmaceutical use into the physiologically acceptable salts with 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.

Forbindelsene med de generelle formlene II til I anvendt som utgangsmaterialer er kjent fra litteraturen i noen tilfeller, eller kan oppnås ved metoder kjent fra litteraturen (kfr. Eksempler I til XXII) eller metodene beskrevet ovenfor, eventuelt med ytterligere anvendelse av beskyttelsesgrupper (f.eks. forbindelser med formel IV eller VII og VIII). The compounds with the general formulas II to I used as starting materials are known from the literature in some cases, or can be obtained by methods known from the literature (cf. Examples I to XXII) or the methods described above, optionally with the additional use of protecting groups (e.g. .compounds of formula IV or VII and VIII).

Som allerede nevnt ovenfor har forbindelsene med den generelle formel I ifølge oppfinnelsen og de fysiologisk akseptable salter derav verdifulle farmakologiske egenskaper, spesielt en hemmende effekt på signaltransduksjon mediert av Epidermal Vekstfaktor-reseptor (EGF-R), idet dette kan oppnås ved for eksempel å hemme ligandbinding, reseptor-dimerisering eller tyrosinkinase selv. Det er også mulig at transmisjon av signaler til komponenter lokalisert videre ned blir blokkert. As already mentioned above, the compounds of the general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, in particular an inhibitory effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R), as this can be achieved by, for example, inhibiting ligand binding, receptor dimerization or tyrosine kinase itself. It is also possible that the transmission of signals to components located further down is blocked.

De biologiske egenskapene til de nye forbindelsene ble undersøkt som følger: Hemning av human EGF-reseptor kinase ble bestemt ved anvendelse av cytoplasmatisk tyrosinkinase-domene (metionin 664 til alanin 1186 basert på sekvensen publisert i Nature 309 (1984), 418). For dette ble proteinet uttrykt i Sf9 insektceller som GST-fusjonsprotein ved anvendelse av Baculovirus-ekspresjonssystem. The biological properties of the new compounds were investigated as follows: Inhibition of human EGF receptor kinase was determined using the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186 based on the sequence published in Nature 309 (1984), 418). For this, the protein was expressed in Sf9 insect cells as GST fusion protein using Baculovirus expression system.

Enzymaktiviteten ble målt i nærvær eller fravær av testforbindelsene i serie-fortynninger. Polymeren pEY (4:1) oppnådd fra SIGMA ble anvendt som substrat. Biotinylert pEY (bio-pEY) ble tilsatt som tracer-substrat. 100 ul av reaksjonsløsningen inneholdt 10 ul av inhibitoren i 50% DMSO, 20 ul av substratløsning (200 mM HEPES pH 7,4, 50 mM magnesiumacetat, 2,5 mg/ml poly(EY), 5 ug/ml bio-pEY) og 20 ul av enzympreparat. Enzymreaksjonen ble startet ved tilsetning av 50 ul av en 100 uM ATP-løsning i 10 mM av magnesiumklorid. Fortynning av enzympreparatet ble regulert slik at innføring av fosfat i bio-pEY ble lineær når det gjelder tid og mengde av enzym. Enzympreparatet ble fortynnet i 20 mM HEPES pH 7,4, 1 mM EDTA, 130 mM vanlig salt, 0,05% Triton X-100, 1 mM DTT og 10% glycerol. Enzyme activity was measured in the presence or absence of the test compounds in serial dilutions. The polymer pEY (4:1) obtained from SIGMA was used as substrate. Biotinylated pEY (bio-pEY) was added as a tracer substrate. 100 µl of the reaction solution contained 10 µl of the inhibitor in 50% DMSO, 20 µl of substrate solution (200 mM HEPES pH 7.4, 50 mM magnesium acetate, 2.5 mg/ml poly(EY), 5 µg/ml bio-pEY) and 20 µl of enzyme preparation. The enzyme reaction was started by adding 50 µl of a 100 µM ATP solution in 10 mM magnesium chloride. Dilution of the enzyme preparation was regulated so that the introduction of phosphate into bio-pEY was linear in terms of time and amount of enzyme. The enzyme preparation was diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM normal salt, 0.05% Triton X-100, 1 mM DTT and 10% glycerol.

Enzymforsøket ble utført ved omgivelsestemperatur over en periode på 30 minutter og endte ved tilsetning av 50 ul som en stoppløsning (250 mM EDTA i 20 mM HEPES pH 7,4). 100 ul ble plassert på en streptavidin-belagt mikrotiter-plate og inkubert i 60 minutter ved omgivelsestemperatur. Deretter ble platen vasket med 200 ul av en vaskeløsning (50 mM Tris, 0,05% Tween 20). Etter tilsetning av 100 ul av et HRPO-merket anti-PY antistoff (PY20H Anti-PTyr:HRP fremstilt av Transduction Laboratories, 250 ng/ml) ble formuleringen inkubert i 60 minutter. Deretter ble mikrotiter-platen vasket tre ganger med 200 ul av vaskeløsning. Prøvene ble deretter kombinert med 100 ul av en TMB-peroksydase-løsning (A:B = 1:1, Kirkegaard Perry Laboratories). Etter 10 minutter ble reaksjonen stanset. Ekstinksjonen ble målt ved OD450nm med en ELISA leser. Alle resultatene ble målt tre ganger. The enzyme assay was performed at ambient temperature over a period of 30 minutes and terminated by the addition of 50 µl as a stop solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 µl was placed on a streptavidin-coated microtiter plate and incubated for 60 min at ambient temperature. Then the plate was washed with 200 µl of a washing solution (50 mM Tris, 0.05% Tween 20). After addition of 100 µl of an HRPO-labeled anti-PY antibody (PY20H Anti-PTyr:HRP manufactured by Transduction Laboratories, 250 ng/ml), the formulation was incubated for 60 minutes. Then the microtiter plate was washed three times with 200 µl of washing solution. The samples were then combined with 100 µl of a TMB peroxidase solution (A:B = 1:1, Kirkegaard Perry Laboratories). After 10 minutes the reaction was stopped. Extinction was measured at OD450nm with an ELISA reader. All results were measured three times.

Dataene ble tilpasset iterativ beregning ved anvendelse av et analyse-pogram for sigmoidale kurver (Graph Pad Prism Versjon 3.0) med variabel Hill pitch. Alle de gjentatte data produsert hadde en korrelasjonskoeffisient på mer enn 0,9 og de øvre og nedre verdier av kurvene viste en spredning med minst en faktor på 5. Konsentrasjonen av den aktive substans som hemmer aktiviteten til EGF-reseptor-kinase med 50% (IC50) ble avledet fra kurvene. The data were adapted to iterative calculation using an analysis program for sigmoidal curves (Graph Pad Prism Version 3.0) with variable Hill pitch. All the repeated data produced had a correlation coefficient of more than 0.9 and the upper and lower values of the curves showed a spread of at least a factor of 5. The concentration of the active substance that inhibits the activity of EGF receptor kinase by 50% ( IC50) was derived from the curves.

De følgende resultater ble oppnådd: The following results were obtained:

Forbindelsene med den generelle formel I ifølge oppfinnelsen hemmer således signaltransduksjon av tyrosinkinaser, som demonstrert ved eksemplet på den humane EGF-reseptor og er derfor anvendelige for fremstilling av medikamenter for behandling av patofysiologiske prosesser forårsaket av hyperfunksjon av tyrosinkinaser. Disse er f.eks. godartede eller ondartede tumorer, spesielt tumorer av epitelial og neuroepitelial opprinnelse, metastasering og unormal proliferasjon av vaskulære endotel-celler (neoangiogenese). The compounds of the general formula I according to the invention thus inhibit signal transduction of tyrosine kinases, as demonstrated by the example of the human EGF receptor and are therefore applicable for the production of drugs for the treatment of pathophysiological processes caused by hyperfunction of tyrosine kinases. These are e.g. benign or malignant tumors, especially tumors of epithelial and neuroepithelial origin, metastasis and abnormal proliferation of vascular endothelial cells (neoangiogenesis).

Forbindelsene ifølge oppfinnelsen er også anvendelige for fremstilling av medikamenter for forhindring og behandling av sykdommer i luftveiene og lungene som blir ledsaget av øket eller endret produksjon av slim forårsaket av stimulering av tyrosinkinaser, f.eks. ved inflammatoriske sykdommer i luftveiene så som kronisk bronkitt, kronisk obstruktiv bronkitt, astma, bronkiektasi, allergisk eller ikke-allergisk rhinitt eller sinusitt, cystisk fibrose, a1-antitrypsin-mangel eller hoste, pulmonalt emfysem, pulmonal fibrose og hyperreaktive luftveier. The compounds according to the invention are also applicable for the production of drugs for the prevention and treatment of diseases in the respiratory tract and lungs which are accompanied by increased or altered production of mucus caused by stimulation of tyrosine kinases, e.g. in inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, a1-antitrypsin deficiency or cough, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.

Forbindelsene er også egnet for fremstilling av medikamenter for behandling av sykdommer i mave-tarm-kanalen og gallegang og galleblære som er forbundet med avbrutt aktivitet til tyrosinkinaser, så som kan finnes ved f.eks. kronisk inflammatoriske endringer så som cholecystitt, Crohn's sykdom, ulcerativ kolitt og ulcere i mave-tarm-kanalen eller så som kan forekomme ved sykdommer i mave-tarm-kanalen som er forbundet med økede sekresjoner, så som Ménétrier's sykdom, sekreterende adenomer og proteintap-syndrom. The compounds are also suitable for the production of drugs for the treatment of diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with interrupted activity of tyrosine kinases, such as can be found in e.g. chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract associated with increased secretions, such as Ménétrier's disease, secretory adenomas and protein loss syndrome.

I tillegg kan forbindelsene med den generelle formel I og de fysiologisk akseptable salter derav anvendes for fremstilling av medikamenter for å behandle andre sykdommer forårsaket av unormal funksjon av tyrosinkinaser, så som f.eks. epidermal hyperproliferasjon (psoriasis), godartet prostata hyperplasi (BPH), inflammatoriske prosesser, sykdommer i immunsystemet, hyperproliferasjon av hematopoetiske celler, behandling av nasale polypper, etc. In addition, the compounds of the general formula I and the physiologically acceptable salts thereof can be used for the preparation of medicaments to treat other diseases caused by abnormal function of tyrosine kinases, such as e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, treatment of nasal polyps, etc.

På grunn av deres biologiske egenskaper kan forbindelsene anvendes alene eller sammen med andre farmakologisk aktive forbindelser, for eksempel ved tumorterapi, som monoterapi eller sammen med andre anti-tumor terapeutiske midler, for eksempel i kombinasjon med topoisomerase-inhibitorer (f.eks. etoposid), mitose-inhibitorer (f.eks. vinblastin), forbindelser som interagerer med nukleinsyrer (f.eks. cisplatin, cyklofosfamid, adriamycin), hormon-antagonister (f.eks. tamoxifen), inhibitorer av metabolske prosesser (f.eks. 5-FU etc), cytokiner (f.eks. interferoner), antistoffer, etc. For behandling av luftveissykdommer kan disse forbindelser anvendes alene eller sammen med andre terapeutiske midler for luftveiene, så som substanser med sekretolytisk (f.eks. ambroxol, N-acetylcystein), bronkolytisk (f.eks. tiotropium eller ipratropium eller fenoterol, salmeterol, salbutamol) og/eller anti-inflammatorisk aktivitet (f.eks. teofyllin eller glukokortikoider). For behandling av sykdommer i regionen av mave-tarm-kanalen, kan disse forbindelser også administreres alene eller sammen med substanser som har en effekt på motilitet eller sekresjon. Disse kombinasjoner kan administreres enten samtidig eller sekvensielt. Due to their biological properties, the compounds can be used alone or together with other pharmacologically active compounds, for example in tumor therapy, as monotherapy or together with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide) , mitosis inhibitors (e.g. vinblastine), compounds that interact with nucleic acids (e.g. cisplatin, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5 -FU etc), cytokines (e.g. interferons), antibodies, etc. For the treatment of respiratory diseases, these compounds can be used alone or together with other therapeutic agents for the respiratory tract, such as substances with secretolytic (e.g. ambroxol, N- acetylcysteine), broncholytic (eg tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and/or anti-inflammatory activity (eg theophylline or glucocorticoids). For the treatment of diseases in the region of the gastrointestinal tract, these compounds can also be administered alone or together with substances that have an effect on motility or secretion. These combinations can be administered either simultaneously or sequentially.

Disse forbindelser kan administreres enten alene eller sammen med andre aktive substanser ved intravenøs, subkutan, intramuskulær, intraperitoneal eller intranasal rute, ved inhalering eller transdermalt eller oralt, idet aerosol-preparater er spesielt egnet for inhalering. These compounds can be administered either alone or together with other active substances by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation or transdermally or orally, aerosol preparations being particularly suitable for inhalation.

For farmasøytisk anvendelse blir forbindelsene ifølge oppfinnelsen generelt anvendt for varmblodige virveldyr, spesielt mennesker, i doser på 0,01- For pharmaceutical use, the compounds according to the invention are generally used for warm-blooded vertebrates, especially humans, in doses of 0.01-

100 mg/kg kroppsvekt, fortrinnsvis 0,1-15 mg/kg. For administrering blir de formulert med én eller flere konvensjonelle inerte bærere og/eller fortynningsmidler, f.eks. med maisstivelse, laktose, glukose, mikrokrystallinsk cellulose, magnesiumstearat, polyvinylpyrrolidon, sitronsyre, vinsyre, vann, vann/etanol, vann/glycerol, vann/sorbitol, vann/polyetylenglykol, propylenglykol, stearylalkohol, karboksymetylcellulose eller fett-substanser så som hardt fett eller egnede blandinger derav i konvensjonelle galeniske preparater så som ubehandlede eller belagte tabletter, kapsler, pulvere, suspensjoner, løsninger, spray-preparater eller suppositorier. 100 mg/kg body weight, preferably 0.1-15 mg/kg. For administration, they are formulated with one or more conventional inert carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as untreated or coated tablets, capsules, powders, suspensions, solutions, spray preparations or suppositories.

De følgende Eksempler skal illustrere foreliggende oppfinnelse: The following Examples shall illustrate the present invention:

Fremstilling av utgangsforbindelsene: Preparation of the output compounds:

Eksempel I Example I

4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-benzyloksy-kinazolin-hydroklorid 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline hydrochloride

En blanding av 10,84 g 4-klor-6-(tetrahydropyran-4-yloksy)-7-benzyloksy-kinazolin og 4,50 g 3-klor-4-fluoranilin i 300 ml isopropanol blir tilbakeløpskokt i fire timer og får deretter stå natten over ved omgivelsestemperatur. Fellingen dannet blir sugefiltrert, vasket med isopropanol og omrørt med 150 ml metanol. Suspensjonen blir omrørt i ytterligere en halv time ved omgivelsestemperatur og deretter sugefiltrert. Filterkaken blir vasket gjentatte ganger med metanol og A mixture of 10.84 g of 4-chloro-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline and 4.50 g of 3-chloro-4-fluoroaniline in 300 ml of isopropanol is refluxed for four hours and then given stand overnight at room temperature. The precipitate formed is suction filtered, washed with isopropanol and stirred with 150 ml of methanol. The suspension is stirred for a further half hour at ambient temperature and then suction filtered. The filter cake is washed repeatedly with methanol and

tørket. dried.

Utbytte: 9,07 g (60 % av teoretisk) Yield: 9.07 g (60% of theoretical)

Rf verdi: 0,27 (silikagel, cykloheksan/etylacetat = 1:1) Rf value: 0.27 (silica gel, cyclohexane/ethyl acetate = 1:1)

Massespektrum (ESI ): m/z = 478, 480 [M-H]" Mass spectrum (ESI ): m/z = 478, 480 [M-H]"

De følgende forbindelser blir oppnådd analogt med Eksempel I: The following compounds are obtained analogously to Example I:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-tetrahydrofuran-3-yloksy)-7-benzyloksy-kinazolin-hydroklorid (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-quinazoline hydrochloride

Rf verdi: 0,34 (silikagel, cykloheksan/etylacetat = 1:1) Rf value: 0.34 (silica gel, cyclohexane/ethyl acetate = 1:1)

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

(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-trifluoracetyl-piperidin-4-yloksy)-kinazolin-hydroklorid (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline hydrochloride

Rf verdi: 0,17 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.17 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 469, 471 [M+H]<+>Mass spectrum (ESI<+>): m/z = 469, 471 [M+H]<+>

(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-trifluoracetyl-piperidin-4-yloksy)-7-acetoksy-kinazolin-hydroklorid (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxyquinazoline hydrochloride

Rf verdi: 0,70 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) Rf value: 0.70 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 90:10:1)

Massespektrum (ESI<+>): m/z = 527, 529 [M+H]<+>Mass spectrum (ESI<+>): m/z = 527, 529 [M+H]<+>

(4) 4-[(3-etynyl-fenyl)amino]-6-acetoksy-7-metoksy-kinazolin Rf verdi: 0,59 (silikagel, etylacetat) (4) 4-[(3-ethynyl-phenyl)amino]-6-acetoxy-7-methoxyquinazoline Rf value: 0.59 (silica gel, ethyl acetate)

Massespektrum (ESI<+>): m/z = 334 [M+H]<+>Mass spectrum (ESI<+>): m/z = 334 [M+H]<+>

Eksempel II Example II

4-klor-6-(tetrahydropyran-4-yloksy)-7-benzyloksy-kinazolin Fremstilt ved omsetning av 6-(tetrahydropyran-4-yloksy)-7-benzyloksy-3H-kinazolin-4-on med tionylklorid i nærvær av N,N-dimetylformamid i acetonitril ved tilbakeløpstemperatur. 4-chloro-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline Prepared by reaction of 6-(tetrahydropyran-4-yloxy)-7-benzyloxy-3H-quinazolin-4-one with thionyl chloride in the presence of N ,N-dimethylformamide in acetonitrile at reflux temperature.

Rf verdi: 0,90 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.90 (silica gel, ethyl acetate/methanol = 9:1)

De følgende forbindelser blir oppnådd analogt med Eksempel II: The following compounds are obtained analogously to Example II:

(1) 4-klor-6-((S)-tetrahydrofuran-3-yloksy)-7-benzyloksy-kinazolin Rf verdi: 0,85 (silikagel, etylacetat/metanol = 9:1) (2) 4-klor-6-(1 -trifluoracetyl-piperidin-4-yloksy)-kinazolin Rf verdi: 0,92 (silikagel, etylacetat) (3) 4-klor-6-(1-trifluoracetyl-piperidin-4-yloksy)-7-acetoksy-kinazolin Eksempel III (1) 4-chloro-6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-quinazoline Rf value: 0.85 (silica gel, ethyl acetate/methanol = 9:1) (2) 4-chloro- 6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline Rf value: 0.92 (silica gel, ethyl acetate) (3) 4-chloro-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy -quinazoline Example III

6-(tetrahydropyran-4-yloksy)-7-benzyloksy-3/-/-kinazolin-4-on En blanding av 15,08 g 2-amino-4-benzyloksy-5-(tetrahydropyran-4-yloksy)-benzosyre og 14,40 g formamidin-acetat i 250 ml absolutt etanol blir tilbakeløpskokt natten over. Den avkjølte reaksjonsblandingen blir kombinert med 250 ml vann. Fellingen dannet blir sugefiltrert og tørket ved 70°C i tørkeskap. 6-(tetrahydropyran-4-yloxy)-7-benzyloxy-3/-/-quinazolin-4-one A mixture of 15.08 g of 2-amino-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid and 14.40 g of formamidine acetate in 250 ml of absolute ethanol are refluxed overnight. The cooled reaction mixture is combined with 250 ml of water. The precipitate formed is suction filtered and dried at 70°C in a drying cabinet.

Utbytte: 10,00 g (65 % av teoretisk) Yield: 10.00 g (65% of theoretical)

Rf verdi: 0,40 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.40 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 353 [M+H]<+>Mass spectrum (ESI<+>): m/z = 353 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel III: The following compounds are obtained analogously to Example III:

(1) 6-((S)-tetrahydrofuran-3-yloksy)-7-benzyloksy-3H-kinazolin-4-on Rf verdi: 0,60 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) (1) 6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-3H-quinazolin-4-one Rf value: 0.60 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water / trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 339 [M+H]<+>Mass spectrum (ESI<+>): m/z = 339 [M+H]<+>

(2) 6-[1-(tert.-butyloksykarbonyl)-piperidin-4-yloksy]-3H-kinazolin-4-on Rf verdi: 0,48 (silikagel, etylacetat/metanol = 9:1) (2) 6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-3H-quinazolin-4-one Rf value: 0.48 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 346 [M+H]<+>Mass spectrum (ESI<+>): m/z = 346 [M+H]<+>

(3) 6-[1-(tert.-butyloksykarbonyl)-piperidin-4-yloksy]-7-hydroksy-3H-kinazolin- (3) 6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-hydroxy-3H-quinazoline-

4-on 4-Mon

Rf verdi: 0,35 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 362 [M+H]<+>Mass spectrum (ESI<+>): m/z = 362 [M+H]<+>

Eksempel IV Example IV

2-amino-4-benzyloksy-5-(tetrahydropyran-4-yloksy)-benzosyre 16,40 g 2-nitro-4-benzyloksy-5-(tetrahydropyran-4-yloksy)-benzosyre blir hydrogenert i nærvær av 1,64 g Raney-nikkel i 800 ml metanol ved 55°C, inntil den beregnede mengde av hydrogen er tatt opp. Katalysatoren blir filtrert fra og filtratet inndampet, hvoretter det ønskede produkt krystalliserer ut. 2-amino-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid 16.40 g of 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid are hydrogenated in the presence of 1.64 g of Raney nickel in 800 ml of methanol at 55°C, until the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate evaporated, after which the desired product crystallizes out.

Utbytte: 15,08 g (100 % av teoretisk) Yield: 15.08 g (100% of theoretical)

Rf verdi: 0,60 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.60 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

De følgende forbindelser blir oppnådd analogt med Eksempel IV: The following compounds are obtained analogously to Example IV:

(1) benzyl 2-amino-4-benzyloksy-5-((S)-tetrahydrofuran-3-yloksy)-benzoat Rf verdi: 0,70 (silikagel, cykloheksan/etylacetat = 1:1) (1) benzyl 2-amino-4-benzyloxy-5-((S)-tetrahydrofuran-3-yloxy)-benzoate Rf value: 0.70 (silica gel, cyclohexane/ethyl acetate = 1:1)

Massespektrum (ESI<+>): m/z = 420 [M+H]<+>Mass spectrum (ESI<+>): m/z = 420 [M+H]<+>

(2) 2-amino-5-[1-(tert.-butyloksykarbonyl)-piperidin-4-yloksy]-benzosyre Rf verdi: 0,43 (silikagel, metylenklorid/metanol = 9:1) (2) 2-amino-5-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid Rf value: 0.43 (silica gel, methylene chloride/methanol = 9:1)

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

(3) 2-amino-4-hydroksy-5-[1-(tert.-butyloksykarbonyl)-piperidin-4-yloksy]-benzosyre (3) 2-amino-4-hydroxy-5-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid

Rf verdi: 0,23 (silikagel, metylenklorid/metanol/eddiksyre = 90:10:1) Rf value: 0.23 (silica gel, methylene chloride/methanol/acetic acid = 90:10:1)

Eksempel V Example V

2-nitro-4-benzyloksy-5-(tetrahydropyran-4-yloksy)-benzosyre Fremstilt ved forsåpning av benzyl-2-nitro-4-benzyloksy-5-(tetrahydropyran-4-yloksy)-benzoat med 1N natriumhydroksyd-løsning i metanol ved 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid Prepared by saponification of benzyl-2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoate with 1N sodium hydroxide solution in methanol wood

omgivelsestemperatur. ambient temperature.

Rf verdi: 0,20 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.20 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 374 [M+H]<+>Mass spectrum (ESI<+>): m/z = 374 [M+H]<+>

Eksempel VI Example VI

Benzyl-2-nitro-4-benzyloksy-5-(tetrahydro-pyran-4-yloksy)-benzoat 42,60 g kalium-tert.-butoksyd blir satt til 38 ml tetrahydrofuran-4-ol i 228 ml N,N-dimetylformamid under avkjøling med et isbad. Blandingen blir omrørt i én time ved omgivelsestemperatur, deretter blir 22,90 g 6-nitro-benzo[1,3]dioksol-5-karboksylsyre tilsatt. Etter 1,5 timer er reaksjonen fullstendig i henhold til tynnskiktskromatografi og 28,94 ml benzylbromid blir tilsatt dråpevis under avkjøling med et isbad. Reaksjonsblandingen blir omrørt natten over ved omgivelsestemperatur, kombinert med 100 ml 10% sitronsyre og omrørt i en dag til ved omgivelsestemperatur. Deretter blir reaksjonsblandingen inndampet i vakuum ved 60°C og satt til 800 ml isvann. Den vandige fasen blir ekstrahert med etylacetat og de samlede ekstrakter blir vasket med vann og mettet natriumklorid-løsning, tørket over magnesiumsulfat og inndampet. Benzyl-2-nitro-4-benzyloxy-5-(tetrahydro-pyran-4-yloxy)-benzoate 42.60 g of potassium tert.-butoxide is added to 38 ml of tetrahydrofuran-4-ol in 228 ml of N,N- dimethylformamide while cooling with an ice bath. The mixture is stirred for one hour at ambient temperature, then 22.90 g of 6-nitro-benzo[1,3]dioxole-5-carboxylic acid is added. After 1.5 hours the reaction is complete according to thin layer chromatography and 28.94 ml of benzyl bromide is added dropwise while cooling with an ice bath. The reaction mixture is stirred overnight at ambient temperature, combined with 100 ml of 10% citric acid and stirred for one more day at ambient temperature. The reaction mixture is then evaporated in vacuo at 60°C and added to 800 ml of ice water. The aqueous phase is extracted with ethyl acetate and the combined extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated.

Residuet blir omrørt med dietyleter, mens 2-nitro-4-benzyloksy-5-(tetrahydropyran-4-yloksy)-benzosyre krystalliserer ut som et biprodukt. Dette blir filtrert fra og filtratet blir inndampet. Det gjenværende hovedprodukt er benzyl 2-nitro-4-benzyloksy-5-(tetrahydro-pyran-4-yloksy)-benzoat, som blir forsåpet uten noen ytterligere rensning for å danne karboksylsyre (se Eksempel The residue is stirred with diethyl ether, while 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid crystallizes out as a by-product. This is filtered off and the filtrate is evaporated. The remaining major product is benzyl 2-nitro-4-benzyloxy-5-(tetrahydro-pyran-4-yloxy)-benzoate, which is saponified without any further purification to form the carboxylic acid (see Example

V). V).

De følgende forbindelser blir oppnådd analogt med Eksempel VI: The following compounds are obtained analogously to Example VI:

(1) benzyl-2-nitro-4-benzyloksy-5-((S)-tetrahydrofuran-3-yloksy)-benzoat Rf verdi: 0,75 (silikagel, cykloheksan/etylacetat = 1:1) (1) benzyl-2-nitro-4-benzyloxy-5-((S)-tetrahydrofuran-3-yloxy)-benzoate Rf value: 0.75 (silica gel, cyclohexane/ethyl acetate = 1:1)

Massespektrum (ESI<+>): m/z = 450 [M+H]<+>Mass spectrum (ESI<+>): m/z = 450 [M+H]<+>

(2) 2-nitro-4-hydroksy-5-[1-(tert.-butyloksykarbonyl)-piperidin-4-yloksy]-benzosyre (2) 2-nitro-4-hydroxy-5-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid

Ingen reaksjon blir utført med benzylbromid. No reaction is carried out with benzyl bromide.

Rf verdi: 0,40 (silikagel, metylenklorid/metanol/eddiksyre = 90:10:1) Massespektrum (ESI ): m/z = 381 [M-H]" Rf value: 0.40 (silica gel, methylene chloride/methanol/acetic acid = 90:10:1) Mass spectrum (ESI ): m/z = 381 [M-H]"

Eksempel VII Example VII

4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[2-(tert.-butyloksykarbonylamino)-etyl]-piperidin-4-yloksy}-7-metoksy-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-7-methoxyquinazoline

En blanding av 410 mg 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-metoksy-kinazolin-dihydroklorid, 240 mg N-(tert.-butyloksykarbonyl)-2-brom-etylamin og 360 mg kaliumkarbonat i 5 ml N,N-dimetylformamid blir omrørt natten over ved omgivelsestemperatur. Deretter blir ytterligere 80 mg N-(tert.-butyloksykarbonyl)-2-brom-etylamin tilsatt og reaksjonsblandingen blir omrørt i ytterligere fire timer ved omgivelsestemperatur. For opparbeiding blir det fortynnet med vann og ekstrahert med etylacetat. De samlede organiske faser blir vasket med mettet natriumklorid-løsning, tørket over magnesiumsulfat og inndampet. Residuet blir kromatografert gjennom en silikagel-kolonne med etylacetat/metanol (95:5 til 90:1) som elueringsmiddel. A mixture of 410 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline dihydrochloride, 240 mg of N-(tert-butyloxycarbonyl) -2-bromoethylamine and 360 mg of potassium carbonate in 5 ml of N,N-dimethylformamide are stirred overnight at ambient temperature. Then a further 80 mg of N-(tert-butyloxycarbonyl)-2-bromoethylamine is added and the reaction mixture is stirred for a further four hours at ambient temperature. For processing, it is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is chromatographed through a silica gel column with ethyl acetate/methanol (95:5 to 90:1) as eluent.

Utbytte: 370 mg (79 % av teoretisk) Yield: 370 mg (79% of theoretical)

Rf verdi: 0,33 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.33 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI ): m/z = 544, 546 [M-H]" Mass spectrum (ESI ): m/z = 544, 546 [M-H]"

Den følgende forbindelse blir oppnådd analogt med Eksempel VII: The following compound is obtained analogously to Example VII:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[2-(tert.-butyloksykarbonylamino)-etyl]-piperidin-4-yloksy}-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-quinazoline

Rf verdi: 0,38 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.38 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 516, 518 [M+H]<+>Mass spectrum (ESI<+>): m/z = 516, 518 [M+H]<+>

Eksempel VIII Example VIII

4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-metoksy-kinazolin-dihydroklorid 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline dihydrochloride

Fremstilt ved behandling av 4-[(3-klor-4-fluor-fenyl)amino]-6-[1-(tert.-butyloksykarbonyl)-piperidin-4-yloksy]-7-metoksy-kinazolin med konsentrert saltsyre i dioksan ved omgivelsestemperatur. Prepared by treating 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxyquinazoline with concentrated hydrochloric acid in dioxane at ambient temperature.

Rf verdi: 0,53 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.53 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 403, 405 [M+H]<+>Mass spectrum (ESI<+>): m/z = 403, 405 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel VIII: The following compounds are obtained analogously to Example VIII:

(1) 6-(piperidin-4-yloksy)-3/-/-kinazolin-4-on x 2 trifluoreddiksyre Utført med trifluoreddiksyre i metylenklorid. (1) 6-(piperidin-4-yloxy)-3/-/-quinazolin-4-one x 2 trifluoroacetic acid Performed with trifluoroacetic acid in methylene chloride.

Massespektrum (ESI<+>): m/z = 246 [M+H]<+>Mass spectrum (ESI<+>): m/z = 246 [M+H]<+>

(2) 6-(piperidin-4-yloksy)-7-hydroksy-3/-/-kinazolin-4-on Utført med trifluoreddiksyre i metylenklorid. (2) 6-(piperidin-4-yloxy)-7-hydroxy-3/-/-quinazolin-4-one Performed with trifluoroacetic acid in methylene chloride.

Rf verdi: 0,60 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.60 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 262 [M+H]<+>Mass spectrum (ESI<+>): m/z = 262 [M+H]<+>

Eksempel IX Example IX

4-[(3-klor-4-fluor-fenyl)amino]-6-[1-(tert.-butyloksykarbonyl)-piperidin-4-yloksy]-7-metoksy-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxyquinazoline

En løsning av 7,80 ml dietyl-azodikarboksylat i 100 ml metylenklorid blir satt dråpevis til en blanding av 10,00 g 4-[(3-klor-4-fluor-fenyl)amino]-6-hydroksy-7-metoksy-kinazolin og 9,40 g 1-(tert.-butyloksykarbonyl)-4-hydroksy-piperidin og 12,40 g trifenylfosfin i 400 ml metylenklorid ved omgivelsestemperatur. Suspensjonen blir omrørt i tre dager ved omgivelsestemperatur og deretter sugefiltrert. Filtratet blir inndampet og kromatografert gjennom en silikagel-kolonne med metylenklorid/metanol (98:2 auf 95:5) som elueringsmiddel. Råproduktet oppnådd blir kombinert med diisopropyleter, omrørt natten over deri, sugefiltrert og tørket. A solution of 7.80 ml of diethyl azodicarboxylate in 100 ml of methylene chloride is added dropwise to a mixture of 10.00 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy- quinazoline and 9.40 g of 1-(tert-butyloxycarbonyl)-4-hydroxy-piperidine and 12.40 g of triphenylphosphine in 400 ml of methylene chloride at ambient temperature. The suspension is stirred for three days at ambient temperature and then suction filtered. The filtrate is evaporated and chromatographed through a silica gel column with methylene chloride/methanol (98:2 auf 95:5) as eluent. The crude product obtained is combined with diisopropyl ether, stirred overnight therein, suction filtered and dried.

Utbytte: 5,34 g (34 % av teoretisk) Yield: 5.34 g (34% of theoretical)

Rf verdi: 0,46 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.46 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 503, 505 [M+H]<+>Mass spectrum (ESI<+>): m/z = 503, 505 [M+H]<+>

Eksempel X Example X

4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(4-brom-butyloksy)-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(4-bromo-butyloxy)-quinazoline

En blanding av 500 mg 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-hydroksy-kinazolin, 165 pl 1-brom-4-klor-propan og 360 mg kaliumkarbonat i 5 ml N,N-dimetylformamid blir omrørt natten over ved 80°C. For opparbeiding blir reaksjonsblandingen fortynnet med vann og ekstrahert med etylacetat. De samlede organiske faser blir vasket med mettet natriumklorid-løsning, tørket over magnesiumsulfat og inndampet. Råproduktet blir videre omsatt uten ytterligere rensning. A mixture of 500 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxyquinazoline, 165 µl of 1-bromo-4-chloro-propane and 360 mg of potassium carbonate in 5 ml of N,N-dimethylformamide is stirred overnight at 80°C. For work-up, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The raw product is further sold without further purification.

Utbytte: 650 mg (97 % av teoretisk) Yield: 650 mg (97% of theoretical)

De følgende forbindelser blir oppnådd analogt med Eksempel X: The following compounds are obtained analogously to Example X:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-tetrahydrofuran-3-yloksy)-7-(4-brom-butyloksy)-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-(4-bromo-butyloxy)-quinazoline

Rf verdi: 0,84 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.84 (silica gel, ethyl acetate/methanol = 9:1)

(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-trifluoracetyl-piperidin-4-yloksy)-7-etoksy-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

Massespektrum (ESI<+>): m/z = 513, 515 [M+H]<+>Mass spectrum (ESI<+>): m/z = 513, 515 [M+H]<+>

(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-trifluoracetyl-piperidin-4-yloksy)-7-(2-metoksy-etoksy)-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

Rf verdi: 0,38 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1)

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

Eksempel XI Example XI

1-(2-hydroksy-etyl)-3-metyl-tetrahydropyrimidin-2-on 1-(2-hydroxyethyl)-3-methyl-tetrahydropyrimidin-2-one

Fremstilt ved hydrogenolytisk spaltning av 1-(2-benzyloksy-etyl)-3-metyl-tetrahydropyrimidin-2-on i nærvær av palladium på aktivert trekull i metanol ved omgivelsestemperatur. Prepared by hydrogenolytic cleavage of 1-(2-benzyloxy-ethyl)-3-methyl-tetrahydropyrimidin-2-one in the presence of palladium on activated charcoal in methanol at ambient temperature.

Rf verdi: 0,23 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 159 [M+H]<+>Rf value: 0.23 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 159 [M+H]<+>

Eksempel XII Example XII

1-(2-benzyloksy-etyl)-3-metyl-tetrahydropyrimidin-2-on 1-(2-Benzyloxy-ethyl)-3-methyl-tetrahydropyrimidin-2-one

Fremstilt ved omsetning av 1-(2-benzyloksy-etyl)-tetrahydropyrimidin-2-on med metyljodid i nærvær av kalium-tert.-butoksyd i N,N-dimetylformamid ved omgivelsestemperatur. Prepared by reaction of 1-(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-one with methyl iodide in the presence of potassium tert-butoxide in N,N-dimethylformamide at ambient temperature.

Rf verdi: 0,62 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 249 [M+H]<+>Rf value: 0.62 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 249 [M+H]<+>

Eksempel XIII Example XIII

1-(2-benzyloksy-etyl)-tetrahydropyrimidin-2-on 1-(2-Benzyloxy-ethyl)-tetrahydropyrimidin-2-one

Fremstilt ved behandling av 1-(2-benzyloksy-etyl)-3-(3-klor-propyl)-urinstoff med kalium-tert.-butoksyd i N,N-dimetylformamid ved omgivelsestemperatur. Prepared by treating 1-(2-benzyloxy-ethyl)-3-(3-chloro-propyl)-urea with potassium tert-butoxide in N,N-dimethylformamide at ambient temperature.

Rf verdi: 0,42 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 235 [M+H]<+>Rf value: 0.42 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 235 [M+H]<+>

Eksempel XIV Example XIV

1-(2-benzyloksy-etyl)-tetrahydropyrimidin-2-on 1-(2-Benzyloxy-ethyl)-tetrahydropyrimidin-2-one

Fremstilt ved omsetning av 2-benzyloksy-etylamin med 3-klor-propyl-isocyanat i tetrahydrofuran. Produced by reacting 2-benzyloxy-ethylamine with 3-chloro-propyl isocyanate in tetrahydrofuran.

Rf verdi: 0,73 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 271, 273 [M+H]<+>Rf value: 0.73 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 271, 273 [M+H]<+>

Eksempel XV Example XV

3-(tert.-butyloksykarbonylamino)-cykloheksanol 3-(tert-butyloxycarbonylamino)-cyclohexanol

Fremstilt ved omsetning av 3-amino-cykloheksanol med di-tert.butyl-pyrokarbonat i nærvær av trietylamin i en blanding av dioksan/vann (2:1) ved 50°C. Prepared by reaction of 3-amino-cyclohexanol with di-tert.butyl-pyrocarbonate in the presence of triethylamine in a mixture of dioxane/water (2:1) at 50°C.

Rf verdi: 0,34 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) Rf value: 0.34 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 90:10:1)

Massespektrum (ESI ): m/z = 214 [M-H]" Mass spectrum (ESI ): m/z = 214 [M-H]"

Den følgende forbindelse blir oppnådd analogt med Eksempel XV: The following compound is obtained analogously to Example XV:

(1) cis-4-[N-(tert.-butyloksykarbonyl)-N-metyl-amino]-cykloheksanol Reaksjonen finner sted i metanol. (1) cis-4-[N-(tert-butyloxycarbonyl)-N-methyl-amino]-cyclohexanol The reaction takes place in methanol.

Rf verdi: 0,70 (silikagel, etylacetat) Rf value: 0.70 (silica gel, ethyl acetate)

Massespektrum (ESI<+>): m/z = 230 [M+H]<+>Mass spectrum (ESI<+>): m/z = 230 [M+H]<+>

Eksempel XVI Example XVI

6-(1-trifluoracetyl-piperidin-4-yloksy)-3/-/-kinazolin-4-on 6-(1-trifluoroacetyl-piperidin-4-yloxy)-3/-/-quinazolin-4-one

Fremstilt ved omsetning av 6-(piperidin-4-yloksy)-3/-/-kinazolin-4-on x 2 trifluoreddiksyre med trifluoreddiksyreanhydrid i nærvær av trietylamin i tetrahydrofuran. Prepared by reacting 6-(piperidin-4-yloxy)-3/-/-quinazolin-4-one x 2 trifluoroacetic acid with trifluoroacetic anhydride in the presence of triethylamine in tetrahydrofuran.

Rf verdi: 0,48 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.48 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 342 [M+H]<+>Mass spectrum (ESI<+>): m/z = 342 [M+H]<+>

Den følgende forbindelse blir oppnådd analogt med Eksempel XVI: The following compound is obtained analogously to Example XVI:

(1) 6-(1 -trifluoracetyl-piperidin-4-yloksy)-7-hydroksy-3H-kinazolin-4-on Utført med metyl-trifluoracetat i nærvær av Hunig base i metanol. (1) 6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-one Performed with methyl trifluoroacetate in the presence of Hunig's base in methanol.

Rf verdi: 0,80 (silikagel, metylenklorid/metanol =4:1) Rf value: 0.80 (silica gel, methylene chloride/methanol = 4:1)

Massespektrum (ESI<+>): m/z = 358 [M+H]<+>Mass spectrum (ESI<+>): m/z = 358 [M+H]<+>

Eksempel XVII Example XVII

2-nitro-5-[1-(tert.-butyloksykarbonyl)-piperidin-4-yloksy]-benzosyre 21,00 g kalium-tert.-butoksyd blir satt satsvis til 25,14 g 1-(tert.-butyloksykarbonyl)-piperidin-4-ol i 120 ml N,N-dimetylformamid under avkjøling med et isbad, mens temperaturen blir holdt under 10°C. Blandingen blir omrørt i ytterligere 30 minutter under avkjøling med et isbad, deretter blir 11,60 g 5- 2-nitro-5-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid 21.00 g potassium tert-butoxide is added batchwise to 25.14 g 1-(tert-butyloxycarbonyl) -piperidin-4-ol in 120 ml of N,N-dimethylformamide under cooling with an ice bath, while keeping the temperature below 10°C. The mixture is stirred for a further 30 minutes while cooling with an ice bath, then 11.60 g of 5-

fluor-2-nitro-benzosyre tilsatt. Etter ytterligere tre timer blir reaksjonsblandingen hellet i vann, regulert til pH 1 med kons. saltsyre og ekstrahert med etylacetat. De samlede organiske faser blir vasket med fortynnet sitronsyreløsning, tørket over magnesiumsulfat og inndampet. Residuet blir utgnidd med dietyleter, sugefiltrert og tørket. Mer produkt krystalliserer ut av filtratet etter henstand i noen tid og dette blir også sugefiltrert og tørket. fluoro-2-nitro-benzoic acid added. After a further three hours, the reaction mixture is poured into water, adjusted to pH 1 with conc. hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with dilute citric acid solution, dried over magnesium sulfate and evaporated. The residue is triturated with diethyl ether, suction filtered and dried. More product crystallizes out of the filtrate after standing for some time and this is also suction filtered and dried.

Utbytte: 9,58 g (42 % av teoretisk) Yield: 9.58 g (42% of theoretical)

Rf verdi: 0,43 (silikagel, metylenklorid/metanol/eddiksyre = 90:10:1) Massespektrum (ESI<+>): m/z = 367[M+H]<+>Rf value: 0.43 (silica gel, methylene chloride/methanol/acetic acid = 90:10:1) Mass spectrum (ESI<+>): m/z = 367[M+H]<+>

Eksempel XVIII Example XVIII

4-[(3-klor-4-fluor-fenyl)amino]-6-(1-bromacetyl-piperidin-4-yloksy)-kinazolin og 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-kloracetyl-piperidin-4-yloksy)-kinazolin Fremstilt ved omsetning av 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-kinazolin med bromeddiksyreklorid i nærvær av Hunig base i tetrahydrofuran ved omgivelsestemperatur. En blanding av brom- og klor-forbindelser blir oppnådd. 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-bromoacetyl-piperidin-4-yloxy)-quinazoline and 4-[(3-chloro-4-fluoro-phenyl)amino]- 6-(1-Chloroacetyl-piperidin-4-yloxy)-quinazoline Prepared by reaction of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-quinazoline with bromoacetic acid chloride in presence of Hunig's base in tetrahydrofuran at ambient temperature. A mixture of bromine and chlorine compounds is obtained.

Rf verdi: 0,43 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.43 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 493, 495, 497 [M1+H]<+>og 449, 451, 453 [M2+H]<+>Mass spectrum (ESI<+>): m/z = 493, 495, 497 [M1+H]<+>and 449, 451, 453 [M2+H]<+>

Den følgende forbindelse blir oppnådd analogt med Eksempel XVIII: The following compound is obtained analogously to Example XVIII:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1 -kloracetyl-piperidin-4-yloksy)-7-metoksy-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-chloroacetyl-piperidin-4-yloxy)-7-methoxyquinazoline

Reaksjonen finner sted med kloracetylklorid. The reaction takes place with chloroacetyl chloride.

Rf verdi: 0,59 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI ): m/z = 477, 479, 481 [M-H]- Rf value: 0.59 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI ): m/z = 477, 479, 481 [M-H]-

Eksempel XIX Example XIX

1 -metyl-3-[([1,4]oksazepan-4-yl)karbonyl]-3/-/-imidazol-1 -ium-jodid Fremstilt ved omsetning av 3-[([1,4]oksazepan-4-yl)karbonyl]-3/-/-imidazol med metyljodid i acetonitril ved omgivelsestemperatur. Råproduktet blir omsatt 1 -Methyl-3-[([1,4]oxazepan-4-yl)carbonyl]-3/-/-imidazol-1 -ium iodide Prepared by reaction of 3-[([1,4]oxazepan-4 -yl)carbonyl]-3/-/-imidazole with methyl iodide in acetonitrile at ambient temp. The raw product is sold

videre uten mer rensning. further without further purification.

De følgende forbindelser blir oppnådd analogt med Eksempel XIX: The following compounds are obtained analogously to Example XIX:

(1) 1 -metyl-3-[(cis-2,6-dimetyl-morfolin-4-yl)karbonyl]-3H-imidazol-1 -ium-jodid Rf verdi: 0,12 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) (2) 1-metyl-3-[(2-metyl-morfolin-4-yl)karbonyl]-3H-imidazol-1-ium-jodid Rf verdi: 0,02 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) (1) 1-methyl-3-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-3H-imidazol-1-ium iodide Rf value: 0.12 (silica gel, ethyl acetate/methanol/ conc. aqueous ammonia = 90:10:1) (2) 1-methyl-3-[(2-methyl-morpholin-4-yl)carbonyl]-3H-imidazol-1-ium iodide Rf value: 0.02 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1)

Eksempel XX Example XX

3- [([1,4]oksazepan-4-yl)karbonyl]-3/-/-imidazol 3- [([1,4]oxazepan-4-yl)carbonyl]-3/-/-imidazole

Fremstilt ved omsetning av [1,4]oksazepan med N.N-karbonyldiimidazol i nærvær av trietylamin i tetrahydrofuran ved omgivelsestemperatur. Prepared by reaction of [1,4]oxazepane with N.N-carbonyldiimidazole in the presence of triethylamine in tetrahydrofuran at ambient temperature.

Rf verdi: 0,30 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 196 [M+H]<+>Rf value: 0.30 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 196 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel XX: The following compounds are obtained analogously to Example XX:

(1) 3-[(cis-2,6-dimetyl-morfolin-4-yl)karbonyl]-3H-imidazol Rf verdi: 0,46 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) (1) 3-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-3H-imidazole Rf value: 0.46 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1 )

(2) 3-[(2-metyl-morfolin-4-yl)karbonyl]-3H-imidazol (2) 3-[(2-methyl-morpholin-4-yl)carbonyl]-3H-imidazole

Rf verdi: 0,43 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Rf value: 0.43 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1)

Eksempel XXI Example XXI

4- [(3-klor-4-fluor-fenyl)amino]-6-(1-trifluoracetyl-piperidin-4-yloksy)-7-hydroksy-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxyquinazoline

Fremstilt ved behandling av 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-trifluoracetyl-piperidin-4-yloksy)-7-acetoksy-kinazolin-hydroklorid med mettet natriumhydrogenkarbonat-løsning i metanol ved omgivelsestemperatur. I tillegg til det ønskede produkt, blir noe 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4- Prepared by treating 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxyquinazoline hydrochloride with saturated sodium bicarbonate solution in methanol at ambient temperature. In addition to the desired product, some 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidine-4-

yloksy)-7-hydroksy-kinazolin også isolert som et biprodukt. yloxy)-7-hydroxy-quinazoline also isolated as a by-product.

Rf verdi: 0,20 (silikagel, metylenklorid/metanol = 20:1) Rf value: 0.20 (silica gel, methylene chloride/methanol = 20:1)

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

Den følgende forbindelse blir oppnådd analogt med Eksempel XXI: The following compound is obtained analogously to Example XXI:

(1) 4-[(3-etynyl-fenyl)amino]-6-hydroksy-7-metoksy-kinazolin Utført med 40 % natriumhydroksyd-løsning i etanol. (1) 4-[(3-ethynyl-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline Performed with 40% sodium hydroxide solution in ethanol.

Rf verdi: 0,32 (silikagel, etylacetat) Rf value: 0.32 (silica gel, ethyl acetate)

Massespektrum (ESI<+>): m/z = 292 [M+H]<+>Mass spectrum (ESI<+>): m/z = 292 [M+H]<+>

Eksempel XXII Example XXII

6-(1-trifluoracetyl-piperidin-4-yloksy)-7-acetoksy-3H-kinazolin-4-on Fremstilt ved omsetning av 6-(1-trifluoracetyl-piperidin-4-yloksy)-7-hydroksy-3H-kinazolin-4-on med eddiksyreanhydrid i pyridin ved 80°C. 6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-3H-quinazolin-4-one Prepared by reaction of 6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-3H-quinazoline -4-one with acetic anhydride in pyridine at 80°C.

Rf verdi: 0,60 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.60 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 400 [M+H]<+>Mass spectrum (ESI<+>): m/z = 400 [M+H]<+>

Fremstilling av sluttprodukter: Manufacture of end products:

Eksempel 1 4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-tetrahydrofuran-3-yloksy)-7-metoksy-kinazolin Example 1 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxyquinazoline

300 mg 4-[(3-klor-4-fluor-fenyl)amino]-6-hydroksy-7-metoksy-kinazolin i 6 ml 300 mg 4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline in 6 ml

acetonitril blandes med 114 ul (f?)-3-hydroksy-tetrahydrofuran og 370 mg trifenylfosfin. Deretter blir 234 ul dietyl-azodikarboksylat tilsatt og reaksjonsblandingen blir omrørt natten over ved omgivelsestemperatur. For opparbeiding blir reaksjonsblandingen filtrert og filtratet inndampet i vakuum. Råproduktet blir renset ved kromatografi over en silikagel-kolonne med etylacetat/metanol (95:5) som elueringsmiddel. acetonitrile is mixed with 114 µl of (f?)-3-hydroxy-tetrahydrofuran and 370 mg of triphenylphosphine. Then 234 µl of diethyl azodicarboxylate is added and the reaction mixture is stirred overnight at ambient temperature. For work-up, the reaction mixture is filtered and the filtrate evaporated in vacuo. The crude product is purified by chromatography over a silica gel column with ethyl acetate/methanol (95:5) as eluent.

Utbytte: 53 mg (15 % av teoretisk) Yield: 53 mg (15% of theoretical)

smeltepunkt: 178°C melting point: 178°C

Massespektrum (ESI<+>): m/z = 390, 392 [M+H]<+>Mass spectrum (ESI<+>): m/z = 390, 392 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 1: The following compounds are obtained analogously to Example 1:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-metoksy- kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy- quinazoline

Rf verdi: 0,54 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.54 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 404, 406 [M+H]<+>Mass spectrum (ESI<+>): m/z = 404, 406 [M+H]<+>

(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-[cis-4-(tert.-butyloksykarbonylamino)-cykloheksan-1-yloksy]-7-metoksy-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(tert-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxyquinazoline

Rf verdi: 0,70 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.70 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 517, 519 [M+H]<+>Mass spectrum (ESI<+>): m/z = 517, 519 [M+H]<+>

(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-((/?)-tetrahydrofuran-3-yloksy)-7-metoksy- kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((/?)-tetrahydrofuran-3-yloxy)-7-methoxy- quinazoline

Rf verdi: 0,64 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.64 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 390, 392 [M+H]<+>Mass spectrum (ESI<+>): m/z = 390, 392 [M+H]<+>

(4) 4-[(3-klor-4-fluor-fenyl)amino]-6-[trans-4-(tert.-butyloksykarbonylamino)- cykloheksan-1-yloksy]-7-metoksy-kinazolin (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(tert-butyloxycarbonylamino)- cyclohexan-1-yloxy]-7-methoxyquinazoline

Rf verdi: 0,65 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.65 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 517, 519 [M+H]<+>Mass spectrum (ESI<+>): m/z = 517, 519 [M+H]<+>

(5) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1-(tert.-butyloksykarbonyl)-piperidin-4-yloksy]-7-metoksy-kinazolin (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxyquinazoline

smeltepunkt: 184°C melting point: 184°C

Massespektrum (ESI<+>): m/z = 503, 505 [M+H]<+>Mass spectrum (ESI<+>): m/z = 503, 505 [M+H]<+>

(6) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-3-yloksy)-7-metoksy- kinazolin (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy- quinazoline

Rf verdi: 0,52 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.52 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 404, 406 [M+H]<+>Mass spectrum (ESI<+>): m/z = 404, 406 [M+H]<+>

(7) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-metyl-piperidin-4-yloksy)-7-metoksy- kinazolin (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy- quinazoline

smeltepunkt: 218°C melting point: 218°C

Massespektrum (ESI<+>): m/z = 417, 419 [M+H]<+ >(8) 4-[(3-klor-4-fluor-fenyl)amino]-6-[(S)-1-(tert.-butyloksykarbonyl)-pyrrolidin-3-yloksy]-7-metoksy-kinazolin Mass spectrum (ESI<+>): m/z = 417, 419 [M+H]<+ >(8) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(S)- 1-(tert-butyloxycarbonyl)-pyrrolidin-3-yloxy]-7-methoxyquinazoline

Utført med diisopropyl-azodikarboksylat i metylenklorid. Performed with diisopropyl azodicarboxylate in methylene chloride.

Rf verdi: 0,51 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.51 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 489, 491 [M+H]<+>Mass spectrum (ESI<+>): m/z = 489, 491 [M+H]<+>

(9) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1-(tert.-butyloksykarbonyl)-piperidin-3-yloksy]-7-metoksy-kinazolin (9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-3-yloxy]-7-methoxyquinazoline

Utført med diisopropyl-azodikarboksylat i metylenklorid. Performed with diisopropyl azodicarboxylate in methylene chloride.

Rf verdi: 0,56 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.56 (silica gel, methylene chloride/methanol = 9:1)

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

(10) 4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-tetrahydrofuran-3-yloksy)-7-[2-(3-metyl-2-okso-heksahydropyrimidin-1-yl)-etoksy]-kinazolin (10) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[2-(3-methyl-2-oxo-hexahydropyrimidine- 1-yl)-ethoxy]-quinazoline

Utført med diisopropyl-azodikarboksylat i metylenklorid. Performed with diisopropyl azodicarboxylate in methylene chloride.

smeltepunkt: 235°C melting point: 235°C

Massespektrum (ESI<+>): m/z = 516, 518 [M+H]<+>Mass spectrum (ESI<+>): m/z = 516, 518 [M+H]<+>

(11) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-(tert.-butyloksykarbonylamino)-cykloheksan-1-yloksy]-7-metoksy-kinazolin (11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(tert-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

Utført med diisopropyl-azodikarboksylat i metylenklorid. Performed with diisopropyl azodicarboxylate in methylene chloride.

Rf verdi: 0,68 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.68 (silica gel, ethyl acetate/methanol = 9:1)

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

(12) 4-[(3-klor-4-fluor-fenyl)amino]-6-{cis-4-[N-(tert.-butyloksykarbonyl)-N-metylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(tert-butyloxycarbonyl)-N-methylamino]-cyclohexane-1-yloxy}-7 -methoxyquinazoline

Utført med diisopropyl-azodikarboksylat i metylenklorid. Performed with diisopropyl azodicarboxylate in methylene chloride.

Rf verdi: 0,37 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.37 (silica gel, methylene chloride/methanol = 9:1)

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

(13) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[N-(tert.-butyloksykarbonyl)-N-metyl-amino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin (13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[N-(tert-butyloxycarbonyl)-N-methyl-amino]-cyclohexane-1-yloxy} -7-Methoxyquinazoline

Utført med diisopropyl-azodikarboksylat i metylenklorid. Performed with diisopropyl azodicarboxylate in methylene chloride.

smeltepunkt: 231 °C melting point: 231 °C

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

Eksempel 2 Example 2

4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-amino-cykloheksan-1-yloksy)-7-metoksy-kinazolin x trifluoreddiksyre 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-amino-cyclohexan-1-yloxy)-7-methoxyquinazoline x trifluoroacetic acid

Fremstilt ved behandling av 4-[(3-klor-4-fluor-fenyl)amino]-6-[cis-4-(tert.-butyloksykarbonylamino)-cykloheksan-1-yloksy]-7-metoksy-kinazolin med trifluoreddiksyre i metylenklorid ved omgivelsestemperatur, Prepared by treating 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(tert-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxyquinazoline with trifluoroacetic acid in methylene chloride at ambient temperature,

smeltepunkt: 221 °C melting point: 221 °C

Massespektrum (ESI<+>): m/z = 417, 419 [M+H]<+>Mass spectrum (ESI<+>): m/z = 417, 419 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 2: The following compounds are obtained analogously to Example 2:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-amino-cykloheksan-1 -yloksy)-7- metoksy-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7- methoxyquinazoline

Massespektrum (ESI<+>): m/z = 417, 419 [M+H]<+>Mass spectrum (ESI<+>): m/z = 417, 419 [M+H]<+>

(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-metoksy-kinazolin x trifluoreddiksyre (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline x trifluoroacetic acid

smeltepunkt: 232°C melting point: 232°C

Massespektrum (ESI<+>): m/z = 403, 405 [M+H]<+>Mass spectrum (ESI<+>): m/z = 403, 405 [M+H]<+>

Eksempel 3 Example 3

4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-metansulfonylamino-cykloheksan-1-yloksy)-7-metoksy-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methanesulfonylamino-cyclohexan-1-yloxy)-7-methoxyquinazoline

Fremstilt ved omsetning av 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-amino-cykloheksan-1-yloksy)-7-metoksy-kinazolin x trifluoreddiksyre med metan su Ifonsyre klorid i nærvær av Hunig base i tetrahydrofuran ved omgivelsestemperatur. Prepared by reaction of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline x trifluoroacetic acid with methane su Ifonic acid chloride in presence of Hunig's base in tetrahydrofuran at ambient temperature.

Rf verdi: 0,77 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 40:10:1) Massespektrum (ESI<+>): m/z = 495, 497 [M+H]<+>Rf value: 0.77 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 40:10:1) Mass spectrum (ESI<+>): m/z = 495, 497 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 3: The following compounds are obtained analogously to Example 3:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-metansulfonylamino-cykloheksan-1 -yloksy)-7-metoksy-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulfonylamino-cyclohexan-1-yloxy)-7-methoxyquinazoline

Rf verdi: 0,20 (silikagel, etylacetat) Rf value: 0.20 (silica gel, ethyl acetate)

Massespektrum (ESI<+>): m/z = 495, 497 [M+H]<+>Mass spectrum (ESI<+>): m/z = 495, 497 [M+H]<+>

(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-metansulfonyl-piperidin-4-yloksy)-7- metoksy-kinazolin Rf verdi: 0,59 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 481, 483 [M+H]<+ >(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-{cis-4-[(3-klor-propyl)sulfonylamino]- cykloheksan-1-yloksy}-7-metoksy-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7- methoxyquinazoline Rf value: 0.59 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 481, 483 [M+H]<+ > (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(3-chloro-propyl)sulfonylamino]- cyclohexan-1-yloxy}-7-methoxyquinazoline

Reaksjonen finner sted med 3-klorpropansulfonylklorid. The reaction takes place with 3-chloropropanesulfonyl chloride.

Rf verdi: 0,79 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.79 (silica gel, ethyl acetate/methanol = 9:1)

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

(4) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(3-klor-propyl)sulfonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(3-chloro-propyl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Reaksjonen finner sted med 3-klorpropansulfonylklorid. The reaction takes place with 3-chloropropanesulfonyl chloride.

Rf verdi: 0,42 (silikagel, etylacetat) Rf value: 0.42 (silica gel, ethyl acetate)

Massespektrum (ESI<+>): m/z = 557, 559, 561 [M+H]<+>Mass spectrum (ESI<+>): m/z = 557, 559, 561 [M+H]<+>

(5) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-metylkarbonyl-piperidin-4-yloksy)-7- metoksy-kinazolin (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methylcarbonyl-piperidin-4-yloxy)-7- methoxyquinazoline

Reaksjonen finner sted med eddiksyreanhydrid. The reaction takes place with acetic anhydride.

smeltepunkt: 216°C melting point: 216°C

Massespektrum (ESI<+>): m/z = 445, 447 [M+H]<+>Mass spectrum (ESI<+>): m/z = 445, 447 [M+H]<+>

(6) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(dimetylamino)karbonyl]-piperidin-4-yl- oksy}-7-metoksy-kinazolin (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonyl]-piperidin-4-yl- oxy}-7-methoxyquinazoline

Reaksjonen finner sted med N,N-dimetylkarbamoylklorid. The reaction takes place with N,N-dimethylcarbamoyl chloride.

Rf verdi: 0,28 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.28 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 474, 476 [M+H]<+>Mass spectrum (ESI<+>): m/z = 474, 476 [M+H]<+>

(7) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(morfolin-4-yl)karbonyl]-piperidin-4-yl- oksy}-7-metoksy-kinazolin (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl- oxy}-7-methoxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)karbonylklorid i acetonitril. The reaction takes place with (morpholin-4-yl)carbonyl chloride in acetonitrile.

Rf verdi: 0,37 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.37 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 516, 518 [M+H]<+>Mass spectrum (ESI<+>): m/z = 516, 518 [M+H]<+>

(8) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(metoksymetyl)karbonyl]-piperidin-4-yl- oksy}-7-metoksy-kinazolin (8) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yl- oxy}-7-methoxyquinazoline

Reaksjonen finner sted med metoksyeddiksyreklorid. The reaction takes place with methoxyacetic acid chloride.

Rf verdi: 0,80 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.80 (silica gel, methylene chloride/methanol = 9:1)

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

(9) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-cyano-piperidin-4-yloksy)-7-metoksy-kinazolin (9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxyquinazoline

Reaksjonen finner sted med bromcyanogen i metylenklorid. The reaction takes place with bromocyanogen in methylene chloride.

Rf verdi: 0,40 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.40 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 428, 430 [M+H]<+>Mass spectrum (ESI<+>): m/z = 428, 430 [M+H]<+>

(10) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(dimetylamino)sulfonyl]-piperidin-4-yl- oksy}-7-metoksy-kinazolin (10) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)sulfonyl]-piperidin-4-yl- oxy}-7-methoxyquinazoline

Reaksjonen finner sted med N,N-dimetylsulfamoylklorid i acetonitril. The reaction takes place with N,N-dimethylsulfamoyl chloride in acetonitrile.

Rf verdi: 0,24 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.24 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 510, 512 [M+H]<+>Mass spectrum (ESI<+>): m/z = 510, 512 [M+H]<+>

(11) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1 -[(morfolin-4-yl)sulfonyl]-piperidin-4-yl-oksy}-7-metoksy-kinazolin (11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)sulfonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline

Reaksjonen finner sted med (morfolin-4-yl)sulfonylklorid i acetonitril. The reaction takes place with (morpholin-4-yl)sulfonyl chloride in acetonitrile.

Rf verdi: 0,29 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.29 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 552, 554 [M+H]<+>Mass spectrum (ESI<+>): m/z = 552, 554 [M+H]<+>

(12) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-metansulfonyl-piperidin-3-yloksy)-7-metoksy-kinazolin (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-3-yloxy)-7-methoxyquinazoline

Rf verdi: 0,33 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.33 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 481, 483 [M+H]<+>Mass spectrum (ESI<+>): m/z = 481, 483 [M+H]<+>

(13) 4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-1-metansulfonyl-pyrrolidin-3-yloksy)-7-metoksy-kinazolin (13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-1-methanesulfonyl-pyrrolidin-3-yloxy)-7-methoxyquinazoline

smeltepunkt: 249°C melting point: 249°C

Massespektrum (ESI<+>): m/z = 467, 469 [M+H]<+>Mass spectrum (ESI<+>): m/z = 467, 469 [M+H]<+>

(14) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1 -(2-metansulfonylamino-etyl)-piperidin-4-yloksy]-7-metoksy-kinazolin (14) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methanesulfonylamino-ethyl)-piperidin-4-yloxy]-7-methoxyquinazoline

Rf verdi: 0,49 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.49 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

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

(15) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1 -(2-acetylamino-etyl)-piperidin-4-yloksy]-7-metoksy-kinazolin (15) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1 -(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

Reaksjonen finner sted med eddiksyreanhydrid. The reaction takes place with acetic anhydride.

Rf verdi: 0,51 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.51 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 488, 490 [M+H]<+>Mass spectrum (ESI<+>): m/z = 488, 490 [M+H]<+>

(16) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(dimetylamino)sulfonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin (16) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxyquinazoline

Reaksjonen finner sted med N,N-dimetylsulfamoylklorid i acetonitril. The reaction takes place with N,N-dimethylsulfamoyl chloride in acetonitrile.

Rf verdi: 0,69 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 524, 526 [M+H]<+ >(17) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(morfolin-4-yl)karbonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin Rf value: 0.69 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 524, 526 [M+H]<+ >(17) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)karbonylklorid i acetonitril. The reaction takes place with (morpholin-4-yl)carbonyl chloride in acetonitrile.

Rf verdi: 0,38 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.38 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 530, 532 [M+H]<+>Mass spectrum (ESI<+>): m/z = 530, 532 [M+H]<+>

(18) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(morfolin-4-yl)sulfonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin (18) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexane-1-yloxy}-7-methoxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)sulfonylklorid i acetonitril. The reaction takes place with (morpholin-4-yl)sulfonyl chloride in acetonitrile.

smeltepunkt: 237°C melting point: 237°C

Massespektrum (ESI ): m/z = 564, 566 [M-H]" Mass spectrum (ESI ): m/z = 564, 566 [M-H]"

(19) 4-[(3-klor-4-fluor-fenyl)amino]-6-(3-metansulfonylamino-cykloheksan-1 - (19) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-methanesulfonylamino-cyclohexane-1 -

yloksy)-7-metoksy-kinazolin yloxy)-7-methoxyquinazoline

Rf verdi: 0,66 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.66 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI ): m/z = 493, 495 [M-H]" Mass spectrum (ESI ): m/z = 493, 495 [M-H]"

(20) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(2-acetylamino-etoksy)-kinazolin (20) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline

Reaksjonen finner sted med acetylklorid i acetonitril. The reaction takes place with acetyl chloride in acetonitrile.

smeltepunkt: 224°C melting point: 224°C

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

(21) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(2-metansulfonylamino-etoksy)-kinazolin (21) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonylamino-ethoxy)-quinazoline

smeltepunkt: 227°C melting point: 227°C

Massespektrum (ESI<+>): m/z = 511, 513 [M+H]<+>Mass spectrum (ESI<+>): m/z = 511, 513 [M+H]<+>

(22) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-3-acetylamino-cykloheksan-1-yloksy)-7-metoksy-kinazolin (22) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-3-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Reaksjonen finner sted med acetylklorid i acetonitril. Cis- og trans-isomer blir separert ved kromatografi over en silikagel-kolonne. The reaction takes place with acetyl chloride in acetonitrile. Cis and trans isomers are separated by chromatography over a silica gel column.

Rf verdi: 0,43 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) Rf value: 0.43 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 90:10:1)

Massespektrum (ESI<+>): m/z = 459, 461 [M+H]<+>Mass spectrum (ESI<+>): m/z = 459, 461 [M+H]<+>

(23) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-3-acetylamino-cykloheksan-1-yloksy)-7-metoksy-kinazolin (23) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-3-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Reaksjonen finner sted med acetylklorid i acetonitril. Cis- og trans-isomer blir separert ved kromatografi over en silikagel-kolonne. The reaction takes place with acetyl chloride in acetonitrile. Cis and trans isomers are separated by chromatography over a silica gel column.

Rf verdi: 0,49 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) Rf value: 0.49 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 90:10:1)

Massespektrum (ESI<+>): m/z = 459, 461 [M+H]<+>Mass spectrum (ESI<+>): m/z = 459, 461 [M+H]<+>

(24) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(3-acetylamino-propyloksy)-kinazolin (24) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-acetylamino-propyloxy)-quinazoline

Reaksjonen finner sted med acetylklorid. The reaction takes place with acetyl chloride.

smeltepunkt: 225°C melting point: 225°C

Massespektrum (ESI<+>): m/z = 489, 491 [M+H]<+>Mass spectrum (ESI<+>): m/z = 489, 491 [M+H]<+>

(25) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(3-metansulfonylamino-propyloksy)-kinazolin (25) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-methanesulfonylamino-propyloxy)-quinazoline

smeltepunkt: 222°C melting point: 222°C

Massespektrum (ESI<+>): m/z = 525, 527 [M+H]<+>Mass spectrum (ESI<+>): m/z = 525, 527 [M+H]<+>

(26) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-metansulfonyl-piperidin-4-yloksy)-kinazolin (26) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-quinazoline

Rf verdi: 0,44 (silikagel, metylenklorid /metanol = 9:1) Rf value: 0.44 (silica gel, methylene chloride / methanol = 9:1)

Massespektrum (ESI<+>): m/z = 451, 453 [M+H]<+>Mass spectrum (ESI<+>): m/z = 451, 453 [M+H]<+>

(27) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(morfolin-4-yl)karbonyl]-piperidin-4-yloksyj-kinazolin (27) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)karbonylklorid i acetonitril. The reaction takes place with (morpholin-4-yl)carbonyl chloride in acetonitrile.

Rf verdi: 0,40 (silikagel, metylenklorid /metanol = 9:1) Rf value: 0.40 (silica gel, methylene chloride / methanol = 9:1)

Massespektrum (ESI<+>): m/z = 486, 488 [M+H]<+>Mass spectrum (ESI<+>): m/z = 486, 488 [M+H]<+>

(28) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-acetyl-piperidin-4-yloksy)-kinazolin Reaksjonen finner sted med eddiksyreanhydrid. (28) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-quinazoline The reaction takes place with acetic anhydride.

Rf verdi: 0,50 (silikagel, metylenklorid /metanol = 9:1) Rf value: 0.50 (silica gel, methylene chloride / methanol = 9:1)

Massespektrum (ESI<+>): m/z = 415, 417 [M+H]<+>Mass spectrum (ESI<+>): m/z = 415, 417 [M+H]<+>

(29) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(dimetylamino)karbonyl]-piperidin-4-yloksyj-kinazolin (29) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonyl]-piperidin-4-yloxyquinazoline

Reaksjonen finner sted med N,N-dimetylkarbamoylklorid. The reaction takes place with N,N-dimethylcarbamoyl chloride.

Rf verdi: 0,47 (silikagel, metylenklorid /metanol = 9:1) Rf value: 0.47 (silica gel, methylene chloride / methanol = 9:1)

Massespektrum (ESI<+>): m/z = 444, 446 [M+H]<+>Mass spectrum (ESI<+>): m/z = 444, 446 [M+H]<+>

(30) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-acetylamino-cykloheksan-1-yloksy}-7-metoksy-kinazolin (30) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-acetylamino-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Reaksjonen finner sted med eddiksyreanhydrid. The reaction takes place with acetic anhydride.

Rf verdi: 0,50 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 459, 461 [M+H]<+>Mass spectrum (ESI<+>): m/z = 459, 461 [M+H]<+>

(31) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(dimetylamino)karbonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin (31) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Reaksjonen finner sted med N,N-dimetylkarbamoylklorid. The reaction takes place with N,N-dimethylcarbamoyl chloride.

Rf verdi: 0,40 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 488, 490 [M+H]<+>Mass spectrum (ESI<+>): m/z = 488, 490 [M+H]<+>

(32) 4-[(3-klor-4-fluor-fenyl)amino]-6-[trans-4-(2-metoksy-acetylamino)-cykloheksan-1-yloksy]-7-metoksy-kinazolin (32) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(2-methoxy-acetylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

Reaksjonen finner sted med metoksyeddiksyreklorid. The reaction takes place with methoxyacetic acid chloride.

Rf verdi: 0,35 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 489, 491 [M+H]<+>Mass spectrum (ESI<+>): m/z = 489, 491 [M+H]<+>

(33) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1-(2-metoksy-acetyl)-piperidin-4-yloksy]-kinazolin (33) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-quinazoline

Reaksjonen finner sted med metoksyeddiksyreklorid. The reaction takes place with methoxyacetic acid chloride.

Rf verdi: 0,41 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.41 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 445, 447 [M+H]<+>Mass spectrum (ESI<+>): m/z = 445, 447 [M+H]<+>

(34) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-isopropyloksykarbonyl-piperidin-4-yloksy)-7-metoksy-kinazolin (34) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

Reaksjonen finner sted med isopropylklorformiat. The reaction takes place with isopropyl chloroformate.

Rf verdi: 0,67 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 98:2:1) Massespektrum (ESI<+>): m/z = 489, 491 [M+H]<+ >(35) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-cyano-piperidin-4-yloksy)-kinazolin Reaksjonen finner sted med bromcyanogen i metylenklorid. Rf value: 0.67 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 98:2:1) Mass spectrum (ESI<+>): m/z = 489, 491 [M+H]<+ >(35) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-quinazoline The reaction takes place with bromocyanogen in methylene chloride.

Rf verdi: 0,49 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.49 (silica gel, methylene chloride/methanol = 9:1)

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

(36) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(dimetylamino)sulfonyl]-piperidin-4-yloksyj-kinazolin (36) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)sulfonyl]-piperidin-4-yloxyquinazoline

Reaksjonen finner sted med N,N-dimetylsulfamoylklorid i acetonitril. The reaction takes place with N,N-dimethylsulfamoyl chloride in acetonitrile.

Rf verdi: 0,34 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.34 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 480, 482 [M+H]<+ >(37) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(morfolin-4-yl)sulfonyl]-piperidin-4-yloksyj-kinazolin Mass spectrum (ESI<+>): m/z = 480, 482 [M+H]<+ >(37) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[( morpholin-4-yl)sulfonyl]-piperidin-4-yloxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)sulfonylklorid i acetonitril. The reaction takes place with (morpholin-4-yl)sulfonyl chloride in acetonitrile.

Rf verdi: 0,15 (silikagel, cykloheksan/etylacetat = 1:1) Rf value: 0.15 (silica gel, cyclohexane/ethyl acetate = 1:1)

Massespektrum (ESI<+>): m/z = 522, 524 [M+H]<+>Mass spectrum (ESI<+>): m/z = 522, 524 [M+H]<+>

(38) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1-(2-acetylamino-etyl)-piperidin-4-yloksy]-kinazolin (38) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-quinazoline

Reaksjonen finner sted med eddiksyreanhydrid i acetonitril. The reaction takes place with acetic anhydride in acetonitrile.

smeltepunkt: 221 °C melting point: 221 °C

Massespektrum (ESI<+>): m/z = 458, 460 [M+H]<+>Mass spectrum (ESI<+>): m/z = 458, 460 [M+H]<+>

(39) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(dietylamino)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin (39) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(diethylamino)carbonyl]-piperidin-4-yloxy}-7-methoxyquinazoline

Reaksjonen finner sted med N,N-dietylkarbamoylklorid. The reaction takes place with N,N-diethylcarbamoyl chloride.

Rf verdi: 0,40 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 95:5:1) Massespektrum (ESI<+>): m/z = 502, 504 [M+H]<+ >(40) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1 -[(piperidin-1 -yl)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin Rf value: 0.40 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 95:5:1) Mass spectrum (ESI<+>): m/z = 502, 504 [M+H]<+ >(40) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxyquinazoline

Reaksjonen finner sted med (piperidin-1 -yl)karbonylklorid. The reaction takes place with (piperidin-1-yl)carbonyl chloride.

Rf verdi: 0,51 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 95:5:1) Massespektrum (ESI"): m/z = 512, 514 [M-H]" Rf value: 0.51 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 95:5:1) Mass spectrum (ESI"): m/z = 512, 514 [M-H]"

(41) 4-[(3-klor^-fluor-fenyl)amino]-6-{1-[(pyrrolidin-1-yl)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin (41) 4-[(3-Chloro^-fluoro-phenyl)amino]-6-{1-[(pyrrolidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxyquinazoline

Reaksjonen finner sted med (pyrrolidin-l-yl)karbonylklorid. The reaction takes place with (pyrrolidin-1-yl)carbonyl chloride.

smeltepunkt: 237°C melting point: 237°C

Massespektrum (ESI<+>): m/z = 500, 502 [M+H]<+>Mass spectrum (ESI<+>): m/z = 500, 502 [M+H]<+>

(42) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(4-metyl-piperazin-1-yl)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin (42) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(4-methyl-piperazin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy -quinazoline

Reaksjonen finner sted med (4-metyl-piperazin-1-yl)karbonylklorid-hydroklorid. Rf verdi: 0,28 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) The reaction takes place with (4-methyl-piperazin-1-yl)carbonyl chloride hydrochloride. Rf value: 0.28 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 90:10:1)

Massespektrum (ESI ): m/z = 527, 529 [M-H]" Mass spectrum (ESI ): m/z = 527, 529 [M-H]"

(43) 4-[(3-klor-4-fluor-fenyl)amino]-6-[cis-4-(N-metansulfonyl-N-metyl-amino)-cykloheksan-1-yloksy]-7-metoksy-kinazolin (43) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy- quinazoline

Reaksjonen finner sted i metylenklorid. The reaction takes place in methylene chloride.

Rf verdi: 0,71 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.71 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 509, 511 [M+H]<+>Mass spectrum (ESI<+>): m/z = 509, 511 [M+H]<+>

(44) 4-[(3-klor-4-fluor-fenyl)amino]-6-[cis-4-(N-acetyl-N-metyl-amino)-cykloheksan-1-yloksy]-7-metoksy-kinazolin (44) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy- quinazoline

Reaksjonen finner sted med eddiksyreanhydrid. The reaction takes place with acetic anhydride.

smeltepunkt: 234°C melting point: 234°C

Massespektrum (ESI<+>): m/z = 473, 475 [M+H]<+>Mass spectrum (ESI<+>): m/z = 473, 475 [M+H]<+>

(45) 4-[(3-klor-4-fluor-fenyl)amino]-6-{cis-4-[N-(2-metoksy-acetyl)-N-metylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin (45) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methylamino]-cyclohexan-1-yloxy}- 7-Methoxyquinazoline

Reaksjonen finner sted med metoksyeddiksyreklorid. The reaction takes place with methoxyacetic acid chloride.

Rf verdi: 0,40 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.40 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 503, 505 [M+H]<+>Mass spectrum (ESI<+>): m/z = 503, 505 [M+H]<+>

(46) 4-[(3-klor-4-fluor-fenyl)amino]-6-[cis-4-(N-dimetylaminokarbonyl-N-metylamino)-cykloheksan-1-yloksy]-7-metoksy-kinazolin (46) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminocarbonyl-N-methylamino)-cyclohexane-1-yloxy]-7-methoxyquinazoline

Reaksjonen finner sted med N,N-dimetylkarbamoylklorid. The reaction takes place with N,N-dimethylcarbamoyl chloride.

Rf verdi: 0,51 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.51 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 502, 504 [M+H]<+>Mass spectrum (ESI<+>): m/z = 502, 504 [M+H]<+>

(47) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-{N-[(morfolin-4-yl)karbonyl]-N-metylamino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin (47) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methylamino}-cyclohexane-1- yloxy)-7-methoxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)karbonylklorid. The reaction takes place with (morpholin-4-yl)carbonyl chloride.

Rf verdi: 0,50 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.50 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 544, 546 [M+H]<+>Mass spectrum (ESI<+>): m/z = 544, 546 [M+H]<+>

(48) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-{N-[(morfolin-4-yl)sulfonyl]-N-metylamino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin (48) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methylamino}-cyclohexane-1- yloxy)-7-methoxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)sulfonylklorid i acetonitril. The reaction takes place with (morpholin-4-yl)sulfonyl chloride in acetonitrile.

Rf verdi: 0,24 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.24 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 580, 582 [M+H]<+>Mass spectrum (ESI<+>): m/z = 580, 582 [M+H]<+>

(49) 4-[(3-klor-4-fluor-fenyl)amino]-6-[cis-4-(N-dimetylaminosulfonyl-N-metylamino)-cykloheksan-1-yloksy]-7-metoksy-kinazolin (49) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminosulfonyl-N-methylamino)-cyclohexane-1-yloxy]-7-methoxyquinazoline

Reaksjonen finner sted med N,N-dimetylsulfamoylklorid i acetonitril. The reaction takes place with N,N-dimethylsulfamoyl chloride in acetonitrile.

Rf verdi: 0,53 (silikagel, etylacetat) Rf value: 0.53 (silica gel, ethyl acetate)

Massespektrum (ESI<+>): m/z = 538, 540 [M+H]<+>Mass spectrum (ESI<+>): m/z = 538, 540 [M+H]<+>

(50) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-etansulfonylamino-cykloheksan-1 -yloksy)-7-metoksy-kinazolin (50) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulfonylamino-cyclohexan-1-yloxy)-7-methoxyquinazoline

Reaksjonen finner sted med etansulfonsyreklorid i metylenklorid. The reaction takes place with ethanesulfonic acid chloride in methylene chloride.

Rf verdi: 0,41 (silikagel, etylacetat) Rf value: 0.41 (silica gel, ethyl acetate)

Massespektrum (ESI<+>): m/z = 509, 511 [M+H]<+>Mass spectrum (ESI<+>): m/z = 509, 511 [M+H]<+>

(51) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1 -[(morfolin-4-yl)karbonyl]-piperidin-4-yloksy}-7-etoksy-kinazolin (51) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-ethoxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)karbonylklorid. The reaction takes place with (morpholin-4-yl)carbonyl chloride.

Rf verdi: 0,48 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.48 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 530, 532 [M+H]<+>Mass spectrum (ESI<+>): m/z = 530, 532 [M+H]<+>

(52) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-metansulfonyl-piperidin-4-yloksy)-7-etoksy-kinazolin (52) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

Rf verdi: 0,50 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 495, 497 [M+H]<+>Mass spectrum (ESI<+>): m/z = 495, 497 [M+H]<+>

(53) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1-(2-metoksy-acetyl)-piperidin-4-yloksy]-7-etoksy-kinazolin (53) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-ethoxy-quinazoline

Reaksjonen finner sted med metoksyeddiksyreklorid. The reaction takes place with methoxyacetic acid chloride.

Rf verdi: 0,40 (silikagel, metylenklorid/metanol = 20:1) Rf value: 0.40 (silica gel, methylene chloride/methanol = 20:1)

Massespektrum (ESI<+>): m/z = 489, 491 [M+H]<+>Mass spectrum (ESI<+>): m/z = 489, 491 [M+H]<+>

(54) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-metansulfonyl-piperidin-4-yloksy)-7-(2-metoksy-etoksy)-kinazolin (54) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

Rf verdi: 0,47 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.47 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 525, 527 [M+H]<+>Mass spectrum (ESI<+>): m/z = 525, 527 [M+H]<+>

(55) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(morfolin-4-yl)karbonyl]-piperidin-4-yloksy}-7-(2-metoksy-etoksy)-kinazolin (55) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy- ethoxy)-quinazoline

Reaksjonen finner sted med (morfolin-4-yl)karbonylklorid. The reaction takes place with (morpholin-4-yl)carbonyl chloride.

Rf verdi: 0,48 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.48 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 560, 562 [M+H]<+>Mass spectrum (ESI<+>): m/z = 560, 562 [M+H]<+>

(56) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1-(2-metoksy-acetyl)-piperidin-4-yloksy]-7-(2-metoksy-etoksy)-kinazolin (56) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)- quinazoline

Reaksjonen finner sted med metoksyeddiksyreklorid. The reaction takes place with methoxyacetic acid chloride.

Rf verdi: 0,48 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.48 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 519, 521 [M+H]<+>Mass spectrum (ESI<+>): m/z = 519, 521 [M+H]<+>

(57) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-acetylamino-cykloheksan-1-yloksy)-7-metoksy-kinazolin (57) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Reaksjonen finner sted med eddiksyreanhydrid. The reaction takes place with acetic anhydride.

smeltepunkt: 281 °C melting point: 281 °C

Massespektrum (ESI<+>): m/z = 459, 461 [M+H]<+>Mass spectrum (ESI<+>): m/z = 459, 461 [M+H]<+>

(58) 4-[(3-klor-4-fluor-fenyl)amino]-6-[cis-4-(2-metoksy-acetylamino)-cykloheksan-1-yloksy]-7-metoksy-kinazolin (58) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(2-methoxy-acetylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

Reaksjonen finner sted med metoksyeddiksyreklorid. The reaction takes place with methoxyacetic acid chloride.

smeltepunkt: 264°C melting point: 264°C

Massespektrum (ESI<+>): m/z = 489, 491 [M+H]<+>Mass spectrum (ESI<+>): m/z = 489, 491 [M+H]<+>

(59) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)karbonyl]-N-metyl-amino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin (59) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexane- 1-yloxy)-7-methoxyquinazoline

Reaksjonen finner sted med (piperidin-1-yl)karbonylklorid. The reaction takes place with (piperidin-1-yl)carbonyl chloride.

smeltepunkt: 253°C melting point: 253°C

Massespektrum (ESI<+>): m/z = 542, 544 [M+H]<+>Mass spectrum (ESI<+>): m/z = 542, 544 [M+H]<+>

(60) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-{N-[(4-metyl-piperazin-1- yl)karbonyl]-N-metyl-amino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin Reaksjonen finner sted med (4-metyl-piperazin-1-yl)karbonylklorid-hydroklorid. (60) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazine-1- yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline The reaction takes place with (4-methyl-piperazin-1-yl)carbonyl chloride hydrochloride.

smeltepunkt: 262°C melting point: 262°C

Massespektrum (ESI<+>): m/z = 557, 559 [M+H]<+>Mass spectrum (ESI<+>): m/z = 557, 559 [M+H]<+>

(61) 4-[(3-klor-4-fluor-fenyl)amino]-6-[cis-4-(N-etansulfonyl-N-metyl-amino)-cykloheksan-1-yloksy]-7-metoksy-kinazolin (61) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-ethanesulfonyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy- quinazoline

Reaksjonen finner sted med etansulfonsyreklorid i metylenklorid. The reaction takes place with ethanesulfonic acid chloride in methylene chloride.

Rf verdi: 0,19 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.19 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 523, 525 [M+H]<+>Mass spectrum (ESI<+>): m/z = 523, 525 [M+H]<+>

(62) 4-[(3-klor-4-fluor-fenyl)amino]-6-{cis-4-[(morfolin-4-yl)karbonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin (62) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)karbonylklorid. The reaction takes place with (morpholin-4-yl)carbonyl chloride.

Rf verdi: 0,33 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.33 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 530, 532 [M+H]<+>Mass spectrum (ESI<+>): m/z = 530, 532 [M+H]<+>

(63) 4-[(3-klor-4-fluor-fenyl)amino]-6-{cis-4-[(morfolin-4-yl)sulfonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin (63) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)sulfonylklorid i acetonitril. The reaction takes place with (morpholin-4-yl)sulfonyl chloride in acetonitrile.

Rf verdi: 0,81 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.81 (silica gel, ethyl acetate/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 566, 568 [M+H]<+>Mass spectrum (ESI<+>): m/z = 566, 568 [M+H]<+>

(64) 4-[(3-etynyl-fenyl)amino]-6-(1-acetyl-piperidin-4-yloksy)-7-metoksy-kinazolin (64) 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxyquinazoline

Reaksjonen finner sted med eddiksyreanhydrid. The reaction takes place with acetic anhydride.

Rf verdi: 0,30 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 417 [M+H]<+ >(65) 4-[(3-etynyl-fenyl)amino]-6-[1-(2-metoksy-acetyl)-piperidin-4-yloksy]-7-metoksy-kinazolin Rf value: 0.30 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 417 [M+H]<+ >(65) 4- [(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

Reaksjonen finner sted med metoksyeddiksyreklorid. The reaction takes place with methoxyacetic acid chloride.

Rf verdi: 0,37 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) Rf value: 0.37 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 90:10:1)

Massespektrum (ESI<+>): m/z = 447 [M+H]<+>Mass spectrum (ESI<+>): m/z = 447 [M+H]<+>

(66) 4-[(3-etynyl-fenyl)amino]-6-(1-metansulfonyl-piperidin-4-yloksy)-7- metoksy-kinazolin Rf verdi: 0,59 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 453 [M+H]<+ >(67) 4-[(3-etynyl-fenyl)amino]-6-{1-[(morfolin-4-yl)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin (66) 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7- methoxyquinazoline Rf value: 0.59 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 453 [M+H]<+ >(67 ) 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)karbonylklorid. The reaction takes place with (morpholin-4-yl)carbonyl chloride.

Rf verdi: 0,43 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 488 [M+H]<+ >(68) 4-[(3-klor-4-fluor-fenyl)amino]-6-[trans-4-(N-metansulfonyl-N-metyl-amino)-cykloheksan-1-yloksy]-7-metoksy-kinazolin Rf value: 0.43 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 488 [M+H]<+ >(68) 4- [(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxyquinazoline

Rf verdi: 0,50 (silikagel, metylenklorid /metanol = 9:1) Rf value: 0.50 (silica gel, methylene chloride / methanol = 9:1)

Massespektrum (ESI<+>): m/z = 509, 511 [M+H]<+>Mass spectrum (ESI<+>): m/z = 509, 511 [M+H]<+>

(69) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-{N-[(morfolin-4-yl)karbonyl]-N-metyl-amino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin (69) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexane- 1-yloxy)-7-methoxyquinazoline

Reaksjonen finner sted med (morfolin-4-yl)karbonylklorid. The reaction takes place with (morpholin-4-yl)carbonyl chloride.

Rf verdi: 0,54 (silikagel, metylenklorid /metanol = 9:1) Rf value: 0.54 (silica gel, methylene chloride / methanol = 9:1)

Massespektrum (ESI<+>): m/z = 544, 546 [M+H]<+>Mass spectrum (ESI<+>): m/z = 544, 546 [M+H]<+>

Eksempel 4 Example 4

4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-{[3-(morfolin-4-yl)-propyl]sulfonylamino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)-propyl]sulfonylamino}-cyclohexan-1-yloxy)-7- methoxyquinazoline

23 ul morfolin blir satt til 60 mg 4-[(3-klor-4-fluor-fenyl)amino]-6-{cis-4-[(3-klor-propyl)sulfonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin i 2 ml acetonitril og reaksjonsblandingen blir tilbakeløpskokt natten over. For opparbeiding blir blandingen tatt opp i etylacetat og vasket med vann. Den organiske fasen blir tørket over magnesiumsulfat og inndampet. Råproduktet blir renset gjennom en silikagel-kolonne med metylenklorid/metanol (9:1) som elueringsmiddel. 23 µl of morpholine is added to 60 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(3-chloro-propyl)sulfonylamino]-cyclohexan-1-yloxy}- 7-methoxyquinazoline in 2 ml of acetonitrile and the reaction mixture is refluxed overnight. For work-up, the mixture is taken up in ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate and evaporated. The crude product is purified through a silica gel column with methylene chloride/methanol (9:1) as eluent.

Utbytte: 18 mg (27% av teoretisk) Yield: 18 mg (27% of theoretical)

Rf verdi: 0,36 (silikagel, metylenklorid /metanol = 9:1) Rf value: 0.36 (silica gel, methylene chloride / methanol = 9:1)

Massespektrum (ESI<+>): m/z = 608, 610 [M+H]<+>Mass spectrum (ESI<+>): m/z = 608, 610 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 4: The following compounds are obtained analogously to Example 4:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-{[3-(morfolin-4-yl)- propyl]sulfonylamino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{[3-(morpholin-4-yl)- propyl]sulfonylamino}-cyclohexan-1-yloxy)-7-methoxyquinazoline

Rf verdi: 0,16 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 608, 610 [M+H]<+ >(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-[4-(morfolin-4-yl)-butyloksy]-kinazolin Rf value: 0.16 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 608, 610 [M+H]<+ >(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[4-(morpholin-4-yl)-butyloxy]-quinazoline

Utført i nærvær av natriumkarbonat og natriumjodid i N-metylpyrrolidon ved 100°C. Performed in the presence of sodium carbonate and sodium iodide in N-methylpyrrolidone at 100°C.

Rf verdi: 0,18 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 40:10:0,5) Rf value: 0.18 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 40:10:0.5)

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

(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-tetrahydrofuran-3-yloksy)-7-[4-(morfolin-4-yl)-butyloksy]-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[4-(morpholin-4-yl)-butyloxy]- quinazoline

Utført i nærvær av natriumkarbonat og natriumjodid i N-metylpyrrolidon ved 100°C. Performed in the presence of sodium carbonate and sodium iodide in N-methylpyrrolidone at 100°C.

Rf verdi: 0,32 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 80:20:1) Massespektrum (ESI<+>): m/z = 517, 519 [M+H]<+ >(4) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(morfolin-4-yl)acetyl]-piperidin-4-yloksyj-kinazolin Rf value: 0.32 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 80:20:1) Mass spectrum (ESI<+>): m/z = 517, 519 [M+H]<+ >(4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)acetyl]-piperidin-4-yloxyquinazoline

Utført i nærvær av Hunig base i tetrahydrofuran ved omgivelsestemperatur. Performed in the presence of Hunig's base in tetrahydrofuran at ambient temperature.

Rf verdi: 0,30 (silikagel, metylenklorid /metanol = 9:1) Rf value: 0.30 (silica gel, methylene chloride / methanol = 9:1)

Massespektrum (ESI<+>): m/z = 500, 502 [M+H]<+>Mass spectrum (ESI<+>): m/z = 500, 502 [M+H]<+>

(5) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-dimetylaminoacetyl-piperidin-4-yloksy)-kinazolin (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-dimethylaminoacetyl-piperidin-4-yloxy)-quinazoline

Utført i nærvær av Hunig base i tetrahydrofuran ved omgivelsestemperatur. Performed in the presence of Hunig's base in tetrahydrofuran at ambient temperature.

Rf verdi: 0,11 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) Rf value: 0.11 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 90:10:1)

Massespektrum (ESI<+>): m/z = 458, 460 [M+H]<+>Mass spectrum (ESI<+>): m/z = 458, 460 [M+H]<+>

(6) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-dimetylaminoacetyl-piperidin-4-yloksy)-7-metoksy-kinazolin (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-dimethylaminoacetyl-piperidin-4-yloxy)-7-methoxyquinazoline

Utført i nærvær av Hunig base i tetrahydrofuran ved omgivelsestemperatur. Performed in the presence of Hunig's base in tetrahydrofuran at ambient temperature.

Rf verdi: 0,19 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 488, 490 [M+H]<+ >(7) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(morfolin-4-yl)acetyl]-piperidin-4- Rf value: 0.19 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 488, 490 [M+H]<+ >(7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)acetyl]-piperidin-4-

yloksy}-7-metoksy-kinazolin yloxy}-7-methoxyquinazoline

Utført i nærvær av Hunig base i tetrahydrofuran ved omgivelsestemperatur. Performed in the presence of Hunig's base in tetrahydrofuran at ambient temperature.

Massespektrum (ESI<+>): m/z = 530, 532 [M+H]<+>Mass spectrum (ESI<+>): m/z = 530, 532 [M+H]<+>

Eksempel 5 Example 5

4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-pyrrolidin-3-yloksy)-7-metoksy-kinazolin-dihydroklorid 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-pyrrolidin-3-yloxy)-7-methoxyquinazoline dihydrochloride

En løsning av 370 mg 4-[(3-klor-4-fluor-fenyl)amino]-6-[(S)-1-(tert.-butyloksy-karbonyl)-pyrrolidin-3-yloksy]-7-metoksy-kinazolin i 5 ml dioksan blir kombinert med 0,32 ml konsentrert saltsyre og omrørt natten over ved omgivelsestemperatur. Fellingen dannet blir sugefiltrert og vasket med rikelige mengder av dioksan. Råproduktet blir oppløst i litt metanol og gjenutfelt ved tilsetning av samme mengde av etylacetat. Det hvite, faste stoffet således oppnådd blir sugefiltrert og tørket. A solution of 370 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(S)-1-(tert-butyloxy-carbonyl)-pyrrolidin-3-yloxy]-7-methoxy -quinazoline in 5 ml of dioxane is combined with 0.32 ml of concentrated hydrochloric acid and stirred overnight at ambient temperature. The precipitate formed is suction filtered and washed with copious amounts of dioxane. The crude product is dissolved in a little methanol and reprecipitated by adding the same amount of ethyl acetate. The white solid thus obtained is suction filtered and dried.

Utbytte: 200 mg (57 % av teoretisk) Yield: 200 mg (57% of theoretical)

smeltepunkt: 281 °C melting point: 281 °C

Massespektrum (ESI<+>): m/z = 389, 391 [M+H]<+>Mass spectrum (ESI<+>): m/z = 389, 391 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 5: The following compounds are obtained analogously to Example 5:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-3-yloksy)-7-metoksy-kinazolin-dihydroklorid (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxyquinazoline dihydrochloride

smeltepunkt: 263°C melting point: 263°C

Massespektrum (ESI<+>): m/z = 403, 505 [M+H]<+>Mass spectrum (ESI<+>): m/z = 403, 505 [M+H]<+>

(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1-(2-amino-etyl)-piperidin-4-yloksy]-7-metoksy-kinazolin-dihydroklorid (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-amino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline dihydrochloride

smeltepunkt: 277°C melting point: 277°C

Massespektrum (ESI<+>): m/z = 446, 448 [M+H]<+>Mass spectrum (ESI<+>): m/z = 446, 448 [M+H]<+>

(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-(3-amino-cykloheksan-1-yloksy)-7-metoksy-kinazolin-dihydroklorid (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline dihydrochloride

Massespektrum (ESI<+>): m/z = 417, 419 [M+H]<+>Mass spectrum (ESI<+>): m/z = 417, 419 [M+H]<+>

(4) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(2-amino-etoksy)-kinazolin-dihydroklorid (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-amino-ethoxy)-quinazoline dihydrochloride

Utført med isopropanolisk saltsyre (5-6 M) i metylenklorid. Performed with isopropanolic hydrochloric acid (5-6 M) in methylene chloride.

Rf verdi: 0,58 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.58 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 433, 435 [M+H]<+>Mass spectrum (ESI<+>): m/z = 433, 435 [M+H]<+>

(5) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(3-amino-propyloksy)-kinazolin-dihydroklorid (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-amino-propyloxy)-quinazoline dihydrochloride

Utført med isopropanolisk saltsyre (5-6 M) i metylenklorid. Performed with isopropanolic hydrochloric acid (5-6 M) in methylene chloride.

Rf verdi: 0,44 (Revers fase bruksklar TLC-plate (E. Merck), metanol/5% vandig natriumklorid-løsning = 7:3) Rf value: 0.44 (Reverse phase ready-to-use TLC plate (E. Merck), methanol/5% aqueous sodium chloride solution = 7:3)

Massespektrum (ESI<+>): m/z = 447, 449 [M+H]<+>Mass spectrum (ESI<+>): m/z = 447, 449 [M+H]<+>

(6) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1-(2-amino-etyl)-piperidin-4-yloksy]-kinazolin-dihydroklorid (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-amino-ethyl)-piperidin-4-yloxy]-quinazoline dihydrochloride

Rf verdi: 0,50 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.50 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

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

(7) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-metylamino-cykloheksan-1-yloksy)-7-metoksy-kinazolin-dihydroklorid (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline dihydrochloride

Utført med isopropanolisk saltsyre (5-6 M) i metylenklorid. Performed with isopropanolic hydrochloric acid (5-6 M) in methylene chloride.

Rf verdi: 0,35 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.35 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 431, 433 [M+H]<+>Mass spectrum (ESI<+>): m/z = 431, 433 [M+H]<+>

(8) 4-[(3-etynyl-fenyl)amino]-6-(piperidin-4-yloksy)-7-metoksy-kinazolin-dihydroklorid (8) 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline dihydrochloride

Utført med isopropanolisk saltsyre (5-6 M) i metylenklorid. Performed with isopropanolic hydrochloric acid (5-6 M) in methylene chloride.

Rf verdi: 0,50 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.50 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 375 [M+H]<+>Mass spectrum (ESI<+>): m/z = 375 [M+H]<+>

(9) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-metylamino-cykloheksan-1- (9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexane-1-

yloksy)-7-metoksy-kinazolin-dihydroklorid yloxy)-7-methoxyquinazoline dihydrochloride

smeltepunkt: 251 °C melting point: 251 °C

Massespektrum (ESI<+>): m/z = 431, 433 [M+H]<+>Mass spectrum (ESI<+>): m/z = 431, 433 [M+H]<+>

Eksempel 6 Example 6

4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-hydroksy-kinazolin En blanding av 9,00 g 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-benzyloksy-kinazolin-hydroklorid og 50 ml trifluoreddiksyre blir oppvarmet til 100°C i 1,5 timer. Deretter blir reaksjonsblandingen inndampet og residuet blir tatt opp i 10 ml acetonitril. Denne løsningen blir satt dråpevis til 100 ml mettet natriumhydrogenkarbonat-løsning med kraftig omrøring. Etter 1,5 timer blir fellingen dannet sugefiltrert og vasket mange ganger med vann. Råproduktet blir omrørt med dietyleter, sugefiltrert og tørket. 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxy-quinazoline A mixture of 9.00 g of 4-[(3-chloro-4-fluoro -phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline hydrochloride and 50 ml of trifluoroacetic acid are heated to 100°C for 1.5 hours. The reaction mixture is then evaporated and the residue is taken up in 10 ml of acetonitrile. This solution is added dropwise to 100 ml of saturated sodium bicarbonate solution with vigorous stirring. After 1.5 hours, the precipitate formed is suction filtered and washed many times with water. The crude product is stirred with diethyl ether, suction filtered and dried.

Utbytte: 5,90 g (87 % av teoretisk) Yield: 5.90 g (87% of theoretical)

Rf verdi: 0,21 (silikagel, etylacetat) Rf value: 0.21 (silica gel, ethyl acetate)

Massespektrum (ESI<+>): m/z = 390, 392 [M+H]<+>Mass spectrum (ESI<+>): m/z = 390, 392 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 6: The following compounds are obtained analogously to Example 6:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-tetrahydrofuran-3-yloksy)-7-hydroksy-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxyquinazoline

Rf verdi: 0,44 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.44 (silica gel, ethyl acetate/methanol = 9:1)

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

Eksempel 7 Example 7

4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-[3-(morfolin-4-yl)-propyloksy]-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[3-(morpholin-4-yl)-propyloxy]-quinazoline

En blanding av 300 mg 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-hydroksy-kinazolin, 130 mg 3-(morfolin-4-yl)-propylklorid og 530 mg kaliumkarbonat i 5 ml N,N-dimetylformamid blir omrørt natten over ved 80°C. For opparbeiding blir reaksjonsblandingen fortynnet med 25 ml vann og ekstrahert med etylacetat. De samlede organiske faser blir vasket med mettet natriumklorid-løsning, tørket over magnesiumsulfat og inndampet. Residuet blir omrørt med dietyleter, sugefiltrert og tørket. A mixture of 300 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxyquinazoline, 130 mg of 3-(morpholin-4-yl)- propyl chloride and 530 mg of potassium carbonate in 5 ml of N,N-dimethylformamide are stirred overnight at 80°C. For work-up, the reaction mixture is diluted with 25 ml of water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is stirred with diethyl ether, suction filtered and dried.

Utbytte: 250 mg (63 % av teoretisk) Yield: 250 mg (63% of theoretical)

smeltepunkt: 205°C melting point: 205°C

Massespektrum (ESI<+>): m/z = 517, 519 [M+H]<+>Mass spectrum (ESI<+>): m/z = 517, 519 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 7: The following compounds are obtained analogously to Example 7:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-[2-(morfolin-4-yl)-etoksy]-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[2-(morpholin-4-yl)-ethoxy]-quinazoline

Rf verdi: 0,33 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 40:10:0,5) Rf value: 0.33 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 40:10:0.5)

Massespektrum (ESI<+>): m/z = 503, 505 [M+H]<+>Mass spectrum (ESI<+>): m/z = 503, 505 [M+H]<+>

(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-etoksy- kinazolin Rf verdi: 0,76 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 418, 420 [M+H]<+ >(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-tetrahydrofuran-3-yloksy)-7-[3- (morfolin-4-yl)-propyloksy]-kinazolin Rf verdi: 0,20 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI ): m/z = 501, 503[M-H]" (4) 4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-tetrahydrofuran-3-yloksy)-7-[2- (morfolin-4-yl)-etoksy]-kinazolin Rf verdi: 0,19 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 489, 491 [M+H]<+ >(5) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(2-metoksy-etoksy)-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy- quinazoline Rf value: 0.76 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 418, 420 [M+H]<+ >(3 ) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[3- (morpholin-4-yl)-propyloxy]-quinazoline Rf value: 0.20 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI ): m/z = 501, 503[M-H ]" (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[2- (morpholin-4-yl)-ethoxy]-quinazoline Rf value: 0.19 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 489, 491 [M+H]<+ >(5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

Rf verdi: 0,57 (silikagel, metylenklorid /metanol = 9:1) Rf value: 0.57 (silica gel, methylene chloride / methanol = 9:1)

Massespektrum (ESI<+>): m/z = 448, 450 [M+H]<+>Mass spectrum (ESI<+>): m/z = 448, 450 [M+H]<+>

(6) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-[2-(tert.- (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[2-(tert-

butyloksykarbonylamino)-etoksy]-kinazolin butyloxycarbonylamino)-ethoxy]-quinazoline

Rf verdi: 0,64 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 95:5:0,1) Massespektrum (ESI<+>): m/z = 533, 535 [M+H]<+ >(7) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-[3-(tert.-butyloksykarbonylamino)-propyloksy]-kinazolin Rf value: 0.64 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 95:5:0.1) Mass spectrum (ESI<+>): m/z = 533, 535 [M+H]<+ >( 7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[3-(tert-butyloxycarbonylamino)-propyloxy]-quinazoline

Rf verdi: 0,74 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 95:5:0,1) Massespektrum (ESI<+>): m/z = 547, 549 [M+H]<+>Rf value: 0.74 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 95:5:0.1) Mass spectrum (ESI<+>): m/z = 547, 549 [M+H]<+>

Eksempel 8 Example 8

4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-kinazolin En løsning av 4,55 g 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-trifluoracetyl-piperidin-4-yloksy)-kinazolin-hydroklorid i 35 ml metanol blir blandet med 13 ml (3 N) natriumhydroksyd-løsning og omrørt i omtrent en halv en time ved omgivelsestemperatur. For opparbeiding blir reaksjonsblandingen fortynnet med vann og ekstrahert med etylacetat. De samlede organiske faser blir vasket med mettet natriumklorid-løsning, tørket over magnesiumsulfat og inndampet. Residuet blir omrørt med dietyleter, sugefiltrert og tørket. 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-quinazoline A solution of 4.55 g of 4-[(3-chloro-4-fluoro-phenyl)amino ]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline hydrochloride in 35 ml methanol is mixed with 13 ml (3 N) sodium hydroxide solution and stirred for about half an hour at ambient temperature. For work-up, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is stirred with diethyl ether, suction filtered and dried.

Utbytte: 3,00 g (89 % av teoretisk) Yield: 3.00 g (89% of theoretical)

Rf verdi: 0,48 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.48 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 373, 375 [M+H]<+>Mass spectrum (ESI<+>): m/z = 373, 375 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 8: The following compounds are obtained analogously to Example 8:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-etoksy-kinazolin Rf verdi: 0,20 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-ethoxyquinazoline Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1)

Massespektrum (ESI<+>): m/z = 417, 419 [M+H]<+>Mass spectrum (ESI<+>): m/z = 417, 419 [M+H]<+>

(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-(2-metoksy-etoksy)-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

Rf verdi: 0,10 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) Rf value: 0.10 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 90:10:1)

Massespektrum (ESI<+>): m/z = 447, 449 [M+H]<+>Mass spectrum (ESI<+>): m/z = 447, 449 [M+H]<+>

Eksempel 9 Example 9

4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(etylamino)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(ethylamino)carbonyl]-piperidin-4-yloxy}-7-methoxyquinazoline

Fremstilt ved omsetning av 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-metoksy-kinazolin med etylisocyanat i tetrahydrofuran ved omgivelsestemperatur. Prepared by reacting 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline with ethyl isocyanate in tetrahydrofuran at ambient temperature.

Rf verdi: 0,53 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 474, 476 [M+H]<+>Rf value: 0.53 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 474, 476 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 9: The following compounds are obtained analogously to Example 9:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1 -[(isopropylamino)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(isopropylamino)carbonyl]-piperidin-4-yloxy}-7-methoxyquinazoline

smeltepunkt: 236°C melting point: 236°C

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

(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(fenylamino)karbonyl]-piperidin-4- yloksy}-7-metoksy-kinazolin Rf verdi: 0,70 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 95:5:0,1) Massespektrum (ESI<+>): m/z = 522, 524 [M+H]<+ >(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-{N-[(etylamino)karbonyl]-N-metylamino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(phenylamino)carbonyl]-piperidine-4- yloxy}-7-methoxyquinazoline Rf value: 0.70 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 95:5:0.1) Mass spectrum (ESI<+>): m/z = 522, 524 [ M+H]<+ >(3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(ethylamino)carbonyl]-N-methylamino}-cyclohexane -1-yloxy)-7-methoxyquinazoline

Rf verdi: 0,38 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 502, 504 [M+H]<+>Mass spectrum (ESI<+>): m/z = 502, 504 [M+H]<+>

Eksempel 10 Example 10

4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(dimetylamino)karbonylmetyl]-piperidin-4-yloksyj-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonylmethyl]-piperidin-4-yloxyquinazoline

Fremstilt ved omsetning av 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-kinazolin med 2-klor-N,N-dimetylacetamid i nærvær av kaliumkarbonat i N,N-dimetylformamid ved omgivelsestemperatur. Prepared by reaction of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-quinazoline with 2-chloro-N,N-dimethylacetamide in the presence of potassium carbonate in N,N -dimethylformamide at ambient temperature.

Rf verdi: 0,24 (silikagel, metylenklorid/metanol = 9:1) Rf value: 0.24 (silica gel, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 458, 460 [M+H]<+>Mass spectrum (ESI<+>): m/z = 458, 460 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 10: The following compounds are obtained analogously to Example 10:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1 -[(morfolin-4-yl)karbonylmetyl]-piperidin-4-yloksy}-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonylmethyl]-piperidin-4-yloxy}-quinazoline

Rf verdi: 0,42 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.42 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 500, 502 [M+H]<+>Mass spectrum (ESI<+>): m/z = 500, 502 [M+H]<+>

(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-aminokarbonylmetyl-piperidin-4-yloksy)-7-metoksy-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline

smeltepunkt: 251 °C melting point: 251 °C

Massespektrum (ESI<+>): m/z = 460, 462 [M+H]<+>Mass spectrum (ESI<+>): m/z = 460, 462 [M+H]<+>

(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(dimetylamino)karbonylmetyl]-piperidin-4-yloksy}-7-metoksy-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonylmethyl]-piperidin-4-yloxy}-7-methoxyquinazoline

smeltepunkt: 233°C melting point: 233°C

Massespektrum (ESI<+>): m/z = 488, 490 [M+H]<+>Mass spectrum (ESI<+>): m/z = 488, 490 [M+H]<+>

(4) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(morfolin-4-yl)karbonylmetyl]-piperidin-4-yloksy}-7-metoksy-kinazolin (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonylmethyl]-piperidin-4-yloxy}-7-methoxyquinazoline

smeltepunkt: 245°C melting point: 245°C

Massespektrum (ESI<+>): m/z = 530, 532 [M+H]<+>Mass spectrum (ESI<+>): m/z = 530, 532 [M+H]<+>

Eksempel 11 Example 11

4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(tetrahydropyran-4-yl)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(tetrahydropyran-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxyquinazoline

90 mg 1-hydroksy-1H-benzotriazol og 250 mg 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetrametyluronium-tetrafluorborat blir satt til en blanding av 300 mg 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-metoksy-kinazolin-dihydroklorid, 82 mg tetrahydropyran-4-karboksylsyre og 0,54 ml Hunig base i 5 ml N,N-dimetylformamid. Reaksjonsblandingen blir omrørt natten over ved omgivelsestemperatur. For opparbeiding blir den blandet med 25 ml etylacetat og vasket med vann, 10% kaliumkarbonat-løsning og mettet natriumklorid-løsning. Den organiske fasen blir tørket over magnesiumsulfat og inndampet. Residuet blir omrørt med litt etylacetat, sugefiltrert og tørket. 90 mg of 1-hydroxy-1H-benzotriazole and 250 mg of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate are added to a mixture of 300 mg of 4-[(3-chloro -4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline dihydrochloride, 82 mg tetrahydropyran-4-carboxylic acid and 0.54 ml Hunig base in 5 ml N,N-dimethylformamide . The reaction mixture is stirred overnight at ambient temperature. For work-up, it is mixed with 25 ml of ethyl acetate and washed with water, 10% potassium carbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and evaporated. The residue is stirred with a little ethyl acetate, suction filtered and dried.

Utbytte: 250 mg (77 % av teoretisk) Yield: 250 mg (77% of theoretical)

Rf verdi: 0,43 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 515, 517 [M+H]<+>Rf value: 0.43 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 515, 517 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 11: The following compounds are obtained analogously to Example 11:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(tetrahydropyran-4- yl)karbonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin Rf verdi: 0,44 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 529, 531 [M+H]<+ >(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)karbonyl]-N-metyl-amino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(tetrahydropyran-4- yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline Rf value: 0.44 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m /z = 529, 531 [M+H]<+ >(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4- yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Rf verdi: 0,31 (silikagel, etylacetat/metanol = 9:1) Rf value: 0.31 (silica gel, ethyl acetate/methanol = 9:1)

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

Eksempel 12 Example 12

4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[([1,4]oksazepan-4-yl)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[([1,4]oxazepan-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxyquinazoline

4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-metoksy-kinazolin-dihydroklorid og 1,05 ml trietylamin blir satt til 900 mg 1-metyl-3-[([1,4]oksazepan-4-yl)karbonyl]-3H-imidazol-1-ium-jodid i 10 ml metylenklorid. Den gulaktige suspensjonen blir omrørt i ca. 24 timer ved omgivelsestemperatur. For opparbeiding blir reaksjonsblandingen blandet med 50 ml metylenklorid og ekstrahert med vann så vel som 10% sitronsyre. Den organiske fasen blir vasket med mettet natriumklorid-løsning, tørket over magnesiumsulfat og inndampet. Residuet blir kromatografert gjennom en silikagel-kolonne med metylenklorid/metanol/kons. ammoniakk som 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline dihydrochloride and 1.05 ml of triethylamine are added to 900 mg of 1-methyl-3 -[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazol-1-ium iodide in 10 ml of methylene chloride. The yellowish suspension is stirred for approx. 24 hours at ambient temperature. For workup, the reaction mixture is mixed with 50 ml of methylene chloride and extracted with water as well as 10% citric acid. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is chromatographed through a silica gel column with methylene chloride/methanol/conc. ammonia which

elueringsmiddel. Det ønskede produkt blir omrørt med dietyleter, sugefiltrert og tørket. eluent. The desired product is stirred with diethyl ether, suction filtered and dried.

Utbytte: 800 mg (80 % av teoretisk) Yield: 800 mg (80% of theoretical)

Rf verdi: 0,30 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) Rf value: 0.30 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 90:10:1)

Massespektrum (ESI<+>): m/z = 530, 532 [M+H]<+>Mass spectrum (ESI<+>): m/z = 530, 532 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 12: The following compounds are obtained analogously to Example 12:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(cis-2,6-dimetyl-morfolin-4-yl)karbonyl]- piperidin-4-yloksy}-7-metoksy-kinazolin Rf verdi: 0,41 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 544, 546 [M+H]<+ >(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(2-metyl-morfolin-4-yl)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]- Piperidin-4-yloxy}-7-methoxyquinazoline Rf value: 0.41 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 544, 546 [M+H]<+ >(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidine -4-yloxy}-7-methoxyquinazoline

Rf verdi: 0,50 (silikagel, etylacetat/metanol/kons. vandig ammoniakk = 90:10:1) Massespektrum (ESI<+>): m/z = 530, 532 [M+H]<+>Rf value: 0.50 (silica gel, ethyl acetate/methanol/con. aqueous ammonia = 90:10:1) Mass spectrum (ESI<+>): m/z = 530, 532 [M+H]<+>

Eksempel 13 Example 13

4-[(3-klor-4-fluor-fenyl)amino]-6-(1-metyl-piperidin-4-yloksy)-7-etoksy-kinazolin 35 ul 37 % vandig formalin-løsning og 110 mg natrium triacetoksyborhydrid blir satt til 175 mg 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-etoksy-kinazolin i 1 ml tetrahydrofuran. Reaksjonsblandingen blir omrørt i omtrent fire timer ved omgivelsestemperatur. For opparbeiding blir 5 ml mettet natriumhydrogenkarbonat-løsning tilsatt og blandingen blir omrørt grundig. Deretter blir 20 ml etylacetat tilsatt og den vandige fasen blir separert fra. Den organiske fasen blir vasket med vann og mettet natriumklorid-løsning, tørket over magnesiumsulfat og inndampet. Residuet blir omrørt med diisopropyleter, sugefiltrert og tørket. 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-ethoxyquinazoline 35 µl 37% aqueous formalin solution and 110 mg sodium triacetoxyborohydride are added to 175 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-ethoxyquinazoline in 1 ml of tetrahydrofuran. The reaction mixture is stirred for about four hours at ambient temperature. For work-up, 5 ml of saturated sodium bicarbonate solution is added and the mixture is stirred thoroughly. Then 20 ml of ethyl acetate are added and the aqueous phase is separated from. The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is stirred with diisopropyl ether, suction filtered and dried.

Utbytte: 144 mg (80 % av teoretisk) Yield: 144 mg (80% of theoretical)

Rf verdi: 0,80 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 60:10:1) Rf value: 0.80 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 60:10:1)

Massespektrum (ESI<+>): m/z = 431, 433 [M+H]<+>Mass spectrum (ESI<+>): m/z = 431, 433 [M+H]<+>

De følgende forbindelser blir oppnådd analogt med Eksempel 13: The following compounds are obtained analogously to Example 13:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1 -metyl-piperidin-4-yloksy)-7(2-metoksy-etoksy)-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline

Rf verdi: 0,85 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 60:10:1) Rf value: 0.85 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 60:10:1)

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

(2) 4-[(3-etynyl-fenyl)amino]-6-(1-metyl-piperidin-4-yloksy)-7-metoksy-kinazolin-hydroklorid (2) 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline hydrochloride

Rf verdi: 0,26 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) Rf value: 0.26 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 90:10:1)

Massespektrum (ESI<+>): m/z = 389 [M+H]<+>Mass spectrum (ESI<+>): m/z = 389 [M+H]<+>

(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-dimetylamino-cykloheksan-1-yloksy)-7-metoksy-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Rf verdi: 0,80 (aluminiumoksyd, metylenklorid/metanol = 9:1) Rf value: 0.80 (alumina, methylene chloride/methanol = 9:1)

Massespektrum (ESI<+>): m/z = 445, 447 [M+H]<+>Mass spectrum (ESI<+>): m/z = 445, 447 [M+H]<+>

(4) 4-[(3-klor-4-fluor-fenyl)amino]-S-(1-etyl-piperidin-4-yloksy)-7-metoksy-kinazolinhydroklorid (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-S-(1-ethyl-piperidin-4-yloxy)-7-methoxyquinazoline hydrochloride

Utført med acetaldehyd Done with acetaldehyde

Rf verdi: 0.44 (Omvendt fase ferdiglaget TLC plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.44 (Reverse phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 431, 433 [M+H]<+>Mass spectrum (ESI<+>): m/z = 431, 433 [M+H]<+>

Eksempel 14 Example 14

4-[(3-etynyl-fenyl)amino]-6-[1-(tert.-butyloksykarbonyl)-piperidin-4-yloksy]-7-metoksy-kinazolin 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxyquinazoline

En blanding av 3,00 g 4-[(3-etynyl-fenyl)amino]-6-hydroksy-7-metoksy-kinazolin, 4,50 g 1-(tert.-butyloksykarbonyl)-4-(p-toluolsulfonyloksy)-piperidin og 2,90 g kaliumkarbonat i 30 ml N,N-dimetylformamid blir omrørt i to dager ved 60°C. For opparbeiding blir blandingen blandet med 200 ml etylacetat og ekstrahert med vann. Den organiske fasen blir vasket med mettet natriumklorid-løsning, tørket over magnesiumsulfat og inndampet. Råproduktet blir renset over en silikagel-kolonne med metylenklorid/metanol/kons. ammoniakk som elueringsmiddel. A mixture of 3.00 g of 4-[(3-ethynyl-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline, 4.50 g of 1-(tert-butyloxycarbonyl)-4-(p-toluenesulfonyloxy) -piperidine and 2.90 g of potassium carbonate in 30 ml of N,N-dimethylformamide are stirred for two days at 60°C. For work-up, the mixture is mixed with 200 ml of ethyl acetate and extracted with water. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The crude product is purified over a silica gel column with methylene chloride/methanol/conc. ammonia as eluent.

Utbytte: 3,25 g (67 % av teoretisk) Yield: 3.25 g (67% of theoretical)

Rf verdi: 0,25 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 95:5:1) Rf value: 0.25 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 95:5:1)

Massespektrum (ESI<+>): m/z = 475 [M+H]<+>Mass spectrum (ESI<+>): m/z = 475 [M+H]<+>

Den følgende forbindelse blir oppnådd analogt med Eksempel 14: The following compound is obtained analogously to Example 14:

(1) 4-[(3-etynyl-fenyl)amino]-6-(tetrahydropyran-4-yloksy]-7-metoksy-kinazolin Rf verdi: 0,40 (silikagel, metylenklorid/metanol/kons. vandig ammoniakk = 90:10:1) (1) 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxyquinazoline Rf value: 0.40 (silica gel, methylene chloride/methanol/con. aqueous ammonia = 90 :10:1)

Massespektrum (ESI<+>): m/z = 376 [M+H]<+>Mass spectrum (ESI<+>): m/z = 376 [M+H]<+>

Eksempel 15 Example 15

4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[2-(tert.-butyloksykarbonylamino)-etyl]-piperidin-4-yloksy}-7-metoksy-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-7-methoxyquinazoline

En blanding av 410 mg 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-metoksy-kinazolin-dihydroklorid, 240 mg N-(tert.-butyloksykarbonyl)-2-brom-etylamin og 360 mg kaliumkarbonat i 5 ml N,N-dimetylformamid blir omrørt natten over ved omgivelsestemperatur. Deretter blir ytterligere 80 mg N-(tert-butyloksykarbonyl)-2-brom-etylamin tilsatt og reaksjonsblandingen blir omrørt i ytterligere fire timer ved omgivelsestemperatur. For opparbeiding blir den fortynnet med vann og ekstrahert med etylacetat. De samlede organiske faser blir vasket med mettet natriumklorid-løsning, tørket over magnesiumsulfat og inndampet. Residuet blir kromatografert gjennom en silikagel-kolonne med etylacetat/metanol (95:5 til 90:1) som elueringsmiddel. A mixture of 410 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline dihydrochloride, 240 mg of N-(tert-butyloxycarbonyl) -2-bromoethylamine and 360 mg of potassium carbonate in 5 ml of N,N-dimethylformamide are stirred overnight at ambient temperature. Then a further 80 mg of N-(tert-butyloxycarbonyl)-2-bromoethylamine is added and the reaction mixture is stirred for a further four hours at ambient temperature. For processing, it is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is chromatographed through a silica gel column with ethyl acetate/methanol (95:5 to 90:1) as eluent.

Utbytte: 370 mg (79 % av teoretisk) Yield: 370 mg (79% of theoretical)

Rf verdi: 0,33 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.33 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI ): m/z = 544, 546 [M-H]" Mass spectrum (ESI ): m/z = 544, 546 [M-H]"

Den følgende forbindelse blir oppnådd analogt med Eksempel 15: The following compound is obtained analogously to Example 15:

(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[2-(tert.-butyloksykarbonylamino)-etyl]-piperidin-4-yloksy}-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-quinazoline

Rf verdi: 0,38 (Revers fase bruksklar TLC-plate (E. Merck), acetonitril/vann/ trifluoreddiksyre = 50:50:1) Rf value: 0.38 (Reverse phase ready-to-use TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Massespektrum (ESI<+>): m/z = 516, 518 [M+H]<+>Mass spectrum (ESI<+>): m/z = 516, 518 [M+H]<+>

De følgende forbindelser kan også fremstilles analogt med foregående Eksempler og andre metoder kjent fra litteraturen: The following compounds can also be prepared analogously to the preceding Examples and other methods known from the literature:

Eksempel 16 Example 16

Belagte tabletter inneholdende 75 mg aktiv substans Coated tablets containing 75 mg of active substance

Fremstilling: Manufacturing:

Den aktive substans blir blandet med kalsiumfosfat, maisstivelse, polyvinylpyrrolidon, hydroksypropylmetylcellulose og halve den spesifiserte mengde av magnesiumstearat. Pressede former 13 mm i diameter blir produsert i en tablett-fremstillingsmaskin og disse blir deretter gnidd gjennom en sikt med en mesh-størrelse på 1,5 mm ved anvendelse av en egnet maskin og blandet med resten av magnesiumstearatet. Dette granulatet blir sammenpresset i en tablett-fremstillingsmaskin for å danne tabletter med den ønskede form. The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Pressed forms 13 mm in diameter are produced in a tablet making machine and these are then rubbed through a sieve with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape.

Vekt av kjerne: 230 mg Weight of core: 230 mg

stempel: 9 mm, konveks piston: 9 mm, convex

Tablettkjerner således produsert blir belagt med en film bestående i det vesentlige av hydroksypropylmetylcellulose. De ferdige film-belagte tabletter blir polert med bivoks. Tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax.

Vekt av belagt tablett: 245 mg. Weight of coated tablet: 245 mg.

Eksempel 17 Example 17

Tabletter inneholdende 100 mg aktiv substans Tablets containing 100 mg of active substance

Sammensetning: Composition:

Fremstillingsmetode: Manufacturing method:

Den aktive substans, laktose og stivelse blir blandet sammen og jevnt fuktet med en vandig løsning av polyvinylpyrrolidon. Etter at det fuktige preparatet er siktet (2,0 mm mesh størrelse) og tørket i en stativtype tørker ved 50°C blir det siktet igjen (1,5 mm mesh størrelse) og smøremidlet blir tilsatt. Den ferdige blanding blir sammenpresset for å danne tabletter. The active substance, lactose and starch are mixed together and evenly moistened with an aqueous solution of polyvinylpyrrolidone. After the moist preparation is sieved (2.0 mm mesh size) and dried in a rack-type dryer at 50°C, it is sieved again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.

Vekt av tablett: 220 mg Weight of tablet: 220 mg

Diameter: 10 mm, biplanare, fasettslipt på begge sider og gitt hakk på én side. Diameter: 10 mm, biplanar, faceted on both sides and notched on one side.

Eksempel 18 Example 18

Tabletter inneholdende 150 mg aktiv substans Tablets containing 150 mg of active substance

Sammensetning: Composition:

Fremstilling: Manufacturing:

Den aktive substans blandet med laktose, maisstivelse og silika blir fuktet med en 20% vandig polyvinylpyrrolidonløsning og ført gjennom en sikt med en mesh-størrelse på 1,5 mm. Granulene, tørket ved 45°C, blir ført gjennom samme sikt igjen og blandet med den spesifiserte mengde av magnesiumstearat. Tabletter blir presset fra blandingen. The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a mesh size of 1.5 mm. The granules, dried at 45°C, are passed through the same sieve again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.

Eksempel 19 Example 19

Harde gelatinkapsler inneholdende 150 mg aktiv substans Sammensetning: Hard gelatin capsules containing 150 mg of active substance Composition:

1 kapsel inneholder: 1 capsule contains:

Fremstilling: Manufacturing:

Den aktive substans blir blandet med tilsetningsmidlene, ført gjennom en sikt med en mesh-størrelse på 0,75 mm og homogent blandet ved anvendelse av et egnet apparat. Den ferdige blanding blir pakket i størrelse 1 harde gelatinkapsler. The active substance is mixed with the additives, passed through a sieve with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packaged in size 1 hard gelatin capsules.

Kapsel fylling: ca. 320 mg Capsule filling: approx. 320 mg

Kapselskall: størrelse 1 hard gelatinkapsel. Capsule shell: size 1 hard gelatin capsule.

Eksempel 20 Example 20

Suppositorier inneholdende 150 mg aktiv substans Suppositories containing 150 mg of active substance

Sammensetning: Composition:

Fremstilling: Manufacturing:

Etter at suppositorium-massen er smeltet blir den aktive substans homogent fordelt deri og smeiten blir hellet i avkjølte former. After the suppository mass has been melted, the active substance is homogeneously distributed therein and the mixture is poured into cooled molds.

Eksempel 21 Example 21

Suspensjon inneholdende 50 mg aktiv substans Suspension containing 50 mg of active substance

Sammensetning: Composition:

100 ml suspensjon inneholder: 100 ml suspension contains:

Fremstilling: Manufacturing:

Det destillerte vannet blir oppvarmet til 70°C. Metyl- og propyl-p-hydroksybenzoater sammen med glycerol og natriumsalt av karboksymetylcellulose oppløses deri med omrøring. Løsningen blir avkjølt til omgivelsestemperatur og den aktive substans blir tilsatt og homogent dispergert deri med omrøring. Etter at sukkeret, sorbitolløsningen og smaksmidlene er tilsatt og oppløst, blir suspensjonen evakuert med omrøring for å fjerne luft. The distilled water is heated to 70°C. Methyl and propyl p-hydroxybenzoates together with glycerol and sodium salt of carboxymethyl cellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, sorbitol solution and flavors are added and dissolved, the suspension is evacuated with agitation to remove air.

5 ml suspensjon inneholder 50 mg aktiv substans. 5 ml of suspension contains 50 mg of active substance.

Eksempel 22 Example 22

Ampuller inneholdende 10 mg aktiv substans Ampoules containing 10 mg of active substance

Sammensetning: Composition:

Fremstilling: Manufacturing:

Den aktive substans blir oppløst i den nødvendige mengden av 0,01 N HCI, gjort isotonisk med vanlig salt, sterilfiltrert og overført til 2 ml ampuller. The active substance is dissolved in the required amount of 0.01 N HCI, made isotonic with normal salt, sterile filtered and transferred to 2 ml ampoules.

Eksempel 23 Example 23

Ampuller inneholdende 50 mg aktiv substans Ampoules containing 50 mg of active substance

Sammensetning: Composition:

Fremstilling: Manufacturing:

Den aktive substans blir oppløst i den nødvendige mengden av 0,01 N HCI, gjort isotonisk med vanlig salt, sterilfiltrert og overført til 10 ml ampuller. The active substance is dissolved in the required amount of 0.01 N HCI, made isotonic with normal salt, sterile filtered and transferred to 10 ml ampoules.

Eksempel 24 Example 24

Kapsler for pulver- inhalering inneholdende 5 mg aktiv substans Capsules for powder inhalation containing 5 mg of active substance

1 kapsel inneholder: 1 capsule contains:

Fremstilling: Manufacturing:

Den aktive substans blir blandet med laktose for inhalering. Blandingen blir pakket i kapsler i en kapsel-fremstillingsmaskin (vekt av tom kapsel ca. 50 mg). The active substance is mixed with lactose for inhalation. The mixture is packed into capsules in a capsule-making machine (weight of empty capsule approx. 50 mg).

størrelse av kapsel = 3 size of capsule = 3

Eksempel 25 Example 25

Inhalerbar løsning for håndholdte forstøvere inneholdende 2, 5 mg aktiv substans Inhalable solution for handheld nebulizers containing 2.5 mg of active substance

1 spray inneholder: 1 spray contains:

Fremstilling: Manufacturing:

Den aktive substans og benzalkoniumklorid oppløses i etanol/vann (50/50). pH i løsningen blir regulert med 1N saltsyre. Den resulterende løsning blir filtrert og overført til egnede beholdere for anvendelse i håndholdte forstøvere (patroner). Innhold av beholderen: 4,5 g The active substance and benzalkonium chloride are dissolved in ethanol/water (50/50). The pH of the solution is regulated with 1N hydrochloric acid. The resulting solution is filtered and transferred to suitable containers for use in handheld nebulizers (cartridges). Contents of the container: 4.5 g

Claims (14)

1. Bicyklisk, heterocyklisk forbindelse med den generelle formel 1, hvor Ra betyr et hydrogenatom, R<b> betyr en 3-etynylfenyl-, 3-bromfenyl-, 3,4-difluorfenyl- eller 3-klor-4-fluor-fenylgruppe, en 3-klor-4-benzyloksy-fenyl-, 3-klor-4-[(3-fluor-benzyl)oksy]-fenyl-, 4-(pyridin-3-yloksy)-fenyl-, 4-[(6-metyl-pyridin-3-yl)oksy]-fenyl-, 3-metyl-4-(pyridin-3-yloksy)-fenyl-, 3-metyl-4-[(6-metyl-pyridin-3-yl)oksy]-fenyl-, 3-klor-4-(pyridin-3-yloksy)-fenyl- eller 3-klor-4-[(6-metyl-pyridin-3-yl)oksy]-fenylgruppe, R<c> betyr en cykloheksylgruppe som er substituert i 3-stillingen eller i 4-stillingen med en gruppe R<4->N-R<5>, hvor R<4> betyr et hydrogenatom, en metyl- eller etylgruppe og R<5> betyr et hydrogenatom, en metyl-, aminokarbonylmetyl-, metylamino-karbonylmetyl-, dimetylaminokarbonylmetyl-, pyrrolidin-1-ylkarbonylmetyl-, piperidin-1 -ylkarbonylmetyl-, piperazin-1-ylkarbonylmetyl-, 4-metylpiperazin-1 -ylkarbonylmetyl-, morfolin-4-ylkarbonylmetyl-, 2-(morfolin-4-yl-karbonyl)etyl- eller 3-(morfolin-4-ylkarbonyl)propylgruppe, en etyl-, propyl-, 2-hydroksyetyl-, 3-hydroksypropyl-, 2-metoksyetyl-, 3-metoksypropyl-, 2-(butyloksykarbonylamino)-etyl-, 2-aminoetyl-, 3-aminopropyl-, 2-(acetylamino)etyl-, 3-(acetylamino)propyl-, 2-(etylkarbonylamino)etyl-, 3-(etylkarbonylamino)propyl-, 2-(propylkarbonylamino)etyl-, 3-(propylkarbonylamino)propyl-, 2-(etylaminokarbonylamino)etyl-, 3-(etylaminokarbonylamino)propyl-, 2-(dimetylaminokarbonylamino)etyl-, 3-(dimetylaminokarbonylamino)propyl-, 2-(morfolin-4-ylkarbonylamino)etyl-, 3-(morfolin-4-ylkarbonylamino)propyl-, 2-(metylsulfonyl)etyl-, 3-(metylsulfonyl)propyl-, 2-(metylsulfonylamino)etyl- eller en 3-(metylsulfonylamino)propylgruppe, en 2-(2-okso-pyrrolidin-1-yl)etyl-, 2-(2-oksopiperidin-1-yl)etyl-, 2-(3-okso-morfolin-4-yl)etyl-, 2-(2-okso-imidazolidin-1 -yl)etyl-, 2-(2-okso-3-metyl-imidazolidin-1-yl)etyl-, 2-(2-okso-heksahydropyrimidin-1-yl)etyl- eller en 2- (2-okso-3-metyl-heksahydropyrimidin-1-yl)etylgruppe, en 3-(2-okso-pyrrolidin-1-yl)propyl-, 3-(2-oksopiperidin-1-yl)propyl-, 3-(3-okso-morfolin-4-yl)propyl-, 3-(2-okso-imidazolidin-1-yl)propyl-, 3-(2-okso-3- metyl-imidazolidin-1 -yl)propyl-, 3-(2-okso-heksahydropyrimidin-1 - yl)propyl- eller en 3-(2-okso-3-metyl-heksahydropyrimidin-1-yl)propylgruppe, en metylsulfonyl-, etylsulfonyl-, 3-klorpropylsulfonyl-, 2-(morfolin-4-yl)-etylsulfonyl- eller en 3-(morfolin-4-yl)-propylsulfonylgruppe, en propyloksykarbonyl- eller butyloksykarbonylgruppe, en formyl-, acetyl-, etylkarbonyl-, propylkarbonyl-, metoksyacetyl-, (2-metoksyetyl)karbonyl-, (3-metoksypropyl)karbonyl-, tetrahydrofuran-2-ylkarbonyl-, tetrahydropyran-4-ylkarbonyl-, aminoacetyl-, metylaminoacetyl-, dimetylaminoacetyl-, morfolin-4-ylacetyl, [2-(morfolin-4- yl)etyl]karbonyl-, [3-(morfolin-4-yl)propyl]karbonyl- eller en metylsulfonylacetylgruppe, en cyano-, aminokarbonyl-, metylaminokarbonyl-, dimetylaminokarbonyl-, etylaminokarbonyl-, dietylaminokarbonyl-, propylaminokarbonyl-, (2-metoksyetyl)aminokarbonyl-, N-metyl-N-(2-metoksyetyl)-aminokarbonyl-, (3-metoksypropyl)aminokarbonyl-, N-metyl-N-(3-metoksypropyl)-aminokarbonyl-, fenylaminokarbonyl-, pyrrolidin-1-ylkarbonyl-, piperidin-1-ylkarbonyl-, morfolin-4-ylkarbonyl-, 2-metylmorfolin-4-ylkarbonyl-, 2,6-dimetylmorfolin-4-ylkarbonyl-, homomorfolin-4-ylkarbonyl-, 2-oksa-5-aza-bicyklo[2.2.1]hept-5-ylkarbonyl-, 3-oksa-8-aza-bicyklo[3.2.1]okt-8-ylkarbonyl-, 8-oksa-3-aza-bicyklo[3.2.1]okt-3-ylkarbonyl-, 4-metylpiperazin-1 -ylkarbonyl-, aminosulfonyl-, metylaminosulfonyl-, dimetylaminosulfonyl- eller en morfolin-4-ylsulfonylgruppe, en cykloheksylgruppe som er substituert i 3-stillingen eller i 4-stillingen med en gruppe R<6>, hvor R<6> betyr en 2-okso-pyrrolidin-1-yl-, 2-oksopiperidin-1-yl-, 3-okso-morfolin-4-yl-, 2-okso-imidazolidin-1-yl-, 2-okso-3-metyl-imidazolidin-1-yl-, 2-okso-heksahydropyrimidin-1-yl eller en 2-okso-3-metyl-heksahydropyrimidin-1-ylgruppe, en pyrrolidin-3-ylgruppe som er substituert i 1-stillingen med gruppen R5, hvor R<5> er som ovenfor definert, en piperidin-3-ylgruppe som er substituert i 1-stillingen med gruppen R<5>, hvor R<5 >er som ovenfor definert, en piperidin-4-ylgruppe som er substituert i 1-stillingen med gruppen R<5>, hvor R<5 >er som ovenfor definert, en tetrahydrofuran-3-yl-, tetrahydropyran-3-yl- eller tetrahydropyran-4-ylgruppe, Rd betyr et hydrogenatom, en metoksy-, difluormetoksy- eller etyloksygruppe, en etyloksygruppe som er substituert i 2-stillingen med en gruppe R<6> eller R<7>, hvor R<6> er som ovenfor definert og R<7> betyr en hydroksy-, metoksy-, etoksy-, amino-, dimetylamino-, dietylamino-, bis-(2-metoksyetyl)-amino-, pyrrolidin-1-yl-, piperidin-1-yl-, morfolin-4-yl-, homomorfolin-4-yl-, 2-oksa-5-aza-bicyklo[2.2.1]hept-5-yl-, 3-oksa-8-aza-bicyklo[3.2.1 ]okt-8-yl-, 8-oksa-3-aza-bicyklo[3.2.1 ]okt-3-yl-, piperazin-1-yl-, 4-metylpiperazin-1-yl- eller 4-etylpiperazin-1-ylgruppe, eller en acetylamino-, etylkarbonylamino-, propylkarbonylamino-, butylkarbonylamino-, metoksyacetylamino-, butyloksykarbonylamino-, etylaminokarbonylamino-, dimetylaminokarbonylamino-, pyrrolidin-1 - ylkarbonylamino-, piperidin-1 -ylkarbonylamino-, morfolin-4-ylkarbonylamino-, metylsulfonylamino-, etylsulfonylamino- eller butylsulfonylaminogruppe, en propyloksygruppe som er substituert i 3-stillingen med en gruppe R<6> eller R<7>, hvor R6 og R<7> er som ovenfor definert eller en butyloksygruppe som er substituert i 4-stillingen med en gruppe R<6> eller R<7>, hvor R6 og R<7> er som ovenfor definert og X betyr et nitrogenatom, hvor, hvis ikke angitt på annen måte, de ovennevnte alkylgrupper kan være lineære eller forgrenede, tautomerer, stereoisomerer og salter derav.1. Bicyclic, heterocyclic compound of the general formula 1, where Ra means a hydrogen atom, R<b> means a 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chloro-4-fluorophenyl group, a 3-chloro-4-benzyloxy-phenyl-, 3-chloro-4-[(3-fluoro-benzyl)oxy]-phenyl-, 4-(pyridin-3-yloxy)-phenyl-, 4-[(6 -methyl-pyridin-3-yl)oxy]-phenyl-, 3-methyl-4-(pyridin-3-yloxy)-phenyl-, 3-methyl-4-[(6-methyl-pyridin-3-yl) oxy]-phenyl-, 3-chloro-4-(pyridin-3-yloxy)-phenyl- or 3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group, R<c> means a cyclohexyl group which is substituted in the 3-position or in the 4-position with a group R<4->N-R<5>, where R<4> means a hydrogen atom, a methyl or ethyl group and R<5> means a hydrogen atom, a methyl-, aminocarbonylmethyl-, methylamino-carbonylmethyl-, dimethylaminocarbonylmethyl-, pyrrolidin-1-ylcarbonylmethyl-, piperidin-1-ylcarbonylmethyl-, piperazin-1-ylcarbonylmethyl-, 4-methylpiperazin-1 - ylcarbonylmethyl, morpholin-4-ylcarbonylmethyl, 2-(morpholin-4-ylcarbonyl)ethyl or 3-(morpholin-4-ylcarbonyl)propyl group, an ethyl-, propyl-, 2-hydroxyethyl-, 3-hydroxypropyl-, 2-methoxyethyl-, 3-methoxypropyl-, 2-(butyloxycarbonylamino)-ethyl-, 2-aminoethyl-, 3-aminopropyl-, 2-(acetylamino )ethyl-, 3-(acetylamino)propyl-, 2-(ethylcarbonylamino)ethyl-, 3-(ethylcarbonylamino)propyl-, 2-(propylcarbonylamino)ethyl-, 3-(propylcarbonylamino)propyl-, 2-(ethylaminocarbonylamino)ethyl -, 3-(ethylaminocarbonylamino)propyl-, 2-(dimethylaminocarbonylamino)ethyl-, 3-(dimethylaminocarbonylamino)propyl-, 2-(morpholin-4-ylcarbonylamino)ethyl-, 3-(morpholin-4-ylcarbonylamino)propyl-, 2-(methylsulfonyl)ethyl-, 3-(methylsulfonyl)propyl-, 2-(methylsulfonylamino)ethyl- or a 3-(methylsulfonylamino)propyl group, a 2-(2-oxo-pyrrolidin-1-yl)ethyl-, 2-(2-oxopiperidin-1-yl)ethyl-, 2-(3-oxo-morpholin-4-yl)ethyl-, 2-( 2-oxo-imidazolidin-1 -yl)ethyl-, 2-(2-oxo-3-methyl-imidazolidin-1-yl)ethyl-, 2-(2-oxo-hexahydropyrimidin-1-yl)ethyl- or a 2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl group, a 3-(2-oxo-pyrrolidin-1-yl)propyl-, 3-(2-oxopiperidin-1-yl)propyl-, 3-(3-oxo-morpholin-4-yl)propyl-, 3-( 2-oxo-imidazolidin-1-yl)propyl-, 3-(2-oxo-3-methyl-imidazolidin-1-yl)propyl-, 3-(2-oxo-hexahydropyrimidin-1-yl)propyl- or a 3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)propyl group, a methylsulfonyl, ethylsulfonyl, 3-chloropropylsulfonyl, 2-(morpholin-4-yl)ethylsulfonyl or a 3-(morpholin-4-yl)propylsulfonyl group, a propyloxycarbonyl or butyloxycarbonyl group, a formyl-, acetyl-, ethylcarbonyl-, propylcarbonyl-, methoxyacetyl-, (2-methoxyethyl)carbonyl-, (3-methoxypropyl)carbonyl-, tetrahydrofuran-2-ylcarbonyl-, tetrahydropyran-4-ylcarbonyl-, aminoacetyl-, methylaminoacetyl -, dimethylaminoacetyl-, morpholin-4-ylacetyl, [2-(morpholin-4-yl)ethyl]carbonyl-, [3-(morpholin-4-yl)propyl]carbonyl- or a methylsulfonylacetyl group, a cyano-, aminocarbonyl-, methylaminocarbonyl-, dimethylaminocarbonyl-, ethylaminocarbonyl-, diethylaminocarbonyl-, propylaminocarbonyl-, (2-methoxyethyl)aminocarbonyl-, N-methyl-N-(2-methoxyethyl)aminocarbonyl-, (3-methoxypropyl) aminocarbonyl-, N-methyl-N-(3-methoxypropyl)-aminocarbonyl-, phenylaminocarbonyl-, pyrrolidin-1-ylcarbonyl-, piperidin-1-ylcarbonyl-, morpholin-4-ylcarbonyl-, 2-methylmorpholin-4-ylcarbonyl- , 2,6-dimethylmorpholin-4-ylcarbonyl-, homomorpholin-4-ylcarbonyl-, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl-, 3-oxa-8-aza-bicyclo[ 3.2.1]oct-8-ylcarbonyl-, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl-, 4-methylpiperazin-1-ylcarbonyl-, aminosulfonyl-, methylaminosulfonyl-, dimethylaminosulfonyl- or a morpholin-4-ylsulfonyl group, a cyclohexyl group which is substituted in the 3-position or in the 4-position with a group R<6>, where R<6> means a 2-oxo-pyrrolidin-1-yl-, 2-oxopiperidin-1-yl-, 3-oxo-morpholin-4-yl-, 2-oxo-imidazolidin-1-yl-, 2- oxo-3-methyl-imidazolidin-1-yl-, 2-oxo-hexahydropyrimidin-1-yl or a 2-oxo-3-methyl-hexahydropyrimidin-1-yl group, a pyrrolidin-3-yl group which is substituted in the 1-position with the group R5, where R<5> is as defined above, a piperidin-3-yl group which is substituted in the 1-position with the group R<5>, where R<5> is as defined above, a piperidin-4-yl group which is substituted in the 1-position with the group R<5>, where R<5> is as defined above, a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, Rd means a hydrogen atom, a methoxy, difluoromethoxy or ethyloxy group, an ethyloxy group which is substituted in the 2-position with a group R<6> or R<7>, where R<6> is as defined above and R<7> means a hydroxy-, methoxy-, ethoxy-, amino-, dimethylamino-, diethylamino-, bis-(2-methoxyethyl)-amino-, pyrrolidin-1-yl-, piperidin-1-yl-, morpholine -4-yl-, homomorpholin-4-yl-, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-, 3-oxa-8-aza-bicyclo[3.2.1 ]oct- 8-yl-, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-, piperazin-1-yl-, 4-methylpiperazin-1-yl- or 4-ethylpiperazin-1-yl group, or an acetylamino-, ethylcarbonylamino-, propylcarbonylamino-, butylcarbonylamino-, methoxyacetylamino-, butyloxycarbonylamino-, ethylaminocarbonylamino-, dimethylaminocarbonylamino-, pyrrolidin-1-ylcarbonylamino-, piperidin-1-ylcarbonylamino-, morpholin-4-ylcarbonylamino-, methylsulfonylamino-, ethylsulfonylamino - or butylsulfonylamino group, a propyloxy group which is substituted in the 3-position by a group R<6> or R<7>, where R6 and R<7> are as defined above or a butyloxy group which is substituted in the 4-position with a group R<6> or R<7>, where R6 and R<7> are as defined above and X means a nitrogen atom, wherein, unless otherwise indicated, the above alkyl groups may be linear or branched, tautomers, stereoisomers and salts thereof. 2. Bicyklisk, heterocyklisk forbindelse med den generelle formel I ifølge krav 1, hvor Ra betyr et hydrogenatom, R<b> betyr en 3-bromfenyl-, 3,4-difluorfenyl-, 3-klor-4-fluor-fenyl- eller en 3-etynylfenylgruppe, eller en 3-klor-4-benzyloksy-fenyl-, 3-klor-4-[(3-fluorbenzyl)oksy]-fenyl-, 4-(pyridin-3-yloksy)-fenyl-, 4-[(6-metyl-pyridin-3-yl)oksy]-fenyl-, 3-metyl-4-(pyridin-3-yloksy)-fenyl-, 3-metyl-4-[(6-metyl-pyridin-3-yl)oksy]-fenyl-, 3-klor-4-(pyridin-3-yloksy)-fenyl- eller 3-klor-4-[(6-metyl-pyridin-3-yl)oksy]-fenylgruppe, R<c> betyr en cykloheksylgruppe som er substituert i 3-stillingen med en amino-, acetylamino-, tert.-butyloksykarbonylamino- eller metylsulfonylaminogruppe, en cykloheksylgruppe som er substituert i 4-stillingen med en amino-, metylamino-, etylamino-, dimetylamino-, aminokarbonylmetylamino-, metylaminokarbonylmetylamino-, dimetylaminokarbonylmetylamino-, morfolin-4-ylkarbonylmetylamino-, [3-(morfolin-4-ylkarbonyl)propyl]amino-, [2-(metylsulfonyl)etyl]amino-, [3-(metylsulfonyl)propyl]amino- eller [2-(metylsulfonylamino)etyl]aminogruppe, en cykloheksylgruppe som er substituert i 4-stillingen med en [2-(2-okso-pyrrolidin-1 -yl)etyl]amino-, [2-(2-oksopiperidin-1 -yl)etyl]amino-, [2-(2-okso-imidazolidin-1-yl)etyl]amino-, [2-(2-okso-3-metyl-imidazolidin-1-yl)etyl]amino-, [2-(2-okso-heksahydropyrimidin-1 -yl)etyl]amino- eller [2-(2-okso-3-metyl-heksahydropyrimidin-1-yl)etyl]aminogruppe, en cykloheksylgruppe som er substituert i 4-stillingen med en [3-(2-okso-pyrrolidin-1 -yl)propyl]amino-, [3-(2-oksopiperidin-1 -yl)propyl]amino-, [3-(2-okso-imidazolidin-1 -yl)propyl]amino-, [3-(2-okso-3-metyl-imidazolidin-1 - yl)propyl]amino-, [3-(2-okso-heksahydropyrimidin-1-yl)propyl]amino- eller [3-(2-okso-3-metyl-heksahydropyrimidin-1-yl)propyl]aminogruppe, en cykloheksylgruppe som er substituert i 4-stillingen med en acetylamino-, N-(acetyl)-metylamino-, aminometylkarbonylamino-, metylaminometylkarbonylamino-, dimetylaminometylkarbonylamino-, morfolin-4-ylmetylkarbonylamino-, metoksyacetylamino-, N-(metoksyacetyl)-metylamino-, tetrahydropyran-4-ylkarbonylamino-, N-(tetrahydropyran-4-ylkarbonyl)-metylamino-, tert.-butyloksykarbonylamino-, N-(tert.-butyloksykarbonyl)-metylamino-, aminokarbonylamino-, metylaminokarbonylamino-, N-(etylaminokarbonyl)-metylamino-, dimetylaminokarbonylamino-, N-(dimetylaminokarbonyl)-metylamino-, N-(piperidin-1-ylkarbonyl)-metylamino-, morfolin-4-ylkarbonylamino-, N-(morfolin-4-ylkarbonyl)-metylamino- eller N-(4-metylpiperazin-1-ylkarbonyl)-metylaminogruppe, en cykloheksylgruppe som er substituert i 4-stillingen med en 2-okso-pyrrolidin-1 -yl-, 2-oksopiperidin-1-yl-, 3-okso-morfolin-4-yl-, 2-okso-imidazolidin-1-yl-, 2-okso-3-metyl-imidazolidin-1-yl-, 2-okso-heksahydropyrimidin-1-yl- eller en 2-okso-3-metyl-heksahydropyrimidin-1-ylgruppe, en cykloheksylgruppe som er substituert i 4-stillingen med en metylsulfonylamino-, N-(metylsulfonyl)-metylamino-, etylsulfonylamino-, N-(etylsulfonyl)-metylamino-, dimetylaminosulfonylamino-, N-(dimetylaminosulfonyl)-metylamino-, morfolin-4-ylsulfonylamino-, N-(morfolin-4-ylsulfonyl)-metylamino-3-klorpropylsulfonylamino-, [2-(morfolin-4-yl)-etyl]sulfonylamino- eller [3-(morfolin-4-yl)-propyl]sulfonylamino-gruppe, en pyrrolidin-3-ylgruppe, en pyrrolidin-3-ylgruppe som er substituert i 1-stillingen med en metyl-, acetyl-, metoksyacetyl-, tert.-butyloksykarbonyl-, morfolin-4-ylkarbonyl- eller metylsulfonylgruppe, en piperidin-3-ylgruppe, en piperidin-3-ylgruppe som er substituert i 1-stillingen med en metyl-, acetyl-, metoksyacetyl-, tert.-butyloksykarbonyl-, morfolin-4-ylkarbonyl- eller metylsulfonylgruppe, en piperidin-4-ylgruppe som er substituert i 1-stillingen med en metyl-, etyl-, propyl-, isopropyl-, 2-hydroksyetyl-, 2-metoksyetyl-, 3-metoksypropyl-, 2-(metylsulfonyl)-etyl-, 3-(metylsulfonyl)-propyl-, 2-(tert.-butyloksykarbonylamino)-etyl-, 2-aminoetyl-, 2-(acetylamino)-etyl-, 2-(etylkarbonylamino)-etyl-, 2-(propylkarbonylamino)-etyl-, 2-(etylaminokarbonylamino)-etyl-, 2-(dimetylaminokarbonylamino)-etyl-, 2-(morfolin-4-ylkarbonylamino)-etyl-, 3-(acetylamino)-propyl-, 3-(etylkarbonylamino)-propyl-, 3-(propylkarbonylamino)-propyl-, 3-(etylaminokarbonylamino)-propyl-, 3-(dimetylaminokarbonylamino)-propyl-, 3-(morfolin-4-ylkarbonylamino)-propyl-, 2-(metylsulfonylamino)-etyl-, 3-(metylsulfonylamino)-propyl-, (aminokarbonyl)metyl-, (metylaminokarbonyl)metyl-, (dimetylaminokarbonyl)metyl-, (pyrrolidin-1 - ylkarbonylmetyl-, (morfolin-4-ylkarbonyl)metyl-, 2-(morfolin-4-ylkarbonyl)-etyl-eller 3-(morfolin-4-ylkarbonyl)-propylgruppe, en piperidin-4-ylgruppe som er substituert i 1-stillingen med en 2-(2-okso-pyrrolidin-1 -yl)-etyl-, 2-(2-oksopiperidin-1 -yl)-etyl-, 2-(3-oksomorfolin-4-yl)-etyl-, 2-(2-okso-imidazolidin-1 -yl)-etyl-, 2-(2-okso-3-metyl-imidazolidin-1 -yl)-etyl-, 2-(2-okso-heksahydropyrimidin-1-yl)-etyl- eller 2-(2-okso-3-metyl-heksahydropyrimidin-1-yl)-etylgruppe, en piperidin-4-ylgruppe som er substituert i 1-stillingen med en 3-(2-okso-pyrrolidin-1 -yl)-propyl-, 3-(2-oksopiperidin-1 -yl)-propyl-, 3-(3-oksomorfolin-4-yl)-propyl-, 3-(2-okso-imidazolidin-1 -yl)-propyl-, 3-(2-okso-3-metyl-imidazolidin-1 - yl)-propyl-, 3-(2-okso-heksahydropyrimidin-1-yl)-propyl- eller 3-(2-okso-3-metyl-heksahydropyrimidin-1-yl)-propylgruppe, en piperidin-4-ylgruppe som er substituert i 1-stillingen med en formyl-, acetyl-, metoksyacetyl-, (2-metoksyetyl)karbonyl-, (3-metoksypropyl)karbonyl-, metylsulfonylacetyl-, aminoacetyl-, metylaminoacetyl-, (dimetylamino)acetyl-, (morfolin-4-yl)acetyl-, [2-(morfolin-4-yl)-etyl]karbonyl-, [3-(morfolin-4-yl)-propyl]karbonyl-, tetrahydrofuran-2-ylkarbonyl- eller tetrahydropyran-4-ylkarbonylgruppe, en piperidin-4-ylgruppe som er substituert i 1-stillingen med en cyano-, aminokarbonyl-, metylaminokarbonyl-, etylaminokarbonyl-, (2-metoksyetyl)aminokarbonyl-, N-metyl-N-(2-metoksyetyl)-aminokarbonyl-, (3-metoksypropyl)aminokarbonyl-, N-metyl-N-(3-metoksypropyl)-aminokarbonyl-, isopropylaminokarbonyl-, fenylaminokarbonyl-, dimetylaminokarbonyl-, dietylaminokarbonyl-, pyrrolidin-1-ylkarbonyl-, piperidin-1-ylkarbonyl-, morfolin-4-ylkarbonyl-, 2-metylmorfolin-4-ylkarbonyl-, 2,6-dimetylmorfolin-4-ylkarbonyl-, homomorfolin-4-ylkarbonyl, 2-oksa-5-aza-bicyklo[2.2.1]hept-5-ylkarbonyl-, 3-oksa-8-aza-bicyklo[3.2.1]okt-8-ylkarbonyl-, 8-oksa-3-aza-bicyklo[3.2.1]okt-3-ylkarbonyl-, 4-metylpiperazin-1 -ylkarbonyl-, isopropyloksykarbonyl eller tert.-butyloksykarbonylgruppe, en piperidin-4-ylgruppe som er substituert i 1-stillingen med en metylsulfonyl-, etylsulfonyl-, [2-(morfolin-4-yl)-etyl]sulfonyl-, [3-(morfolin-4-yl)-propyl]sulfonyl-, aminosulfonyl-, metylaminosulfonyl-, dimetylaminosulfonyl- eller morfolin-4-ylsulfonylgruppe, eller en tetrahydrofuran-3-yl-, tetrahydropyran-3-yl- eller tetrahydropyran-4-ylgruppe, Rd betyr et hydrogenatom, en metoksy-, difluormetoksy- eller etyloksygruppe, en 2-(morfolin-4-yl)etyloksy-, 3-(morfolin-4-yl)propyloksy- eller 4-(morfolin-4-yl)butyloksygruppe, en 3-(dimetylamino)propyloksy-, 3-(dietylamino)propyloksy-, 3-[bis-(2-metoksyetyl)-amino]propyloksy-, 3-(piperazin-1 -yl)propyloksy-, 3-(4-metylpiperazin-1 -yl)propyloksy- eller 3-(4-etylpiperazin-1 -yl)propyloksygruppe, en 3-(homomorfolin-4-yl)-propyloksy-, 3-(2-oksa-5-aza-bicyklo[2.2.1]hept-5-yl)-propyloksy-, 3-(3-oksa-8-aza-bicyklo[3.2.1]okt-8-yl)-propyloksy- eller 3-(8-oksa-3-aza-bicyklo[3.2.1]okt-3-yl)-propyloksygruppe, en 2-(2-okso-pyrrolidin-1-yl)-etyloksy-, 2-(2-oksopiperidin-1-yl)-etyloksy-, 2-(3-oksomorfolin-4-yl)-etyloksy-, 2-(2-okso-imidazolidin-1 -yl)-etyloksy-, 2-(2-okso-3-metyl-imidazolidin-1 -yl)-etyloksy-, 2-(2-okso-heksahydropyrimidin-1 -yl)-etyloksy-eller 2-(2-okso-3-metyl-heksahydropyrimidin-1-yl)-etyloksygruppe, en 3-(2-okso-pyrrolidin-1 -yl)-propyloksy-, 3-(2-oksopiperidin-1-yl)-propyloksy-, 3-(3-oksomorfolin-4-yl)-propyloksy-, 3-(2-okso-imidazolidin-1 -yl)-propyloksy-, 3-(2-okso-3-metyl-imidazolidin-1-yl)-propyloksy-, 3-(2-okso-heksahydropyrimidin-1 -yl)-propyloksy- eller 3-(2-okso-3-metyl-heksahydropyrimidin-1 -yl)-propyloksygruppe, en 2-(metoksy)-etyloksy-, 2-(tert.-butyloksykarbonylamino)-etyloksy-, 2-(amino)-etyloksy-, 2-(acetylamino)-etyloksy-, 2-(etylkarbonylamino)-etyloksy-, 2-(propylkarbonylamino)-etyloksy-, 2-(isobutylkarbonylamino)-etyloksy-, 2-(metoksyacetylamino)-etyloksy-, 2-(etylaminokarbonylamino)-etyloksy-, 2-(dimetylaminokarbonylamino)-etyloksy-, 2-(pyrrolidin-1-ylkarbonylamino)-etyloksy-, 2-(piperidin-1 -ylkarbonylamino)-etyloksy-, 2-(morfolin-4-ylkarbonylamino)-etyloksy-, 2-(metylsulfonylamino)-etyloksygruppe, 2-(etylsulfonylamino)-etyloksy- eller 2-(butylsulfonylamino)-etyloksygruppe, eller en 3-(tert.-butyloksykarbonylamino)-propyloksy-, 3-(amino)-propyloksy-, 3-(acetylamino)-propyloksy- eller 3-(metylsulfonylamino)-propyloksygruppe, og X betyr et nitrogenatom, tautomerer, stereoisomerer og salter derav.2. Bicyclic, heterocyclic compound of the general formula I according to claim 1, where Ra means a hydrogen atom, R<b> means a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl or a 3-ethynylphenyl group, or a 3-chloro-4-benzyloxy-phenyl-, 3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl-, 4-(pyridin-3-yloxy)-phenyl-, 4-[(6-methyl -pyridin-3-yl)oxy]-phenyl-, 3-methyl-4-(pyridin-3-yloxy)-phenyl-, 3-methyl-4-[(6-methyl-pyridin-3-yl)oxy] -phenyl-, 3-chloro-4-(pyridin-3-yloxy)-phenyl- or 3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group, R<c> means a cyclohexyl group which is substituted in the 3-position with an amino-, acetylamino-, tert-butyloxycarbonylamino- or methylsulfonylamino group, a cyclohexyl group which is substituted in the 4-position with an amino-, methylamino-, ethylamino-, dimethylamino-, aminocarbonylmethylamino-, methylaminocarbonylmethylamino-, dimethylaminocarbonylmethylamino-, morpholin-4-ylcarbonylmethylamino-, [3-(morpholin-4-ylcarbonyl)propyl ]amino-, [2-(methylsulfonyl)ethyl]amino-, [3-(methylsulfonyl)propyl]amino- or [2-(methylsulfonylamino)ethyl]amino group, a cyclohexyl group which is substituted in the 4-position with a [2-(2-oxo-pyrrolidin-1-yl)ethyl]amino-, [2-(2-oxopiperidin-1-yl)ethyl]amino-, [2- (2-oxo-imidazolidin-1-yl)ethyl]amino-, [2-(2-oxo-3-methyl-imidazolidin-1-yl)ethyl]amino-, [2-(2-oxo-hexahydropyrimidine-1 -yl)ethyl]amino or [2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl]amino group, a cyclohexyl group substituted in the 4-position by a [3-(2-oxo-pyrrolidin-1-yl)propyl]amino-, [3-(2-oxopiperidin-1-yl)propyl]amino-, [3- (2-oxo-imidazolidin-1 -yl)propyl]amino-, [3-(2-oxo-3-methyl-imidazolidin-1 -yl)propyl]amino-, [3-(2-oxo-hexahydropyrimidine-1 -yl)propyl]amino- or [3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)propyl]amino group, a cyclohexyl group which is substituted in the 4-position with an acetylamino-, N-(acetyl)-methylamino-, aminomethylcarbonylamino-, methylaminomethylcarbonylamino-, dimethylaminomethylcarbonylamino-, morpholin-4-ylmethylcarbonylamino-, methoxyacetylamino-, N-(methoxyacetyl)-methylamino- , tetrahydropyran-4-ylcarbonylamino-, N-(tetrahydropyran-4-ylcarbonyl)-methylamino-, tert-butyloxycarbonylamino-, N-(tert-butyloxycarbonyl)-methylamino-, aminocarbonylamino-, methylaminocarbonylamino-, N-(ethylaminocarbonyl) -methylamino-, dimethylaminocarbonylamino-, N-(dimethylaminocarbonyl)-methylamino-, N-(piperidin-1-ylcarbonyl)-methylamino-, morpholin-4-ylcarbonylamino-, N-(morpholin-4-ylcarbonyl)-methylamino- or N -(4-methylpiperazin-1-ylcarbonyl)-methylamino group, a cyclohexyl group substituted in the 4-position by a 2-oxo-pyrrolidin-1-yl-, 2-oxopiperidin-1-yl-, 3-oxo-morpholin-4-yl-, 2-oxo-imidazolidin-1- yl-, 2-oxo-3-methyl-imidazolidin-1-yl-, 2-oxo-hexahydropyrimidin-1-yl- or a 2-oxo-3-methyl-hexahydropyrimidin-1-yl group, a cyclohexyl group which is substituted in the 4-position with a methylsulfonylamino-, N-(methylsulfonyl)-methylamino-, ethylsulfonylamino-, N-(ethylsulfonyl)-methylamino-, dimethylaminosulfonylamino-, N-(dimethylaminosulfonyl)-methylamino-, morpholine-4 -ylsulfonylamino-, N-(morpholin-4-ylsulfonyl)-methylamino-3-chloropropylsulfonylamino-, [2-(morpholin-4-yl)-ethyl]sulfonylamino- or [3-(morpholin-4-yl)-propyl] sulfonylamino group, a pyrrolidin-3-yl group, a pyrrolidin-3-yl group which is substituted in the 1-position with a methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl group, a piperidin-3-yl group, a piperidin-3-yl group which is substituted in the 1-position with a methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl group, a piperidin-4-yl group which is substituted in the 1-position with a methyl-, ethyl-, propyl-, isopropyl-, 2-hydroxyethyl-, 2-methoxyethyl-, 3-methoxypropyl-, 2-(methylsulfonyl)-ethyl- , 3-(methylsulfonyl)-propyl-, 2-(tert-butyloxycarbonylamino)-ethyl-, 2-aminoethyl-, 2-(acetylamino)-ethyl-, 2-(ethylcarbonylamino)-ethyl-, 2-(propylcarbonylamino) -ethyl-, 2-(ethylaminocarbonylamino)-ethyl-, 2-(dimethylaminocarbonylamino)-ethyl-, 2-(morpholin-4-ylcarbonylamino)-ethyl-, 3-(acetylamino)-propyl-, 3-(ethylcarbonylamino)- propyl-, 3-(propylcarbonylamino)-propyl-, 3-(ethylaminocarbonylamino)-propyl-, 3-(dimethylaminocarbonylamino)-propyl-, 3-(morpholin-4-ylcarbonylamino)-propyl-, 2-(methylsulfonylamino)-ethyl -, 3-(methylsulfonylamino)-propyl-, (aminocarbonyl)methyl-, (methylaminocarbonyl)methyl-, (dimethylaminocarbonyl)methyl-, (pyrrolidin-1 - ylcarbonylmethyl-, (morpholin-4-ylcarbonyl)methyl-, 2-( morpholin-4-ylcarbonyl)ethyl or 3-(morpholin-4-ylcarbonyl)propyl group, a piperidin-4-yl group which is substituted in the 1-position with a 2-(2-oxo-pyrrolidin-1-yl)-ethyl-, 2-(2-oxopiperidin-1-yl)-ethyl-, 2-( 3-oxomorpholin-4-yl)-ethyl-, 2-(2-oxo-imidazolidin-1 -yl)-ethyl-, 2-(2-oxo-3-methyl-imidazolidin-1 -yl)-ethyl-, 2-(2-oxo-hexahydropyrimidin-1-yl)-ethyl or 2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyl group, a piperidin-4-yl group which is substituted in the 1-position with a 3-(2-oxo-pyrrolidin-1-yl)-propyl-, 3-(2-oxopiperidin-1-yl)-propyl-, 3-( 3-oxomorpholin-4-yl)-propyl-, 3-(2-oxo-imidazolidin-1 -yl)-propyl-, 3-(2-oxo-3-methyl-imidazolidin-1 -yl)-propyl-, 3-(2-oxo-hexahydropyrimidin-1-yl)-propyl or 3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyl group, a piperidin-4-yl group which is substituted in the 1-position with a formyl-, acetyl-, methoxyacetyl-, (2-methoxyethyl)carbonyl-, (3-methoxypropyl)carbonyl-, methylsulfonylacetyl-, aminoacetyl-, methylaminoacetyl-, ( dimethylamino)acetyl-, (morpholin-4-yl)acetyl-, [2-(morpholin-4-yl)-ethyl]carbonyl-, [3-(morpholin-4-yl)-propyl]carbonyl-, tetrahydrofuran-2 -ylcarbonyl or tetrahydropyran-4-ylcarbonyl group, a piperidin-4-yl group which is substituted in the 1-position with a cyano-, aminocarbonyl-, methylaminocarbonyl-, ethylaminocarbonyl-, (2-methoxyethyl)aminocarbonyl-, N-methyl-N-(2-methoxyethyl)aminocarbonyl-, (3-Methoxypropyl)aminocarbonyl-, N-methyl-N-(3-methoxypropyl)-aminocarbonyl-, isopropylaminocarbonyl-, phenylaminocarbonyl-, dimethylaminocarbonyl-, diethylaminocarbonyl-, pyrrolidin-1-ylcarbonyl-, piperidin-1-ylcarbonyl-, morpholine -4-ylcarbonyl-, 2-methylmorpholin-4-ylcarbonyl-, 2,6-dimethylmorpholin-4-ylcarbonyl-, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5- ylcarbonyl-, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl-, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl-, 4-methylpiperazin-1 -ylcarbonyl, isopropyloxycarbonyl or tert-butyloxycarbonyl group, a piperidin-4-yl group which is substituted in the 1-position with a methylsulfonyl-, ethylsulfonyl-, [2-(morpholin-4-yl)-ethyl]sulfonyl-, [3-(morpholin-4-yl)-propyl] sulfonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl group, or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, Rd means a hydrogen atom, a methoxy, difluoromethoxy or ethyloxy group, a 2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or 4-(morpholin-4-yl)butyloxy group, a 3-(dimethylamino)propyloxy-, 3-(diethylamino)propyloxy-, 3-[bis-(2-methoxyethyl)amino]propyloxy-, 3-(piperazin-1 -yl)propyloxy-, 3-(4- methylpiperazin-1-yl)propyloxy or 3-(4-ethylpiperazin-1-yl)propyloxy group, a 3-(homomorpholin-4-yl)-propyloxy-, 3-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-propyloxy-, 3-(3-oxa-8- aza-bicyclo[3.2.1]oct-8-yl)-propyloxy- or 3-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-propyloxy group, a 2-(2-oxo-pyrrolidin-1-yl)-ethyloxy-, 2-(2-oxopiperidin-1-yl)-ethyloxy-, 2-(3-oxomorpholin-4-yl)-ethyloxy-, 2- (2-oxo-imidazolidin-1 -yl)-ethyloxy-, 2-(2-oxo-3-methyl-imidazolidin-1 -yl)-ethyloxy-, 2-(2-oxo-hexahydropyrimidin-1 -yl)- ethyloxy or 2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyloxy group, a 3-(2-oxo-pyrrolidin-1-yl)-propyloxy-, 3-(2-oxopiperidin-1-yl)-propyloxy-, 3-(3-oxomorpholin-4-yl)-propyloxy-, 3- (2-oxo-imidazolidin-1 -yl)-propyloxy-, 3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyloxy-, 3-(2-oxo-hexahydropyrimidin-1 -yl)- propyloxy or 3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyloxy group, a 2-(Methoxy)-ethyloxy-, 2-(tert-butyloxycarbonylamino)-ethyloxy-, 2-(amino)-ethyloxy-, 2-(acetylamino)-ethyloxy-, 2-(ethylcarbonylamino)-ethyloxy-, 2 -(propylcarbonylamino)-ethyloxy-, 2-(isobutylcarbonylamino)-ethyloxy-, 2-(methoxyacetylamino)-ethyloxy-, 2-(ethylaminocarbonylamino)-ethyloxy-, 2-(dimethylaminocarbonylamino)-ethyloxy-, 2-(pyrrolidine-1 -ylcarbonylamino)-ethyloxy-, 2-(piperidin-1-ylcarbonylamino)-ethyloxy-, 2-(morpholin-4-ylcarbonylamino)-ethyloxy-, 2-(methylsulfonylamino)-ethyloxy group, 2-(ethylsulfonylamino)-ethyloxy- or 2-(butylsulfonylamino)-ethyloxy group, or a 3-(tert-butyloxycarbonylamino)-propyloxy-, 3-(amino)-propyloxy-, 3-(acetylamino)-propyloxy- or 3-(methylsulfonylamino)-propyloxy group, and X means a nitrogen atom, tautomers, stereoisomers and salts thereof. 3. Bicyklisk, heterocyklisk forbindelse med den generelle formel I ifølge krav 1, hvor Ra betyr et hydrogenatom, Rb betyr en 3-klor-4-fluor-fenylgruppe eller en 3-etynylfenylgruppe, R<c> betyr en cykloheksylgruppe som er substituert i 3-stillingen med en amino-, acetylamino-, tert.-butyloksykarbonylamino- eller metylsulfonylaminogruppe, en cykloheksylgruppe som er substituert i 4-stillingen med en amino-, metylamino-, dimetylamino-, acetylamino-, N-(acetyl)-metylamino-, metoksyacetylamino-, N-(metoksyacetyl)-metylamino-, tetrahydropyran-4-ylkarbonylamino-, N-(tetrahydropyran-4-ylkarbonyl)-metylamino-, tert.-butyloksykarbonylamino-, N-(tert.-butyloksykarbonyl)-metylamino-, N-(etylaminokarbonyl)-metylamino-, dimetylaminokarbonylamino-, N-(dimetylaminokarbonyl)-metylamino-, N-(piperidin-1-ylkarbonyl)-metylamino-, morfolin-4-ylkarbonylamino-, N-(morfolin-4-ylkarbonyl)-metylamino-, N-(4-metylpiperazin-1-ylkarbonyl)-metylamino-, metylsulfonylamino-, N-(metylsulfonyl)-metylamino-, etylsulfonylamino-, N-(etylsulfonyl)-metylamino-, dimetylaminosulfonylamino-, N-(dimetylaminosulfonyl)-metylamino-, morfolin-4-ylsulfonylamino-, N-(morfolin-4-ylsulfonyl)-metylamino-, 3-klorpropylsulfonylamino- eller [3-(morfolin-4-yl)-propyl]sulfonylaminogruppe, en pyrrolidin-3-ylgruppe, en pyrrolidin-3-ylgruppe som er substituert i 1-stillingen med en tert.-butyloksykarbonyl- eller metylsulfonylgruppe, en piperidin-3-ylgruppe, en piperidin-3-ylgruppe som er substituert i 1-stillingen med en tert.-butyloksykarbonyl- eller metylsulfonylgruppe, en piperidin-4-ylgruppe, en piperidin-4-ylgruppe som er substituert i 1-stillingen med en metyl-, (aminokarbonyl)metyl-, (dimetylaminokarbonyl)metyl-, (morfolin-4-ylkarbonyl)metyl-, 2-(tert.-butyloksykarbonylamino)etyl-, 2-aminoetyl-, 2-(acetylamino)etyl-, 2-(metylsulfonylamino)etyl-, cyano-, acetyl-, metoksyacetyl-, (dimetylamino)acetyl-, (morfolin-4-yl)acetyl-, tetrahydropyran-4-ylkarbonyl-, etylaminokarbonyl-, isopropylaminokarbonyl-, fenylaminokarbonyl-, dimetylaminokarbonyl-, dietylaminokarbonyl-, pyrrolidin-1-ylkarbonyl-, piperidin-1-ylkarbonyl-, morfolin-4-ylkarbonyl-, 2-metylmorfolin-4-ylkarbonyl-, 2,6-dimetylmorfolin-4-ylkarbonyl-, homomorfolin-4-ylkarbonyl-, 4-metylpiperazin-1 - ylkarbonyl-, isopropyloksykarbonyl-, tert.-butyloksykarbonyl-, metylsulfonyl-, dimetylaminosulfonyl- eller morfolin-4-ylsulfonylgruppe, eller en tetrahydrofuran-3-yl-, tetrahydropyran-3-yl- eller tetrahydropyran-4-ylgruppe, Rd betyr et hydrogenatom, en metoksy- eller etyloksygruppe, en 2-(morfolin-4-yl)etyloksy-, 3-(morfolin-4-yl)propyloksy- eller 4-(morfolin-4-yl)butyloksygruppe, en 2-(3-metyl-2-okso-heksahydropyrimidin-1 -yl)-etyloksygruppe, en 2-(metoksy)-etyloksy-, 2-(tert.-butyloksykarbonylamino)-etyloksy-, 2-amino-etyloksy-, 2-(acetylamino)-etyloksy- eller 2-(metylsulfonylamino)-etyloksygruppe eller en 3-(tert.-butyloksykarbonylamino)-propyloksy-, 3-amino-propyloksy-, 3-(acetylamino)-propyloksy- eller 3-(metylsulfonylamino)-propyloksygruppe, og X betyr et nitrogenatom, tautomerer, stereoisomerer og salter derav.3. Bicyclic, heterocyclic compound of the general formula I according to claim 1, where Ra means a hydrogen atom, Rb means a 3-chloro-4-fluoro-phenyl group or a 3-ethynylphenyl group, R<c> means a cyclohexyl group which is substituted in the 3-position with an amino-, acetylamino-, tert-butyloxycarbonylamino- or methylsulfonylamino group, a cyclohexyl group which is substituted in the 4-position by an amino-, methylamino-, dimethylamino-, acetylamino-, N-(acetyl)-methylamino-, methoxyacetylamino-, N-(methoxyacetyl)-methylamino-, tetrahydropyran-4-ylcarbonylamino- , N-(tetrahydropyran-4-ylcarbonyl)-methylamino-, tert-butyloxycarbonylamino-, N-(tert-butyloxycarbonyl)-methylamino-, N-(ethylaminocarbonyl)-methylamino-, dimethylaminocarbonylamino-, N-(dimethylaminocarbonyl)- methylamino-, N-(piperidin-1-ylcarbonyl)-methylamino-, morpholin-4-ylcarbonylamino-, N-(morpholin-4-ylcarbonyl)-methylamino-, N-(4-methylpiperazin-1-ylcarbonyl)-methylamino- , methylsulfonylamino-, N-(methylsulfonyl)-methylamino-, ethylsulfonylamino-, N-(ethylsulfonyl)-methylamino-, dimethylaminosulfonylamino-, N-(dimethylaminosulfonyl)-methylamino-, morpholin-4-ylsulfonylamino-, N-(morpholin-4 -ylsulfonyl)-methylamino-, 3-chloropropylsulfonylamino- or [3-(morpholin-4-yl)-propyl]sulfonylamino group, a pyrrolidin-3-yl group, a pyrrolidin-3-yl group which is substituted in the 1-position with a tert-butyloxycarbonyl or methylsulfonyl group, a piperidin-3-yl group, a piperidin-3-yl group which is substituted in the 1-position with a tert-butyloxycarbonyl or methylsulfonyl group, a piperidin-4-yl group, a piperidin-4-yl group which is substituted in the 1-position with a methyl-, (aminocarbonyl)methyl-, (dimethylaminocarbonyl)methyl-, (morpholin-4-ylcarbonyl)methyl-, 2-(tert-butyloxycarbonylamino)ethyl- , 2-aminoethyl-, 2-(acetylamino)ethyl-, 2-(methylsulfonylamino)ethyl-, cyano-, acetyl-, methoxyacetyl-, (dimethylamino)acetyl-, (morpholin-4-yl)acetyl-, tetrahydropyran-4 -ylcarbonyl-, ethylaminocarbonyl-, isopropylaminocarbonyl-, phenylaminocarbonyl-, dimethylaminocarbonyl-, diethylaminocarbonyl-, pyrrolidin-1-ylcarbonyl-, piperidin-1-ylcarbonyl-, morpholin-4-ylcarbonyl-, 2-methylmorpholin-4-ylcarbonyl-, 2 ,6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, methylsulfonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl group, or a tetrahydrofuran -3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, Rd means a hydrogen atom, a methoxy or ethyloxy group, a 2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or 4-(morpholin-4-yl)butyloxy group, a 2-(3-methyl-2-oxo-hexahydropyrimidin-1-yl)-ethyloxy group, a 2-(methoxy)-ethyloxy-, 2-(tert-butyloxycarbonylamino)-ethyloxy-, 2-amino-ethyloxy-, 2-(acetylamino)-ethyloxy- or 2-(methylsulfonylamino)-ethyloxy group or a 3-(tert-butyloxycarbonylamino)-propyloxy-, 3-amino-propyloxy-, 3-(acetylamino)-propyloxy- or 3-(methylsulfonylamino)-propyloxy group, and X means a nitrogen atom, tautomers, stereoisomers and salts thereof. 4. Følgende forbindelser med den generelle formel I ifølge krav 1: (a) 4-[(3-klor-4-fluor-fenyl)amino]-6-((S)-tetrahydrofuran-3-yloksy)-7-metoksy-kinazolin, (b) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-metoksy-kinazolin, (c) 4-[(3-klor-4-fluor-fenyl)amino]-6-((f?)-tetrahydrofuran-3-yloksy)-7-metoksy-kinazolin, (d) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-amino-cykloheksan-1-yloksy)-7-metoksy-kinazolin, (e) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-metansulfonylamino-cykloheksan-1-yloksy)-7-metoksy-kinazolin, (f) 4-[(3-klor-4-fluor-fenyl)amino]-6-(piperidin-4-yloksy)-7-metoksy-kinazolin, (g) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-metansulfonyl-piperidin-4-yloksy)-7-metoksy-kinazolin, (h) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-{[3-(morfolin-4-yl)-propyl]sulfonyl-amino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin, (i) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-3-yloksy)-7-metoksy-kinazolin, (k) 4-[(3-klor-4-fluor-fenyl)amino]-6-(trans-4-{[3-(morfolin-4-yl)-propyl]sulfonylamino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin, (I) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-metyl-piperidin-4-yloksy)-7-metoksy-kinazolin, (m) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(morfolin-4-yl)karbonyl]-piperidin-4-yl-oksy}-7-metoksy-kinazolin, (n) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(metoksymetyl)karbonyl]-piperidin-4-yloksy}-7-metoksy-kinazolin, (o) 4-[(3-klor-4-fluor-fenyl)amino]-6-(1-cyano-piperidin-4-yloksy)-7-metoksy-kinazolin, (P) 4-[(3-klor-4-fluor-fenyl)amino]-6-{1-[(morfolin-4-yl)sulfonyl]-piperidin-4-yl-oksy}-7-metoksy-kinazolin, (q) 4-[(3-klor-4-fluor-fenyl)amino]-6-[1-(2-acetylamino-etyl)-piperidin-4-yloksy]-7-metoksy-kinazolin, (r) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(dimetylamino)sulfonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin, (s) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(morfolin-4-yl)karbonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin, (t) 4-[(3-klor-4-fluor-fenyl)amino]-6-{trans-4-[(morfolin-4-yl)sulfonylamino]-cykloheksan-1-yloksy}-7-metoksy-kinazolin, (u) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(2-acetylamino-etoksy)-kinazolin, (v) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(2-metansulfonylamino-etoksy)-kinazolin, (w) 4-[(3-klor-4-fluor-fenyl)amino]-6-(tetrahydropyran-4-yloksy)-7-(2-metoksy-etoksy)-kinazolin, (x) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-{N-[(mofrolin-4-yl)karbonyl]-N-metylamino}-cykloheksan-1-yloksy)-7-metoksy-kinazolin, (y) 4-[(3-klor-4-fluor-fenyl)amino]-6-(cis-4-{N-[(mofrolin-4-yl)sulfonyl]-N-metylamino}-cykloheksan-1 -yloksy)-7-metoksy-kinazolin og (z) 4-[(3-klor-4-fluor-fenyl)amino]-6-[cis-4-(N-acetyl-N-metyl-amino)- cykloheksan-1-yloksy]-7-metoksy-kinazolin, og saltene derav.4. The following compounds with the general formula I according to claim 1: (a) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxy -quinazoline, (b) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline, (c) 4-[(3-chloro- 4-fluoro-phenyl)amino]-6-((f?)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline, (d) 4-[(3-chloro-4-fluoro-phenyl)amino]- 6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (e) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulfonylamino -cyclohexane-1-yloxy)-7-methoxyquinazoline, (f) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline, (g) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxyquinazoline, (h) 4-[(3-chloro -4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)-propyl]sulfonyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline, ( i) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxyquinazoline, (k) 4-[(3-chloro-4-fluoro- phenyl)amino]-6-(trans-4-{[3-(morpholin-4-yl)-p ropyl]sulfonylamino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline, (I) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy )-7-methoxy-quinazoline, (m) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl- oxy}-7-methoxy-quinazoline, (n) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7- Methoxy-quinazoline, (o) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, (P) 4-[ (3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)sulfonyl]-piperidin-4-yl-oxy}-7-methoxyquinazoline, (q) 4- [(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (r) 4-[(3- chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (s) 4-[(3-chloro-4 -fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (t) 4-[(3-chloro- 4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexane-1 -yloxy}-7-methoxy-quinazoline, (u) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)- quinazoline, (v) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonylamino-ethoxy)-quinazoline, (w) 4-[ (3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, (x) 4-[(3-chloro-4-fluoro -phenyl)amino]-6-(cis-4-{N-[(mofrolin-4-yl)carbonyl]-N-methylamino}-cyclohexan-1-yloxy)-7-methoxyquinazoline, (y) 4- [(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(mofrolin-4-yl)sulfonyl]-N-methylamino}-cyclohexan-1 -yloxy)-7- methoxyquinazoline and (z) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)- cyclohexan-1-yloxy]-7-methoxyquinazoline, and the salts thereof. 5. Fysiologisk akseptabelt salt av forbindelsene ifølge minst ett av kravene 1 til 4 med uorganiske eller organiske syrer eller baser.5. Physiologically acceptable salt of the compounds according to at least one of claims 1 to 4 with inorganic or organic acids or bases. 6. Farmasøytisk preparat inneholdende en forbindelse ifølge minst ett av kravene 1 til 4 eller et fysiologisk akseptabelt salt ifølge krav 5 eventuelt sammen med én eller flere inerte bærere og/eller fortynningsmidler.6. Pharmaceutical preparation containing a compound according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5, optionally together with one or more inert carriers and/or diluents. 7. Anvendelse av en forbindelse ifølge minst ett av kravene 1 til 5 for fremstilling av et farmasøytisk preparat som er egnet for behandling av godartede eller ondartede tumorer, for forhindring og behandling av sykdommer i luftveiene og lungene og for behandling av sykdommer i mave-tarm-kanalen, gallegang og galleblære.7. Use of a compound according to at least one of claims 1 to 5 for the production of a pharmaceutical preparation which is suitable for the treatment of benign or malignant tumours, for the prevention and treatment of diseases of the respiratory tract and lungs and for the treatment of diseases of the gastrointestinal tract duct, bile duct and gallbladder. 8. Fremgangsmåte for fremstilling av et farmasøytisk preparat ifølge krav 6, karakterisert ved at en forbindelse ifølge minst ett av kravene 1 til 5 blir innført i én eller flere inerte bærere og/eller fortynningsmidler ved en ikke-kjemisk metode.8. Method for producing a pharmaceutical preparation according to claim 6, characterized in that a compound according to at least one of claims 1 to 5 is introduced into one or more inert carriers and/or diluents by a non-chemical method. 9. Fremgangsmåte for fremstilling av forbindelsene med den generelle formel I ifølge kravene 1 til 4, karakterisert ved at en forbindelse med den generelle formel hvor Ra, Rb, Rd og X er som definert i kravene 1 til 4, blir omsatt med en forbindelse med den generelle formel hvor R<c> er som definert i kravene 1 til 4 og Z<1> betyr en utgående gruppe.9. Process for preparing the compounds of the general formula I according to claims 1 to 4, characterized in that a compound with the general formula where Ra, Rb, Rd and X are as defined in claims 1 to 4, are reacted with a compound of the general formula where R<c> is as defined in claims 1 to 4 and Z<1> means a leaving group. 10. Fremgangsmåte for fremstilling av forbindelsene med den generelle formel I ifølge kravene 1 til 4, karakterisert ved at for å fremstille forbindelser med den generelle formel I hvor Rd betyr én av de eventuelt substituerte alkyloksygrupper angitt i kravene 1 til 4, blir en forbindelse med den generelle formel hvor Ra, R<b>, R<c> og X er som definert i kravene 1 til 4, omsatt med en forbindelse med den generelle formel hvor Rd' betyr en Ci-4-alkylgruppe, en metylgruppe substituert med 1 til 3 fluoratomer, en etylgruppe substituert med 1 til 5 fluoratomer, en C2-4-alkylgruppe substituert med en gruppe R6 eller R<7>, hvor R6 og R<7> er som definert i kravene 1 til 4, en Ci^-alkylgruppe som er substituert med en pyrrolidinyl-, piperidinyl- eller homopiperidinylgruppe substituert i 1-stillingen med gruppen R<8> eller en Ci-4-alkylgruppe som er substituert med en morfolinylgruppe substituert i 4-stillingen med gruppen R<8>, hvor R<8> i hvert tilfelle er som definert i kravene 1 til 4 og Z<2> betyr en utgående gruppe.10. Process for preparing the compounds of the general formula I according to claims 1 to 4, characterized in that to prepare compounds of the general formula I where Rd denotes one of the optionally substituted alkyloxy groups specified in claims 1 to 4, becomes a compound with the general formula where Ra, R<b>, R<c> and X are as defined in claims 1 to 4, reacted with a compound of the general formula where Rd' means a C1-4 alkyl group, a methyl group substituted by 1 to 3 fluorine atoms, an ethyl group substituted by 1 to 5 fluorine atoms, a C2-4 alkyl group substituted by a group R6 or R<7>, where R6 and R <7> is, as defined in claims 1 to 4, a C1-4 alkyl group which is substituted with a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1-position with the group R<8> or a C1-4 alkyl group which is substituted with a morpholinyl group substituted in the 4-position by the group R<8>, where R<8> in each case is as defined in claims 1 to 4 and Z<2> means an outgoing group. 11. Fremgangsmåte for fremstilling av forbindelsene med den generelle formel I ifølge kravene 1 til 4, karakterisert ved at for å fremstille forbindelser med den generelle formel I hvor Rd betyr én av alkyloksygruppene nevnt i kravene 1 til 4, som er substituert med en eventuelt substituert amino-, alkylamino- eller dialkylaminogruppe eller med en eventuelt substituert heterocyklisk gruppe bundet via et iminonitrogenatom, blir en forbindelse med den generelle formel hvor Ra, R<b>, R<c> og X er som definert i kravene 1 til 4 og Z<3> betyr en utgående gruppe, omsatt med ammoniakk, en tilsvarende, eventuelt substituert alkylamin-, dialkylamin- eller en imino-forbindelse eller de passende salter eller derivater derav.11. Process for preparing the compounds of the general formula I according to claims 1 to 4, characterized in that to prepare compounds of the general formula I where Rd means one of the alkyloxy groups mentioned in claims 1 to 4, which is substituted with an optionally substituted amino, alkylamino or dialkylamino group or with an optionally substituted heterocyclic group bound via an imino nitrogen atom, a connection with the general formula where Ra, R<b>, R<c> and X are as defined in claims 1 to 4 and Z<3> means a leaving group, reacted with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or the appropriate salts or derivatives thereof. 12. Fremgangsmåte for fremstilling av forbindelsene med den generelle formel I ifølge kravene 1 til 4, karakterisert ved at for å fremstille forbindelser med den generelle formel I hvor Rd betyr en hydroksygruppe, blir en beskyttelsesgruppe spaltet fra en forbindelse med den generelle formel hvor Ra, R<b>, R<c> og X er som definert i kravene 1 til 4 og Rd betyr en gruppe som kan omdannes til en hydroksygruppe.12. Process for preparing the compounds of the general formula I according to claims 1 to 4, characterized in that to prepare compounds of the general formula I where Rd means a hydroxy group, a protecting group is cleaved from a compound of the general formula where Ra, R<b>, R<c> and X are as defined in claims 1 to 4 and Rd means a group that can be converted into a hydroxy group. 13. Fremgangsmåte for fremstilling av forbindelsene med den generelle formel I ifølge kravene 1 til 4, karakterisert ved at for å fremstille forbindelser med den generelle formel I hvor R<c> inneholder en -NH- gruppe, blir en beskyttelsesgruppe spaltet fra en forbindelse med den generelle formel hvor Ra, R<b>, Rd og X er som definert i kravene 1 til 4 og Rc har betydningene gitt for R<c> i kravene 1 til 4, med det forbehold at R<c> inneholder et beskyttet nitrogenatom.13. Process for preparing the compounds of the general formula I according to claims 1 to 4, characterized in that to prepare compounds of the general formula I where R<c> contains a -NH- group, a protecting group is cleaved from a compound of the general formula where Ra, R<b>, Rd and X are as defined in claims 1 to 4 and Rc has the meanings given for R<c> in claims 1 to 4, with the proviso that R<c> contains a protected nitrogen atom. 14. Fremgangsmåte for fremstilling av forbindelsene med den generelle formel I ifølge kravene 1 til 4, karakterisert ved at for å fremstille forbindelser med den generelle formel I hvor R<c> inneholder en alkylgruppe substituert med en eventuelt substituert amino-, alkylamino- eller dialkyaminogruppe eller med en eventuelt substituert heterocyklisk gruppe bundet via et nitrogenatom, blir en forbindelse med den generelle formel hvor Ra, R<b>, Rd og X er som definert i kravene 1 til 4, Z<3> betyr en utgående gruppe og R<c> har betydningene gitt for R<c> i kravene 1 til 4, med det forbehold at et hydrogenatom bundet til et alifatisk karbonatom er erstattet med gruppen Z<3>, omsatt med ammoniakk, en tilsvarende, eventuelt substituert alkylamin-, dialkylamin- eller en imino-forbindelse eller de passende salter eller derivater derav.14. Process for preparing the compounds of the general formula I according to claims 1 to 4, characterized in that to prepare compounds of the general formula I where R<c> contains an alkyl group substituted with an optionally substituted amino, alkylamino or dialkylamino group or with an optionally substituted heterocyclic group bound via a nitrogen atom, becomes a compound with the general formula where Ra, R<b>, Rd and X are as defined in claims 1 to 4, Z<3> means a leaving group and R<c> has the meanings given for R<c> in claims 1 to 4, with the proviso that a hydrogen atom bound to an aliphatic carbon atom is replaced by the group Z<3>, reacted with ammonia, a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or the appropriate salts or derivatives thereof.
NO20043997A 2002-03-30 2004-09-23 4- (N-Phenylamino) quinazolines / quinolines, the preparation thereof, pharmaceutical preparations containing them and the use thereof for the manufacture of medicaments for the treatment of disease NO329271B1 (en)

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Families Citing this family (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EE04748B1 (en) 1999-06-21 2006-12-15 Boehringer Ingelheim Pharma Kg Bicyclic heterocyclic compounds, drugs containing these compounds, their use and methods for their preparation
US7019012B2 (en) 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US6924285B2 (en) 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
EP2277867B1 (en) * 2002-07-15 2012-12-05 Symphony Evolution, Inc. Compounds, pharmaceutical compositions thereof and their use in treating cancer
CA2527017A1 (en) * 2003-05-27 2004-12-09 Pfizer Products Inc. Quinazolines and pyrido [3,4-d] pyrimidines as receptor tyrosine kinase inhibitors
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
WO2006074147A2 (en) 2005-01-03 2006-07-13 Myriad Genetics, Inc. Nitrogen containing bicyclic compounds and therapeutical use thereof
DE10334226A1 (en) * 2003-07-28 2005-02-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
EP1660479A1 (en) * 2003-07-29 2006-05-31 Astrazeneca AB Piperidyl-quinazoline derivatives as tyrosine kinase inhibitors
GB0317665D0 (en) * 2003-07-29 2003-09-03 Astrazeneca Ab Qinazoline derivatives
CN1882573A (en) * 2003-09-16 2006-12-20 阿斯利康(瑞典)有限公司 Quinazoline derivatives as tyrosine kinase inhibitors
WO2005026150A1 (en) * 2003-09-16 2005-03-24 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors
CN1882570B (en) * 2003-09-19 2010-12-08 阿斯利康(瑞典)有限公司 Quinazoline derivatives
ES2279441T3 (en) * 2003-09-19 2007-08-16 Astrazeneca Ab DERIVATIVES OF QUINAZOLINA.
GB0322409D0 (en) * 2003-09-25 2003-10-29 Astrazeneca Ab Quinazoline derivatives
US7456189B2 (en) 2003-09-30 2008-11-25 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
DE10345875A1 (en) * 2003-09-30 2005-04-21 Boehringer Ingelheim Pharma Bicyclic heterocycles, pharmaceutical compositions containing them, their use and methods of preparation
DE10350717A1 (en) * 2003-10-30 2005-06-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
GB0326459D0 (en) 2003-11-13 2003-12-17 Astrazeneca Ab Quinazoline derivatives
MXPA06007017A (en) 2003-12-18 2006-08-31 Janssen Pharmaceutica Nv Pyrido- and pyrimidopyrimidine derivatives as anti- proliferative agents.
WO2005058318A1 (en) 2003-12-18 2005-06-30 Janssen Pharmaceutica N.V. 3-cyano-quinoline derivatives with antiproliferative activity
US20060035893A1 (en) 2004-08-07 2006-02-16 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
NI200700147A (en) 2004-12-08 2019-05-10 Janssen Pharmaceutica Nv QUINAZOLINE DERIVATIVES KINE INHIBITORS TARGETING MULTIP
ATE501148T1 (en) 2004-12-14 2011-03-15 Astrazeneca Ab PYRAZOLOPYRIMIDINE COMPOUNDS AS ANTI-TUMOR AGENTS
PE20060777A1 (en) 2004-12-24 2006-10-06 Boehringer Ingelheim Int INDOLINONE DERIVATIVES FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
MX2007009265A (en) * 2005-02-04 2007-09-07 Boehringer Ingelheim Int Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis.
WO2006081741A1 (en) * 2005-02-05 2006-08-10 Piaoyang Sun Quinazoline compounds or their medical salts and preparation and medical usage thereof
TW200640904A (en) * 2005-02-26 2006-12-01 Astrazeneca Ab Quinazoline derivatives
EP1919900A2 (en) * 2005-08-22 2008-05-14 Boehringer Ingelheim International Gmbh Bicyclic heterocycles medicaments comprising said compounds use and method for production thereof
ATE488513T1 (en) 2005-09-20 2010-12-15 Astrazeneca Ab 4-(1H-INDAZOLE-5-YLAMINO)QUINAZOLINE COMPOUNDS AS ERBB RECEPTOR TYROSINE KINASE INHIBITORS FOR THE TREATMENT OF CANCER
WO2007054550A1 (en) 2005-11-11 2007-05-18 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
BRPI0619603A2 (en) * 2005-12-12 2011-10-11 Boehringer Ingelheim Int bicyclic heterocycles, physiologically compatible salts, medicaments containing such compounds, as well as use and processes for the production of bicyclic heterocycles
WO2007101782A1 (en) * 2006-03-09 2007-09-13 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing these compounds, their use and process for preparing them
WO2008006884A2 (en) 2006-07-13 2008-01-17 Janssen Pharmaceutica N.V. Mtki quinazoline derivatives
WO2008033749A2 (en) * 2006-09-11 2008-03-20 Curis, Inc. Quinazoline based egfr inhibitors containing a zinc binding moiety
SG174772A1 (en) * 2006-09-11 2011-10-28 Curis Inc Multi-functional small molecules as anti-proliferative agents
DK2068880T3 (en) 2006-09-18 2012-07-23 Boehringer Ingelheim Int Method of treating cancer harboring EGFR mutations
EP1921070A1 (en) 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG Bicyclic heterocycles, medicaments comprising them, their use and process for their preparation
EP1956010A1 (en) * 2007-02-06 2008-08-13 Boehringer Ingelheim Pharma GmbH & Co. KG Bicyclical heterocycles, medicines containing these compounds, their application and method for their production
WO2008095847A1 (en) * 2007-02-06 2008-08-14 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
TWI377944B (en) 2007-06-05 2012-12-01 Hanmi Holdings Co Ltd Novel amide derivative for inhibiting the growth of cancer cells
DK2185562T3 (en) 2007-07-27 2016-02-22 Janssen Pharmaceutica Nv PYRROLOPYRIMIDINES SUITABLE FOR TREATING PROLIFERATIVE DISEASES
WO2009098061A1 (en) 2008-02-07 2009-08-13 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles, medicaments containing said compounds, use thereof and method for their production
AU2009247782C1 (en) * 2008-05-13 2013-09-19 Astrazeneca Ab Fumarate salt of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (N-methylcarbamoylmethyl) piperidin- 4-yl] oxy } quinazoline
JP5539351B2 (en) * 2008-08-08 2014-07-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Cyclohexyloxy-substituted heterocycles, medicaments containing these compounds, and methods for producing them
CA2733159A1 (en) 2008-08-08 2010-02-11 Boehringer Ingelheim International Gmbh Cyclohexyloxy-substituted heterocyclics, medicines containing these compounds and method for the production thereof
EP2313377B1 (en) * 2008-08-08 2016-01-06 Boehringer Ingelheim International Gmbh Method for stereoselective synthesis of bicyclic heterocycles
CN101659658B (en) * 2008-08-29 2014-04-02 北大方正集团有限公司 Quinoline substituted by cyan
CN101659657B (en) * 2008-08-29 2014-05-14 北大方正集团有限公司 Quinoline substituted by cyan and preparation method and applications thereof
US8629153B2 (en) * 2008-09-03 2014-01-14 Boehringer Ingelheim International Gmbh Use of quinazoline derivatives for the treatment of viral diseases
SI2451445T1 (en) 2009-07-06 2019-07-31 Boehringer Ingelheim International Gmbh Process for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
CA2775601C (en) 2009-09-28 2017-10-03 Qilu Pharmaceutical Co., Ltd 4-(substituted anilino)-quinazoline derivatives useful as tyrosine kinase inhibitors
US20120046284A1 (en) * 2010-02-15 2012-02-23 Boehringer Ingelheim International Gmbh Salts and hydrates of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4--cyclohexan-1-yloxy)-7-methoxy-quinazoline, their use as a medicament and the preparation thereof
CN102452988B (en) * 2010-10-27 2016-01-27 中国科学院化学研究所 A kind of quinazoline derivant and preparation method thereof
EA023573B1 (en) 2011-02-01 2016-06-30 Бёрингер Ингельхайм Интернациональ Гмбх 9-[4-(3-chlor-2-fluor-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one dimaleate, use thereof as a drug, and production thereof
KR101317809B1 (en) 2011-06-07 2013-10-16 한미약품 주식회사 Pharmaceutical composition comprising amide derivative inhibiting the growth of cancer cell and non-metalic salt lubricant
JP6105631B2 (en) 2012-02-09 2017-03-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Stereoselective synthesis of 1,4-protected 9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecane
EP2752413B1 (en) 2012-03-26 2016-03-23 Fujian Institute Of Research On The Structure Of Matter, Chinese Academy Of Sciences Quinazoline derivative and application thereof
WO2014012859A1 (en) 2012-07-19 2014-01-23 Boehringer Ingelheim International Gmbh Fumaric acid salt of 9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy- chinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one, its use as medicament and the preparation thereof
KR20140096571A (en) 2013-01-28 2014-08-06 한미약품 주식회사 Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one
KR101645112B1 (en) * 2013-03-06 2016-08-02 아스트라제네카 아베 Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
TWI771327B (en) * 2016-10-05 2022-07-21 英商使命醫療公司 Novel compounds
US11365189B2 (en) 2019-04-25 2022-06-21 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of tyrosine kinase
CN114867719A (en) 2019-11-06 2022-08-05 柳韩洋行 Pyrrolidine and piperidine compounds

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5747498A (en) * 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
GB9603095D0 (en) * 1996-02-14 1996-04-10 Zeneca Ltd Quinazoline derivatives
DE19911509A1 (en) * 1999-03-15 2000-09-21 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
GB9910577D0 (en) * 1999-05-08 1999-07-07 Zeneca Ltd Chemical compounds
DE10042058A1 (en) * 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
DE10042059A1 (en) * 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
TW200813014A (en) * 2002-03-28 2008-03-16 Astrazeneca Ab Quinazoline derivatives

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