TWI294422B - Bicyclic heteocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them - Google Patents

Description

1294422

The present invention relates to a bicyclic heterocycle of the formula

Mutual variants, stereoisomers and salts thereof, in particular with physiologically acceptable salts of inorganic or organic acids or bases I, which have valuable pharmacological properties, especially for signal transduction regulation of tyrosine kinase regulation The use thereof for treating diseases, particularly tumor diseases, lung and respiratory diseases, and preparation methods thereof. In the above formula I, a phenyl group which represents a fluorenyl group or a 1-phenylethyl group or a transatom and a trans 2 group, wherein h represents hydrogen, fluorine, gas or a bromine atom, methyl group, trifluoromethyl group, cyano group Or an alkyl group and a hydrogen or fluorine atom,

One of the Rb or Re groups represents R3_(CH2)m-fluorenyl and Rb4Rc, the other group represents a decyloxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclopropylmethoxy group, a cyclobutylmethoxy group, a cyclopentyl group. Methoxy, tetrahydroinden-3-yloxy, tetrahydrop-pyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofurfurylmethoxy or tetrahydrop Beryl methoxy, wherein -I represents N-(2-oxotetrahydrofuran-4-yl)methylamino or N-(2-oxotetrahydrofuran-4-yl)ethylamine , optionally, R4-〇-c:〇_ch2-n-ch2ch2-oh, substituted by 1 or 2 methyl or ethyl groups, wherein the 4 represents a hydrogen atom or a Cw alkyl group, -4- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294422 A7 B7 V. Description of invention (2) or 2 oxomorpholine which may be substituted by 1 or 2 methyl or ethyl groups 4-Based, m represents the number of 2, 3 or 4, except for the following compounds: 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-{ N-(2-hydroxy-2-mercaptopropen-1-yl)-N-[(ethoxycarbonyl)methyl]amino}ethoxy)quinazoline, '[(3-gas-4-fluoro) Phenyl)amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-代吗p林-4-yl)ethoxy]Jun Jun p Lin 'Mo phenyl)amino]-6-[2-(6,6-dimethyl-2-oxo-indol-4-yl) Ethoxy]-7-methoxy π quetium, and '[(3-bromophenyl)amino]-6-{2-[N-(2-oxotetrahydrofuran-4-yl)- N-methylamino]ethoxy}-7-methoxyquinazoline, its tautomers, stereoisomers and salts. Preferably, the compound of formula I above is:

Ra represents benzyl or 1-phenylethyl or phenyl substituted with 1 and 112 groups, wherein h represents hydrogen, fluorine, gas or bromine atoms, methyl, trifluoromethyl, cyano or ethynyl and R2 Represents hydrogen or a fluorine atom, or one of the Re groups represents an R3-(CH2)m-0 group and Rb or Re another group represents a methoxy 'cyclobutoxy group, a cyclopentyloxy group, a cyclopropylmethoxy group, Cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydrop-pyranyl-4-yloxy, tetrahydrofuran Methoxy or tetrahydrop-pyranylmethoxy, wherein R3 represents N-(2: oxotetrahydrofuran-4-yl) decylamino or n-(2-oxotetrahydrofuran-4-yl)ethylamine Base, -5- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1294422 A7 B7 V. Description of invention (3) Depending on the case, the methyl group is substituted by 1 or 2 methyl or ethyl groups. R4_〇-C〇_ ch2-n-ch2ch2-oh, wherein the ulmen 4 represents a hydrogen atom or a Cm-alkyl group, or a 2-oxo odor which can be substituted by 1 or 2 methyl or ethyl groups _4 _ base, m represents the number of 2, 3 or 4, except for the following compounds: 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyl -7-(2-{N-(2_#i-ylmethylpropyl·1·yl)-N-[(ethoxycarbonyl)methyl]amino}ethoxy bizozole ^, 4-[ (3-chloro-4-phenyl)amino]-6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxo-indol-4-yl)ethoxy] Teplin, 4-[(3-bromophenyl)amino]-6-[2-(6,6-dimethyl-2-oxomorpholine-4-yl)ethoxy]-7- ΤΤ ΤΤ Ρ Ρ, 4-[(3·bromophenyl)amino]·6·{2_[Ν·(2· oxotetrahydrofuran·4_yl)_Ν_methylamino] Ethoxy}-7-methoxy quinazoline, 4-[(3-bromophenyl)amino]·6·(2-{Ν-(2-hydroxy-2-methyl-anthracene-yl) )_Ν_[(ethoxycarbonyl)methyl]amino}ethoxy}-7-methoxycarbazole, 4-[(3-bromophenyl)amino]>6-[2-(3) -methyl oxomorpholine _4. yl) ethoxy]_ 7-fluorenyl p-quinone, 4-[(3-bromophenyl)amino]-6-[2-(5,5 -Dimethyl-2-oxomorpholyl)ethoxy]-7-methoxy p-kupan P-line, 4-[P-gas-4.fluorophenyl)amino]-6-[2 -(6,6-Dimethyl-2-oxomorpholine-4) ethoxy]-7-methoxyquinazoline, 4_[(3-carb-4-fluoroindolyl)amino ]-6-[2-(6,6-diamidinooxymorpholine-cardyl)ethoxy]- 7 -cyclobutoxy junjun, this paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1294422 A7 B7

V. DESCRIPTION OF THE INVENTION (4) 4-[(3-Ethyl-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo? 4 spirit) Ethoxy ]]-7-cyclopentyloxy p-kujunlin, 4·[(3- gas-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo琳琳*农) Ethoxy]-7-cyclopropylphosphonium quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6- Dimethyl-2 oxo- phenanthrene _4 ethoxy]-7-cyclopentylmethoxy p-quineline, 4-[(3_chloro-4)fluorophenyl)amino]-6- {2-[N-(2-oxotetrahydrofuranium n-methylamino)ethoxy bromide 7-methoxyquinazoline, 4·[(3-fluoro-4-phenylene)amino ]-6-{2-[Ν-(2-oxotetrahydrofuranyl)-jsj ·methylamino]ethoxy}-7-cyclopentyloxyquinazoline, 4-[(3 - Chloro-4-fluorophenyl)amino]-6-{2-[N-(2-oxotetrahydrocarbamateyl)*N. Methylamino]ethoxy}-7-cyclopentyl Methoxyoxazoline, 4-[(3-zinc-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-inorganic 4-propoxy ]-7-methoxy p-quinone, base) 4-[(3- gas-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo Mouthyloxy]-7-cyclopentyloxy p-kurine, 4-[(J-gas-4-d-phenyl) Amino]-6-[3-(6,6-dimethyl-2-oxoquinone-propoxy]-7-cyclopentylmethoxyquinazoline, (R)-4-[( L-phenylethyl)amino]-6_[3-(6,6-dimethyl-2.oxy)propoxy]-7-cyclopentyloxy ρ 奎 琳, ' Oxygen 4&quot ;·[(3-乱-4--4-phenylphenyl)amino]-7-[2-(6,6-dimercapto-2_ethoxy]-6-methoxy π 奎 淋, base) 4·[(3 - rat said dream base) amine group]-7·[2-(6,6·dimethyloxo oxetine ethane group]-6-cyclobutoxy octopus, this paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1294422 A7 B7 V. Description of invention (5) 4-[(3-chlorofluorophenyl)amino]-7·[2_(6,6- Dimethyl-2-oxoethoxy]-6-cyclopentyloxy 4, violent) 4-[(3-Gas-4-fluorophenyl)amino]-7-[2-(6 ,6-Dimethyl-2-oxo' 0,4 ethoxy]-6-cyclopropylmethoxyquinazoline, 4-[(3-Ga-4-fluorophenyl)amino] -7-[2-(6,6-Dimethyl-2-oxohol, 4 Ή* ethoxy]-6-cyclopentylmethoxyquinazoline, anthracene, yl), 4. 4-[ (3_gas-heart fluorophenyl)amino]-7-{2-[Ν-(2-oxotetrahydrotetramethylamino)ethoxy}-6-methoxyjunjun,4-[(3-fluorofluorophenyl)amino]-7-{2-[Ν-(2-oxotetramethylaminomethyl)ethoxy}-6-cyclopentyloxycarbazole Porphyrin, 4-[(3- gas-4-fluorophenyl)amino]-7-{2-[N-(2-oxotetrahydrofuran)

,])N-methylamino]ethoxy}-6-cyclopentylmethoxyquinazoline, • base:) 4-[(3·chloro-4-fluorophenyl)amino]·7 -[3-(6,6-Dimethyl-2-oxo-methionine-propoxy)-6-methoxy ρ 奎 琳, 4-[(3_乱_4·fluorophenyl)amino ]-7_[3-(6,6·Dimethyl_2_oxo- dailine 4 wu) propyl propyl]-6-cyclopentyloxy thiophene, 4-[(3·-fluorophenyl) Amino]_7-[3-(6,6-dimethyloxo-demethyl) l-propoxy]-6-cyclopentylmethoxy π 奎 君, and (R)-4-[( L-Phenylethyl)amino]-7-[3_0,6-dimethyl-2-oxomorpholine·4·yl)propoxy]-6-cyclopentyloxyu-ku jun p. Especially good for:

Ra represents a 1-phenylethyl group or a phenyl group substituted with a 1^ and a trans 2 group, wherein Ri represents a hydrogen atom, a fluorine, a gas or a bromine atom, a methyl or ethynyl group, and represents a hydrogen or fluorine atom, -8 - The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294422 A7 ____ B7 V. Description of invention (6) One of the core or Rc base represents R3-(CH2)m-fluorenyl and Rb or Rc A group represents methoxy, cyclobutoxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyridyl Ory-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy, wherein I represents N-(2-oxotetrahydrofuran-4) Methylamino, optionally substituted by methyl or i or 2 methyl or ethyl, R4_〇_C (> ch2-n-ch2ch2-〇h*, which represents CN4-alkyl, or may be 1 or 2 methyl-substituted 2-oxomorpholin-4-yl, m represents a number of 2, 3 or 4, except for the following compounds: 4-[(3 -mur-4-fluoro)amino ]-6-cyclopentyloxy-7-(2-{Ν-(2·carbyl-2-methylpropan-1-yl)[(ethoxycarbonyl)methyl]amino}ethoxy > quinazoline, 1294422 V. Description of the invention (7 4_[(3_bromophenyl)amino]-Μ2-(5,5-dimethyl-2-oxo-indolyl-4,yl)ethyl >7-methoxyquinazoline, 4-[(3-chloro-4-hexyl)amino]-6-[2·(6,6-dimethyl-2.oxo gas? Porphyrin, ethoxy]-7-methoxyquinazoline, ·>yl) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-di Methyl-2-oxo-ethoxy]-7-cyclobutoxyquinazoline, fluorenyl) 4-[(3- gas-4-fluorophenyl)amino]-6-[2-( 6,6· dimethyl-2-oxomethoxyethoxy]-7-cyclopentyloxy ρ 奎 4 4 wood, 4-[(3- gas-4-fluoro-based)amino]-6- [2-(6,6-Dimethyl-2-oxo) 咻 ethoxy]-7-cyclopropyl methoxy quinazoline, π-) 4-[(3- gas-4- Fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxoethoxy)-7-cyclopentylmethoxyoxazoline, anthracene, 4, yl) 4-[(3-Gas-4-fluorophenyl)amino]-6-{2-[Ν-(2-oxotetrahydrobatch) methylamino]ethoxy}-7_A Oxyquinazoline, 4·[(3-chloro-fluorophenyl)amino]-6-{2_[N-(2-oxotetrahydrocarbamate~methylamino]ethoxy}-7 -cyclopentyloxyquinazoline, 4·[(3_气_4· Fluorophenyl)amino]-6_{2-[N-(2-oxotetrahydropurine p-South, *methylamino)ethoxycyclopentylmethoxy-4-oxazoline, M (3-gas 4-fluorophenyl)amino]dong[3-(6,*6-dimethyloxopropoxy]-7-methoxyquinazoline, 4-[(3- gas-4- Fluorophenyl)amino]-6-[3·(6,6-dimethyl-2-oxopropoxy)-7-cyclopentyloxyquinazoline, 4_[(3_气_4 _Flutonyl)amino]-6·[3·(6,6·dimethyloxopropoxy)-7-cyclopentyloxy quinazoline, yl) long 咻-4. 咻, 4. Base) Base) -10 This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294422 A7 B7 V. Description of invention (8 (R)_4_[(l-phenyl) Ethyl)amino]-6-[3-(6,6-dimethyl-2-oxo, xylanyl A)propoxy]-7-cyclopentyloxy sulphate, 4 -[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-oxime ethoxy)-6-methoxyquinazoline , base) 4-[(3-chloro-4-fluorophenyl)amino]-7·[2-(6,6-dimethyl-2-oxophenoxyethoxy)-6-cyclobutane Ρ Ρ Ρ ,, base) 4-[(3_chloro_4·fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo) Oxy]-6-cyclopentyloxy 4 Junlin, ^) 4-[(3-chloro-4-fluorophenyl)amino]-7_[2-(6,6-dimethyl-2-oxo Sputum sputum, 4, ethoxy]-6-cyclopropyl methoxy pku jun p, a) 4-[(3-chloro-4-phenylphenyl)amino]-7- [2-(6,6-Dimethyl-2-oxo- ton ethoxy)-6-cyclopentylmethoxy uranium tau tau, 4-[(3-chloro-4-fluorophenyl) Amino]-7-{2-[Ν·(2_oxotetrahydrofuran, 4 methylamino)ethoxy}-6-methoxyquinazoline, 4-[(3-chloro- 4-fluorophenyl)aminophenyl 7-{2-[Ν-(2-oxotetrahydrofuranyl)methylamino]ethoxy}-6-cyclopentyloxy ρ 奎 琳 4 -[(3_ gas·4-fluorophenyl)amino]-7-{2-[Ν-(2-oxotetrahydroindolylmethylamino)ethoxy}-6-cyclopentyl Oxyquinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxopropoxy]-6- Methoxyquinazoline, yl) '[(3-Ga-4-fluorophenyl)amino]-7-[3-(6,6-dimercapto-2-oxopropoxy) ]-6-J pentyloxy ρ kujunlin, 4-[(3- gas-4-fluorochayl)amino]-7-[3-(6,6-dimethyl-; 2-oxygen代丙丙基]-6-cyclopentylmethoxyjunjun, and base) base) - 11 - This paper size applies to Chinese National Standard (CNS) Α4 specification (210Χ297 mm) 1294422 A7 B7 V. Description of invention (9) (R)-4-[(l-phenylethyl)amino]-7· [3. (6,6-Dimethyloxymorpholine-heart group) propoxy]-6-cyclopentyloxyquinazoline, its tautomers, stereoisomers and salts. Particularly preferred compounds of formula I are:

Ra represents 1-phenylethyl or a phenyl group substituted by [^ and !^, wherein Ri represents a fluorine, chlorine or bromine atom and represents hydrogen or an atom,

One of the Rb or Re groups represents R3-(CH2)m-0 group and Rb or R. The other group represents methoxy, cyclobutoxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran- 3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy, wherein I represents N-(2-oxotetrahydrofuran-4-yl)methylamine A 2-oxomorpholin-4-yl group substituted with one or two methyl groups, and m represents a number of 2, 3 or 4, except for the following compounds: 4-[(3-Gas-4-fluorobenzene) Amino]-6-cyclopentyloxy-7-[2_(6,6-dimethyl-2-oxymorpholin-4-yl)ethoxy]quinazoline, 4-[(3-苯基 phenyl)amino]]_6_[2_(6,6•didecyl-2-oxo-oxo_4_yl)ethoxy]·7-methoxy p-kujun, heart [(3-苯基Phenyl)amino]-6-{2-[Ν♦ oxotetrahydrofuran]-methylamino]ethoxy bromide 7-methoxy-4-oxazoline, soil 4. ))]]6_[2_(3_methyl_2•oxo- phenanthyl) ethoxy 7-methoxy is awesome,

A7 B7

, basal) ethoxy, 4, basal) Ρ林, 4, 基) "休, 4, base) 咻, 4, base) • 4 基 base 'base), base) 1294422 V. Invention Description (1〇) 4-[(3-Bromophenyl)amino]-6-[2-(5,5-dimethyl-2-oxo-inorganic, 4-yl]-7-methoxy Quinazoline, 4_[(3_gas-4_fluorophenyl)amino]-6-[2_(6,6-dimethyl-2-oxo^ethoxy]-7-decyloxyquin Oxazoline, 4-[(3-chlorofluorophenyl)amino]-6-[2-(6,6-diamidino-2-oxo@ethoxy b-7-cyclobutoxyquinazoline , 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-dimethyloxoethoxy)-7-cyclopentyloxyquinazoline, 4-[(3-chlorofluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxoethoxy)-7-cyclopropylmethoxyquinazoline , 4-[(3- gas-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxoethoxy)-7-cyclopentylmethoxy Oxazoline, 4-[(3-chloro-4-cyclophenyl)amino]-6-{2·[Ν-(2.oxotetrahydrotetramethylamino)ethoxy}-7 -Methoxyquinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{2_[N-(2.oxotetrachloropyranylmethylamino)ethoxylate }-7-cyclopentyloxyquinazoline, 4-[(3_气Phenyl)amino]-6_{2_[N-(2-oxotetrahydrofuran, 4 methylamino)ethoxy}-7-cyclopentylmethoxyoxazoline, 4-[( 3-oxo-4-fluorophenyl)amino]-6-[3-(6,'6-didecyl-2-oxo- phenoxypropoxy]-7-methoxyjunjun, M (3-Gas-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxo-phenoxypropoxy]-7-cyclopentyloxy p-kujun , 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxopropoxy]-7-cyclopentylmethoxy Base quinazoline, this paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 'Hui + base' -13- .4·1294422 A7 B7 V. Invention description (11 ) (R) -4- [(l-Phenylethyl)amino]-6-[3-(6,6-dimethyl-2-oxo-heptyl)propoxy]-7-cyclopentyloxy 4, 4-[(3-chloro-4-fluorophenyl)amino]-7-[2_(6,6-dimethyl-2-oxo- phenothi-ethoxy)-6-methoxy Quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-endoline 4 ethoxy]-6- Cyclobutoxyquinazoline, yl) 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-phenoline 4 B Oxy]-6-cyclopentyloxy p-kut , 4-[(3-chloro-4_traylphenyl)amino]-7-[2-(6,6-dimethyl-2-oxo-nosyloxy)-6-cyclopropyl Methoxyquinazoline, 4-[(3- gas-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl.2_oxo?p?)ethoxy ]-6-Cyclopentylmethoxy 4 Junlin, ^ ^ Ν· 4-[(3-Actyl-4-ranylphenyl)amino]_7-{2_[Ν-(2-oxotetrahydro)吱 义)) mercaptoamine]ethoxy}_6_methoxy-4-oxazoline, & 4-[(3- gas-4-fluorophenyl)amino]-7-{2-[Ν- (2_oxotetrahydrofurfurylmethylamino)ethoxy}-6-cyclopentyloxyquinazoline, 4-[(3- gaso-fluorophenyl)amino]-7-{2 -[Ν-(2-oxotetrahydrofuran-4 meaning) methylamino]ethoxy}-6-cyclopentylmethoxyquinazoline, ~yl)-Ν· 订%k base) 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(6,*6-dimethyl-2-oxo oxime?-propoxy]-6-methoxy Quinazozoline, 4-[(3-chloro-4-d-phenylphenyl)amino]·7-[3-(6,6-dimethyl-2-oxo-inulin, 4) propoxy ]-6-cyclopentyloxy π quinidine, 4-[(3*·chloro-4-fluoroindolyl)amino]-indole _(6,6-dimethyloxo-endoline 4'-yl) Oxydi 6-cyclopentylmethoxyoxazoline, and -14- 12 94422 A7 B7 V. INSTRUCTIONS (12) (R)-4-[(1-Phenylethyl)amino]_7_[3·(6,6-dimethyl-2-oxomorpholine_4_yl a propoxy]-6-cyclopentyloxy quinone, a tautomer, a stereoisomer, and a salt thereof. A particularly preferred compound is a compound of formula I wherein:

Ra represents 1-propenylethyl, 3-oxiphenyl or 3-chloro-4-mercapto,

Rb represents R3-(CH2)m-0, wherein I represents 2-oxomorpholine-4-yl substituted with one or two methyl groups, and m represents a number of 2 or 3, and I represents a methoxy group. , cyclobutoxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy, except for the following compounds: 4-[(3-bromophenyl)amino] -6-[2-(6,6-Dimethyl-2-oxomorpholine-4-yl)ethoxy]-7-methoxy. Quivin, 4-[(3-bromophenyl)amino]-6-[2-(3-methyl-2-oxo- phenanthyl)ethoxy]7-methoxyp-quine , 4-[(3-Bromophenyl)amino]-6-[2-(5,5-dimethyl-2-oxo- phenanthrene-4-yl)ethoxy]-7-methoxy Quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6,6-didecyl-2-oxo-phenanthyl) ethoxy]- 7-Methoxy 4 olfactory, '4-[(3-A-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo- narline 4 Ethoxy]-7-cyclobutoxyquinazoline, 4·[(3·chloro-4-d-phenylphenyl)amino]-6-[2-(6,6-dimethyl-2-) Oxygenated p-lining 4) ethoxyl l''cyclo-n-methoxy quinazoline, 4-[(3- gas·4·fluorophenyl)amino]-6_[3-(6,6 - dimethyl-2-oxo morphine) -15- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) ' -- 1294422 V. Invention description (13 ) A7 B7

Propyl]-7-methoxyquinazoline, M(3-vapor-4-fluorophenyl)amino]-6-|>(6,6-dimercapto-2-oxo- phenanthrene Ethoxy]-7-cyclopentyloxy π kujun #木, 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2 - oxoline _4 propoxy]-7-cyclopentyloxyoxazoline, and -yl) (R)-4-[(l-phenylethyl)amino]6_[3_(6 , 6-dimethyloxomethoxy)propoxy]-7-cyclopentyloxyquinazoline, its tautomers, stereoisomers and salts. The most preferred compound is a compound of formula I, wherein: Ra stands for 3-gas-4-fluorophenyl,

Rb represents cyclopentyloxy, cyclopropyldecyloxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy or tetrahydrofuranylmethoxy, and represents R3-(CH2)m-0, wherein R3 represents 2-oxomorpholin-4-yl substituted by one or two methyl groups, and m represents the number of 2, except for the following compounds: 4-[(3-chloro-4-fluorophenyl)amino]- 6-cyclopentyloxy-7-[2-(6,6-dimethyl-2-oxazolin-4-yl)ethoxy]quinazoline u, 4-[〇-chloro-4- Fluorophenyl)amino]-7-[2-(6;6-dimethyl-2-oxo-indolyl) ethoxy]-6-cyclopentyloxy-salt, heart[(3 _ gas-heart fluorophenyl)amino]- Η2-(6,6-dimethyl I oxo morphinyl) ethoxy]-6-cyclopropyl methoxy quinazoline, and '[( 3-chloro-4-fluorophenyl)amino]-7-[2-(6,6-dimethyl-2-oxo, lin-4-yl)ethoxy]-6-cyclopentyl Methoxy ρ 奎 君, -16 - This paper size applies to Chinese National Standard (CNS) Α 4 specifications (210 X 297 mm)

Binding

1294422 A7

Its tautomers, stereoisomers and salts. The T compounds show the best compounds: (1) 4_[(3-chloro-4-fluorophenyl)amino]-6-cyclopentylmethoxy-7_[2 oxymorpholino) ethoxylate a quinazoline, (2) 4_[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-{2h(2 hydroquinone-4-yl)-N- Mercaptoamine]ethoxy}quinazoline, (3) 4_[(3-Gas-4-fluorophenyl)amino]-6-cyclopropylmethoxylate 6 oxo morphine·4 - Ethyl]p-oxyquinone p-lin, (4) 4-[(3'chloro-4-fluorophenyl)amino]-7-cyclobutoxy-6-[3, (2 0 ^ • Dimethyl 6-oxo- phenanthyl-4-yl)propoxy]p-kuyin p, soil (5) 4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropane Methoxy-6q3, (2 2 yl-6-oxomorpholine-4-yl)propoxy]oxazoline, (6) '[(3-Ga-4-fluorophenyl)amino] -6-cyclopropylmethoxytetrahydrofuran-4-yl)-N-methylamino]ethoxy}oxazoline, (7) 4-[(3-bromophenyl)amino]-6 -[2-((S)-6-fluorenyl-2-oxo- phenanthroethoxy]-7-methoxyp-quine, (8) 4-[(3-bromophenyl)amino ]-6-[2-((R)-6-Methyl-2-oxo-ethanyl]-7-methoxy P Kui Jun P, (9) 4-[(3-gas-4 -fluorophenyl)amino]-6-[2-((R)-6-A Benzyl-2-oxou 4-yl)ethoxy]-7-methoxyquinazoline, (10) 4-[(3-Ga-4-fluorophenyl)amino]-6-[3 -((R)-6-methyl-2-oxo-repressed p-lin, 4-yl)propoxy]-7-methoxyp-quine, (11) 4-[(R)-l- (phenylethyl)amino]-6-[3-((S)-6-methyl-2-oxo-indenyl-4-yl)propoxy]-7-methoxyjunjun • Oxygen tetramethyl hydrazine • [ΝΑ gas base] This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) -17- 1294422 A7 B7 V. Description of invention (15 (12) 4-[ (R)_l-(phenylethyl)amino]-6_[2-((S)-6-methyl-2-oxo-indol-4-yl)ethoxy]-7-methoxy Jun Junlin, and (1j) 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxo- phenanthene 4-yl Ethoxy]-7-methoxyquinazoline, its tautomers, stereoisomers and salts. The compounds of formula I can be prepared by the following methods, for example: a) Compounds of the formula:

RawH

N

among them

Ra is as defined above,

Rb· or R. 'One represents methoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy and Rb, or the other represents 21-((3) ^12) 111-0, wherein m is as defined above, and 4 represents a leaving group such as a _ atom or a sulfomethoxy group such as a gas or bromine atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and Reaction of a compound of the formula: - H-R3 (III) wherein r3 is as defined above. The reaction is optionally in a solvent or solvent mixture such as di-methane, acetonitrile, dimethylmethylamine, dimethyl carbamide, cyclobutyl benzene, benzene. , toluene, chlorobenzene, tetra•18- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 public) 1294422 A7 B7 V. Description of invention (16) Hydroquinone, benzene/tetrahydrofuran or two 4, preferably in the presence of a tertiary organic test such as triethylamine or N-ethyldiisopropylamine (and the base can be used as a solvent at the same time) or in the presence of an inorganic base such as sodium carbonate or potassium carbonate, expected to be -20 The temperature to 200 ° C is preferably carried out at a temperature of from 0 to 150 ° C. b) cyclization of the following compound in the reaction mixture as appropriate:

, (IV) where

Ra is as defined above,

One of Rb" or R," represents methoxy, cyclobutoxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentyloxy and Rb" or Re" another The base represents R3'-(CH2)m-0, wherein m is as defined above, and R3' represents r4-〇_co-ch2-n which is optionally substituted with 1 or 2 methyl or ethyl groups. a -ch2ch2-oh group, wherein R4 represents a hydrogen atom or an alkyl group. The reaction may be mixed in a solvent or a solvent as the case may be, for example, methylene chloride, acetonitrile, dimethyl decylamine, dimethyl hydrazine, cyclobutyl, benzene, toluene, benzene, tetrahydrofuran, benzene/tetrahydrofuran or hydrazine. In the alkane, it is preferably in the presence of an anhydrous acid such as trifluoroacetic acid, methanesulfonic acid or sulfuric acid, or in a dehydrating agent such as isobutyl chloroformate, sulfite si chloride, trimethyl chloride, trimethylated ruthenium, five Phosphorus oxide, N,N,-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxyamber-19- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1294422 A7 B7 V. Description of the invention (17 醯 imine or; U hydroxybenzotriazole, or triphenylphosphine / tetra-carbonized carbon, at a temperature of -20 to 200 ° C, preferably It is carried out at a temperature of from -10 to 160 ° C. In the foregoing reaction, any reactive group such as a hydroxyl group, a carboxyl group or an imine group may be protected during the reaction by a conventional protecting group which can be cleaved after the reaction. The base may be trimethyldecyl, ethyl hydrazide, benzamethylene tertyl ethyl, second butyl, xylyl, aryl or tetrahydro P a ketone group, the carboxy protecting group may be a trimethyl decyl group, a methyl group, an ethyl group, a tert-butyl group, a benzyl group or a tetrahydropyranyl group, and the imine protecting group may be a mercapto group or an ethyl fluorenyl group. Tri-a decyl, ethoxylated, second butoxycarbonyl, decyloxycarbonyl, decyl, methoxybenzyl or 2,'diethoxyaryl. Any protecting group used, for example, in aqueous solutions such as water, Propanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or yiufe or in the presence of a metal such as hydroxide steel or hydroxide, or protonic For example, in the presence of iodotrimethylnonane, the temperature is 〇 to 12 〇. The temperature of hydrazine is preferably hydrolyzed at a temperature of 10 to 10 CTC and then cleaved. ...:, lower group, methoxybenzyl or oxiranyloxy group By, for example, in the presence of a catalyst such as palladium/carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid,

In the case of adding an acid such as hydrochloric acid, the temperature is 0 to 10 ° C, preferably 20 to 6 (the ambient temperature of TC, argon is argon to 7 bar, preferably 3 to 5 bar hydrogen pressure to break. However, the 2,4-dimethoxybenzyl group is preferably cleaved in the presence of anisole in trifluoroacetic acid. The first butyl or the second butoxycarbonyl group is preferably an acid such as trifluoroacetic acid or hydrochloric acid. - This paper scales the standard of the coffee (CNS) domain - χ 297 public) 1294422

V. Description of the invention (18) cleavage with iodine trimethyl decane, optionally using a solvent such as di-methane, dioxane, methanol or diethyl ether. The difluoroacetin group is preferably acid-based, such as hydrochloric acid. The solvent is treated in the presence of a solvent such as acetic acid at a temperature of from 50 to 12 GO or by a sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at a temperature of from 0 to 5 (TC). Further, the resulting compound of formula I can be resolved into its Enantiomers and/or diastereomers, as described above. Thus, for example, a cis/trans mixture can be resolved into its cis and trans isomers' and has at least one optically active carbon atom. The compound can be separated into its enantiomers. Thus, for example, a cis/trans mixture can be resolved by chromatography into its cis and anti-isomers, and the compound of the formula (4) is known by itself. Method Separation (Ref. AUinger NL and Eliel EL., Stereochemical Title, Vol. 6, WUey lnterscience, 1971), obtaining its optical enantiomers and compounds of formula I having up to V 2 asymmetric carbon atoms Use this book based on its physical and chemical differences Known methods such as resolution to its diastereomers by chromatography and/or fractional crystallization, and if such compounds are obtained in the racemic state, can then be resolved to the above enantiomers. Preferably, the isomer is separated from the column of the palm phase or recrystallized from an optically active solvent or reacted with an optically active substance such as an ester or a guanamine such as an ester or a racemic compound (especially an acid thereof) Separating the activated derivative or alcohol), and separating the salt or diastereomeric mixture obtained by differential resolution, and the free enantiomer can be released from the pure diastereomeric salt or derivative by appropriate pharmaceutical agent Conventional active acid is, for example, D- and L-state tartaric acid or benzoyl tartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphor-21 - this paper scale applies to gg home Standard (CNS) A4 specification (21GX297 public) '~~ ------- A7 B7 1294422 V. Description of invention (19) Sulfonic acid, proline, aspartic acid or guar acid. Optically active thiol groups which may be, for example, (+) or (-)-menthol and guanamine may be, for example, (+)- or (-)-menthyl Further, the compound of the formula I can be converted into a salt thereof, especially for conversion to a physiologically acceptable salt of a compound or an organic acid for medical use. The acid usable for this purpose comprises, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid. , formic acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. In addition, when the compound of formula I contains a carboxyl group, a hydroxyphosphonium group, a sulfo group or a 5-tetrazolyl group, Inorganic or organic bases are converted into their salts, especially for pharmaceutical use, converted into their pharmaceutically acceptable salts. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, Diethanolamine and triethanolamine. Some of the compounds of the formulae II to IV as starting materials are known in the literature or can be obtained by known methods in the literature (see Examples I to XIV). As just mentioned, the formula of the present invention: [the compound and its physiologically acceptable salt have the pharmacological properties of sputum, especially the signal transduction effect of the epidermal growth factor receptor (egf_r), and it can be borrowed. For example, inhibition of coordination, binding, receptor dimerization or lysine kinase itself is achieved. It is also possible to block the transmission of the signal to the component one located further downstream. The biological properties of the novel compounds are studied as follows: - Signal transduction inhibition of R-depletion can be performed by, for example, cells expressing humans and whose survival and proliferation are related to the stimulation of egf or TGF^. Functional human EGF_R interleukin 3 (IL_3)-related murine source cell line. Known as fyl-HERc

: 297 mm) 1294422 A7 B7 _ V. Description of the invention (2〇) Cell proliferation can be stimulated by murine IL-3 or by EGF (see von Ruden, T. et al., EMBO J. 2, 2749-2756 ( 1988) and Pierce, J. Η. et al., Science 239; 628-63 1 (1988)) The starting material for F/L-HERc cells is the cell line FDC-P, the manufacture of which has been described in Dexter , TM et al., J. Exp. Med. 152, 1036-1047 (1980). Alternatively, other growth factor-related cells may be used (see, for example, Pierce, JH et al, Science 239, 628-63 1 (1988), Shibuya, Η· et al, Cell ΐα, 57-67 (1992) And Alexander, WS et al., EMBO J. 1 £, 3683-3691 (1991)). For the expression of human EGF-R cDNA (see Ullrich, Α· et al, Nature 309, 418-425 (1984)), eg von RGden, Τ· et al, EMBO J. 2, 2749-2756 (1988) Recombinant retroviruses are used, but the retroviral vector LXSN (see Miller, AD et al, BioTechniques 2, 980-990 (1989)) is used to express EGF-R cDNA and to use GP + E86 strain as packaging cells (see Markowitz, D. et al., J. Virol, pp. 1 120-1 124 (1988)). The test was carried out as follows: F/L-HERc cells were supplemented with 10% fetal calf serum (FCS, Boehringer Mannheim), 2 mM amide (BioWhittaker), standard antibiotics and 20 ng/ml human EGF (PromSga) RPMI /1640 medium (BioWhittaker) was incubated at 37 ° C and 5% CO 2 . To assess the inhibitory activity of the compounds of the invention, 1.5 x 104 cells per well were incubated three times in 96-well plates in the above medium (2 mM) in EGF (20 Ng/ml) or murine IL-3. Stimulate cell proliferation _. The IL-3 used was obtained from the culture supernatant of the cell strain X63/0 mlL-3 (see Karasuyama, H. et al., Eur. J. Immunol JLS〇97--23- This paper wave scale applies to the Chinese national standard ( CNS) A4 size (210X297 mm) 1294422 A7 B7 V. Description of invention (21) 104 (1988)). The compound of the present invention was dissolved in 100% dimethylhydrazine (DMSO) and added to the medium at various dilutions with a maximum DMSO concentration of 1%. The medium was incubated at 37 ° C for 48 hours. To determine the inhibitory activity of the compounds of the invention, the relative cell number was measured in units of O.D. using a Cell Titrator 96TM aqueous non-radioactive cell proliferation assay (Promega). The relative cell number and the concentration of the active substance (ic5〇) at which 50% of the cell proliferation was inhibited were calculated as a percentage of the control group (F/LHERc cells without inhibitor). The following results were obtained: Compound (Example No.) EGF-related proliferation inhibition (IC50) [nM] 1 59 1 (0 29 1(2) 29 2(1) 36 The compound of the formula I of the present invention thus inhibits tyrosine kinase Signal transmission, as evidenced by the example of human EGF receptors, can be used to treat pathological processes caused by dysfunction of tyrosine kinases, such as tumors or tumors of benign or malignant tumors, especially epidermal and neuroepidermal sources. Migration and abnormal proliferation of vascular endothelial cells (angiogenesis). The compounds of the present invention can also be used for the prevention and treatment of airway and lung diseases caused by mucosal increase or alteration caused by lysine kinase stimulation, such as airway inflammatory diseases. For example, chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, pan-anti-proteolysis, or cough, emphysema, pulmonary fibrosis and airway Allergies -24- This paper size applies to Chinese National Standard (CNS) Α4 size (210 X 297 mm) 1294422 A7 B7

1294422

2, such as substances that inhibit secretion, inhibit bronchial and / or anti-inflammatory activity. For the treatment of diseases in the intestinal tract, these compounds may also be used in combination with substances which are effective for automatization or secretion or with anti-inflammatory substances. The compositions can be administered simultaneously or sequentially. The compounds may be administered intravenously, subcutaneously, intramuscularly, intrarectally, intraperitoneally or intranasally, inhaled or transdermally or orally, in combination with other active substances, and aerosol formulations are especially suitable for inhalation. For medical use, the compounds of the present invention are generally used for warm-blooded vertebrates, especially humans, (4) Xuanwei 〇. 〇 1-100 mg / kg body weight, preferably _ 1 _ 15 mg / kg. For administration, it may be formulated with one or more conventional inert carriers and/or diluted % hydrazine, such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid. , water, water/ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, stearin, carboxymethyl cellulose or fatty substances such as hard fat or a suitable mixture thereof Known statutory preparations, such as plain tablets or coated ingots, capsules, powders, suspensions, solutions, syrups or suppositories. The following examples are illustrative of the invention and are not intended to limit the invention: Preparation of the starting product: Example I - M(3-indole-4-fluorophenyl)amino 1-6-cycloindole A methyl bromoethoxy Rabbit 4.84 g of potassium carbonate was added to 3.50 g of 4·[(3-chloro-'fluorophenyl)amino]_6•cyclodecylmethoxy-7:hydroxyquinazoline and 6.89 ml1, 40 ml of 2-dibromoethane in hydrazine, hydrazine-dimethylformamide. The reaction mixture was at 8 Torr. Stirring in nitrogen. j 5 -26- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

Binding 1294422 A7 B7 V. Invention description (Μ) hours. After cooling to ambient temperature, the reaction mixture was filtered and the filtrate was evaporated to dryness. The oily brown residue was cooled in an ice bath and dispersed with a small portion of methanol to give a yellow solid. The precipitate was filtered off with suction, washed with cold methanol and dried in a hollow dryer. Yield: 2.60 grams (58% of theory)

Rt, 値: 0.82 (silicone, di-methane/methanol = 9: 1), shell #*(ESI+): m/z = 494,496,498 [M + H]+. The following compounds were prepared analogously to Example I: (1) '[(3-Gas-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(2-bromoethoxy) 4 porphyrin (The reaction is carried out using acetonitrile as a solvent),

Rr値: 0.72 (silicone, di-methane/methanol/concentrated ammonia solution = 9 〇 : 1 〇 : 0.1), mass spectrum (ESI·): m/z = 464, 466, 468 [Μ-ΗΓ. (2) 4-[(3-Ga-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-bromoethoxy) Jun Junlin, IM straight: 0.65 (矽, 2 Methyl chloride/methanol/concentrated ammonia solution = 9 〇: 1 〇: 0.1), mass spectrum (ESI): m/z = 478, 480, 482 [M-Η]·. (3) 4-[(3-Gas-4-fluorophenyl)amino]-7-cyclobutoxy-6-(3-dipropyloxy)4oxazoline (reaction with acetonitrile as solvent), R〆!: ··· 0.62 (silicone, dichloromethane/methanol = 9:1), mass spectrum (ESI·): m/z = 478, 480, 482 [Μ-ΗΓ. (4) 4-[(3-Gas-4Γfluorophenyl)amino]-7-cyclopropylmethoxy-6-(3-bromopropoxy)quinazoline (reaction with acetonitrile as solvent) , -27- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294422 A7 ___B7 I, invention description (25~~"

Rf値·· 0.74 (silicone, dichloromethane/methanol = 9 : u, mass spectrum (ESI·): m/z = 478, 480, 482 [M-Η]-. (5) 4-[(3-bromo Phenyl)amino]bromoethoxy)-7-methoxyquinazoline, m.p.: 244°C, MS (ESI+): m/z = 452, 454, 456 [M + H]+. (6) 4-[(R)-(l-epiethyl)amino]-6-(3-bromopropoxy)-7-methoxyp-quinone (reaction with second butanol 4 A as an inspection),

Rt, 値: 0.60 (gelatin, ethyl acetate / methanol = 9 : (7) 4-[(R)-(l-benzylethyl)amino]-6-(2-bromoethoxy)- 7-decyloxy porphyrin (reaction with potassium t-butoxide as base), melting point: 255 ° C, mass spectrum (ESI+): m/z = 402, 404 [M+H] + (8) 4 -[(3-Ga-4-fluorophenyl)amino]-6-(3-hydroxypropoxy)-7-cyclobutoxy phenoxy-p-lin,

Rt, 値: 0.5 0 (silicone, methylene chloride / methanol = 9 〇 : 1 〇), mass spectrum (ESI + ): m/z = 418, 420 [M + H]+. (9) 4-[(3-Gas-4-fluorophenyl)amino]-6-(3-hydroxypropoxy)-7-cyclopropylmethoxy p-Quinylline, : 0.2 1 (石Ethylene, aerated gas / methyl alcohol = 95 : 5), mass spectrum (ESI + ): m/z = 418, 420 [M + H]+. (10) 4-[(3-Chloro-4-fluorophenyl)amino]-6-(2-bromoethoxy)-7-cyclopentyloxy 4 bite,

Rt, 値: 0.67 (/ oxime, dioxin/methanol = 9 〇 : 1 〇), mass spectrum (ESI+): m/z = 480, 482, 484 [M + H]+. -28- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1294422 A7 ___ B7 ___ V. Description of invention (26 ) (11) '[(3-Chloro-4-fluorophenyl)amine ]]-6-(2-Bromoethoxy)-7-cyclopropylmethoxy junjunlin, IM straight · · 0.68 (silicone, di-methane/methanol = 90: 10), mass spectrometry (ESI+) · m/z = 466, 468, 470 [M + H]+. (12) 4-[(3-Gas-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(3-hydroxypropoxy) ketidine

Rf値,: 0.53 (矽, methane/methanol = 90: 10), mass spectrum (ESI+): m/z = 418, 420 [M + H]+. (13) 4-[(3-Gas_4-fluorophenyl)amino]-6-(4-hydroxybutoxy)-7-cyclopentyloxy

Rt, 値: 0.46 (gelatin, ethyl acetate). (14) 4-[(3-Gas-4-fluorophenyl)amino]-6-(2-bromoethoxy)-7-((R)-tetrahydrofuran-3-yloxy)p-kulin ,

Rf値: 0.37 (silicone, di-methane/methanol = 9: 1), mass spectrum (ESI·): m/z = 480, 482, 484 [Μ-ΗΓ. (15) 4-[(3 -Gaxo-4-(phenyl)amino]]oxyethoxy)-7-[(R)-(tetrachlorofuran-2-yl)methoxy]oxazoline, Mass Spectrum (ESI·): m/z = 494, 496, 498 [Μ-ΗΓ. (16) 4-[(3-Gas-4-fluorophenyl)amino]-7:(2-溪ethoxy)-6-[(5)-(tetrahydrofuran-2-yl)- Oxy]u kujunlin, mass spectrum (ESI·): m/z = 494, 496, 498 [Μ-ΗΓ. Example Π 4-『(3 -Gas-4 -Phenylphenyl)amino 1-6-cyclopentylmethyl group - 7-3⁄4 base p Kui Junlin 4.99 g 4-[(3-gas-4-fluoro Phenyl)amino]-6-cyclopentylmethoxy-7-methylcarbonyl-29- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm)

Binding

1294422 A7 ^_______B7_ V. INSTRUCTIONS (27) The oxytetrazoline was suspended in 80 ml of methanol and added with 1.80 ml of concentrated aqueous ammonia solution. The reaction mixture was stirred overnight at ambient temperature. After the termination, the reaction mixture was diluted with 500 ml of dioxane, washed with water and a saturated sodium chloride solution, dehydrated with sodium sulfate and concentrated by evaporation. Obtained 4 · 30 g of a dark solid. The crude product was stirred in a third butyl methyl ether, filtered off with suction, washed with a small portion of butyl ether and dried at ambient temperature. Yield: 3.59 g (80% of theory), R 〆 straight: 0.48 (silicone, di-methane/methanol/concentrated aqueous solution = 90: 1 〇: 0.1), mass spectrum (ESI + ): m/z = 388, 340 [M + H]+. The following compounds were prepared in analogy to Example II: (1) 4-[(3-Ga-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-hydroxyquinazoline, palpitations: 0·5 6 (silicone, methylene chloride / methanol = 9 : 1), mass spectrum (ESI·): m/z = 358, 360 [Μ-Η]-. (2) 4-[(3-Gas-4-fluorophenyl)amino]-6-cyclopentyloxy-7-hydroxyoxazoline, palpitations: 0.53 (Shixijiao, digassole/methanol) / concentrated ammonia solution = 90 : 10 : 0.1), mass spectrum (ESI: m/z = 374, 376 [M + H] + (3) 6-decyloxy-4-[(3- gas-4- Fluorophenyl)amino]-7-hydroxyquinazoline, 1値: 0.54 (silicone, di-methane/methanol/concentrated aqueous solution = 90:10: 0.1), mass spectrum (ESI): m/z = 396, 398 [M + H]+ (4) 4-[(3-Bromophenyl)amino]-6-hydroxy-7-methoxy-4-oxazoline (reaction in ethanol solution with ethanol as solvent) ), -30- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1294422 A7 _____B7 V. Invention description (28)

Rf 値: 0.23 (gelatin, ethyl acetate), mass spectrum (ESI+): m/z = 346, 348 [M+H]+. (5) 4-[(3-Ga-4-t-phenyl)amino]-7-mercapto-6-((S)-tetrahydrofuran-3-yloxy) Jun Jun P, RHlt · · 0.5 7 (silicone, dichloromethane / methanol = 9 : 1), mass spectrum (ESI+): m/z = 376, 378 [M+H]+. (6) 4-[(3-Chloro-4-fluorophenyl)amino]-7-3⁄4yl-6-[(S)-(tetrahydrofuran-2-yl)methoxy]p-quinone Dripping,

Rt| · · 0.42 (silicone, dichloromethane / methanol = 9: 1).

Example III gas-4-fluorophenyl)amino]-6-cyclopentylmethyl gas _7-methyl oxo group 4 4.03 g 4-random-6-cyclopentylmethyllacyl-7-methyl The carbonyloxy p-quinone was suspended in 70 ml of isopropanol and 1.95 g of 3-vapor-4-fluoroaniline was added. The reaction mixture was refluxed under nitrogen for 2 hr. After cooling to ambient temperature, the pale precipitate formed by evacuation was washed with a small amount of isopropanol and dried in air. Yield: 4.99 g (92% of theory), palpitations: 0.80 (silicone, di-methane/methanol/concentrated ammonia solution = 9 〇: 1 〇: 0.1), - mass spectrometry (ESP): m/z = 430, 432 [M+H]+. The following compounds were prepared in analogy to Example III: (1) 4-[(3-Gas-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-methylcarbonyloxy quinoxyline. Heart palpitations: 0.86 (silicone, methylene chloride / methanol = 9: 1), -31 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) " 1294422 A7 B7__ V. Description of invention ( 29) Mass Spectrum (ESI+): m/z = 402, 404 [M+H]+. (2) 4-[(3-Gas-4-fluorophenyl)amino]-6-cyclopentyloxy-7-methylcarbonyloxycarbazole, 匕, 値: 0·73 (矽, Dioxane methane/methanol/concentrated ammonia solution = 90 ·· 10 : 0.1), mass spectrum (ESI+): m/z = 416, 418 [Μ+Η]+. (3) 6-Ethyloxy-4-[(3- gas-4-n-phenyl)amino]-7-methylphenoxy ρ kujunlin, palpitations: 0.76 (gelatin, di-methane/ Methanol / concentrated ammonia solution = 90 : 10 : 0.1), mass spectrum (Esr): m / z = 438, 440 [Μ + ΗΓ. (4) 4-[(3-Bromophenyl)amino]-6-methylcarbonyloxy-7-methoxyoxazoline,

Rt. 値: 0.50 (gelatin, ethyl acetate), mass spectrum (ESI+): m/z = 388, 390 [M+H]+. (5) 4-[(R)-(1-Phenylethyl)amino]-6-3⁄4yl-7·methoxy p-ku 啦 ( (the ethoxylated ethoxy group has broken under the reaction conditions), n : 0.46 (silicone, ethyl acetate), mass spectrum (ESI): m/z = 296 [M + H]+. (6) 6-methoxy-4-((3-fluoro-4-fluorophenyl)amino]-7-cyclopentyloxyquinazoline (adding leaves [: bite as a secondary test), '

Rt•値: 0.51 (silicone, dichloromethane/methanol = 95: 5), mass 1 (ESI+): m/z = 464, 466 [M + H]+. (7) 4-[(3-Ga-4-fluorophenyl)amino]-7-methylcarbonyloxy-6-((S)-tetrahydrofuran-3-yloxy) quinine 17 sitting, lin,

Rt, 値: 0.67 (Shi Xijiao, dichloromethane / methanol = 9: 1), -32-

1294422 A7 B7 V. INSTRUCTIONS (30) Mass spectrometry (ESI.): m/z = 416, 418 [M-Η]·. (8) 4-[(3-Chloro-4-fluorophenyl)amino]-7-methyl-oxo-6-[(S)-(tetrahydropyran-2-yl)nonyloxy]奎 吐 吐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐 盐

Example IV Bio-gas-6-cyclopentyl decyloxy-7-methylcarbonyloxyoxazoline 3.80 g of 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxyquinazoline Suspended in 90 ml of sulphur sulphur and heated to boiling in nitrogen. After adding 4 drops of N,N-dimethylformamide, the reaction mixture was refluxed for additional 2 hours. After cooling to ambient temperature, excess sulphur oxychloride was distilled off in the water jet twitch. The brown residue was stirred with 30 ml of toluene. The solvent was evaporated to leave 4.30 g of a brown solid which was further purified without purification. Straight: 0.89 (silicone, di-methane/methanol/concentrated ammonia solution = 9 〇: 1 〇: 0.1) 〇 The following compounds were prepared in the same manner as in Example IV: (1) 4- gas-6-cyclopropylmethoxy-7- Methyl carbonyloxy 4 oxazoline, hydrazine: 0.84 (gelatin, di-gas methane / methanol = 9: 1). (2) 4-Chloro-6-cyclopentyl-7-methyloxyoxyp-quine,

Rt. 値: 0.69 (silicone, two gas methane / methanol / concentrated ammonia solution called 〇 : 1 〇 : 0.1). (3) 6-toloxy-4-chloro-7-methylphenoxy p-precipitate,

Mii : 0.77 (/ Ejiao, two gas methane / methanol / concentrated ammonia solution two columns: 1 〇: 0.1) 〇-33 - This paper scale applies to China National Standard (CNS) A4 specifications (210X297 public ^ 7 " ~ ^ - 1294422 A7 _____ B7 V. INSTRUCTIONS (31) (4) 6-Alkyloxy-4-gas-7-cyclopentyloxy,

Rf値: 0.91 (gelatin, dichloromethane/methanol = 9 ·· u. (5) 4-gas-7-mercaptocarbonyloxy-6-((S)-tetrahydrofuran-3-yloxy) quinazole Porphyrin, Rt, 値: 0.83 (gelatin, ethyl acetate / methanol = 9 : i). (6) 4-chloro-7-mercaptocarbonyloxy-6-[(S)-(tetrahydrofuranyl) fluorenyloxy Quinazoline, 値: 0.48 (gelatin, cyclohexane / ethyl acetate = 1: 丨).

Example V Seven Checks. Group 6-Cyclopentylmethoxy-7-methyl 4.30 g of 4,7-dihydroxy-6-cyclopentylmethoxyquinazoline 1 liter of pyridine heated in nitrogen To 80 C.丨 8 ml of acetic anhydride was added to the dark brown suspension. The reaction mixture was stirred at 80X for 3 hours to form the entire solution. After cooling to ambient temperature, the reaction mixture was poured onto about 8 ml of ice water. Pumping over and over forming < precipitation and washing green with water. The light grey solid was dried in a hollower. ^ 1 Yield: 3.82 grams (77% of theory),

Rt, 値: 0.49 (矽, dioxane/methanol = 9 : 〇, shell spectrum (ESI): m/z = 301 [Μ-Η] 〇 Similar Example V The following compounds were prepared: - (1) 4-light -6-cyclopropylmethoxy-7-methylcarbonyloxy-trazoline Rr値: 0.53 (ruthenium, methylene chloride/methanol: 1), mass spectrum (ESI): m/z = 273 [M -Η]-. (2) 4-#-Base-6-cyclopentyloxy-7-methylcarbonyloxyquinazoline Melting point: 209-212 ° C, this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) -34- 1294422 A7 B7 ___ V. Description of invention (32) Mass spectrometry (ESI.): m/z = 287 [MH]_. (3) 6-yanooxy-4-# -7-7-methyl methoxy oxy p-quinone 1 ^, 値: 0.48 (gelatin, dichloromethane / methanol / concentrated aqueous ammonia = 90 · · 10 : 0.1), mass spectrometry (ESI ·) : m / z = 309 [M-Η]-. (4) 4-Hydroxy-7-methylcarbonyloxy-6-((S)-tetrahydrofuran-3-yloxy)oxazoline 1値: 0.62 (reverse phase system) TLC sheet (E· Merck), acetonitrile / water / trifluoroacetic acid = 50 : 50 : 1), mass spectrum (ESr): m / z = 291 [M + H] + (5) 4-hydroxy-7 -methylcarbonyloxy-6-[(S)-(tetrahydrofuran-2-yl)methoxy] quinoline

Rt, 値: 0.5 0 (silicone, di-methane/methanol = 9: 1), mass spectrum (ESP) ·· m/z = 305 [M + H]+.

Example VI 4,7-Dihydroxy-6-cyclopentylmethoxy-4-oxazoline 5.76 g of 2-amino-5-cyclopentylmethoxy-4-transpyridyl formate and $52 g of formazan acetate The 140 ml of ethanol was refluxed for about 3 hours. After termination, the reaction mixture was evaporated to about 1 〇 〇 升 升 and added 300 ml of ice water to form a gray sink. The precipitate was filtered by suction, washed with water and dried in a humidifying dryer. Yield: 4.57 g (77% of theory), IM straight: 0.25 (silicone, dichloromethane/methanol = 95:5), mass spectrum (ESI): m/z = 259 [Μ-ΗΓ. Similar Example VI was prepared with the following compounds: (1) 4,7·Dihydroxy-6-cyclopropylmethoxy-4-oxazoline-35- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1294422 A7 B7 __ V. Description of invention (33)

Rt, 値: 0.45 (silicone, di-methane/methanol/concentrated aqueous solution = 90: 10 0.1), mass spectrum (ESI): m/z = 231 [M-Η]·. (2) 4,7-dihydroxy-6-cyclopentyloxyquinazoline

Rt. 値: 0.42 (silicone, dichloromethane/methanol/concentrated aqueous solution = 90: 10 0.1), mass spectrum (El): m/z = 246 [M]+. (3) 6-decyloxy-4,7-dihydroxyquinazoline

Rt, 値: 〇·44 (矽, methane/methanol/concentrated ammonia solution = 90 : 10 0.1), mass spectrum (ESr): m/z = 267 [M-Η]·. (4) 6-decyloxy-7-camaryl lactyl- 4-3⁄4-based sulphur P-Pulline: 22 1.-2231, mass spectrum (ESP): m/z = 337 [M + H]+. (5) Seven-two-base ^^^^丨-tetrahydrofuran ^^-based oxy group

Rf 値: 0.69 (reverse phase prepared TLC sheet (E. Merck), acetonitrile / water / fluoroacetic acid = 50 : 50 : 1), mass spectrum (ESI) : m / z = 247 [M - Η]. (6) 4,7-di-light-based-6-[(S)-(tetrahydrofuran-~2-yl)methoxy] koukuijunkou 1値: 0.5 6 (矽, di-methane/ Methanol = 9 : 1), mass spectrum (ESI·): m/z = 261 [M-Η].

Example VII 2-Amino-5-cyclopentylmethoxy-4-hydroxymethyl molybdenum 6.50 g of 5-cyclopentyloxy-4-pyridyl-2-nitrobenzoic acid was dissolved in 13〇毫-36 - 1294422 A7 ________B7 V. INSTRUCTION DESCRIPTION (34) In methanol, 2.00 g of Raney nickel was added and the mixture was hydrogenated in a 5 psi hydride at approximately ambient temperature for about 3 hours until the calculated amount of hydrogen had been consumed. The catalyst was filtered off and washed with hot methanol. A brown solid was left which was further reacted without purification. Yield: 5.79 g (100% of theory), 値: 0.67 (Shixijiao 2 gas-burning/methanol = 9:1), mass spectrum (ESI·): m/z = 250 [M-Η]-. The following compounds were prepared in analogy to Example VII: (1) 2-Amino-5-cyclopropylmethoxy-4-3⁄4 benzoic acid hydrazine: 0.51 (gel, methane/methanol / concentrated aqueous ammonia = 9 〇: 1〇: 0.1), mass spectrum (ESI·) ·· m/z = 222 [MH[. (2) 2-Amino-5-cyclopentyloxy-4-hydroxybenzoic acid

Rt·値: 0.38 (silicone, di-methane/methanol/concentrated ammonia solution = 90 : 1 〇 : 0.1), mass spectrum (ESP): m/z = 238 [M + H]+. (3) 2-Amino-5-indenyl-4-indolylbenzoic acid

Rt-値: 0.52 (silicone, di-methane/methanol/concentrated aqueous solution = 90:10: 0.1), - mass spectrum (ESI'): m/z = 258 [M-Η]. (4) 2-Amino-5-nonyloxy-4-cyclopentyloxybenzoic acid cyclopentyl ester (this reaction is carried out in a mixture of methanol and tetrahydrofuran of i:1) 1値: 0.84 (gelatin, acetic acid Ethyl vinegar / cyclohexane: 1), mass spectrum (ESr): m/z = 396 [M + H]+. -37- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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A7 B7 1294422 V. INSTRUCTIONS (3δ ) (5) 2-Amino-4-lightyl_5-((s)-tetrahydrofurfuryloxy)benzoic acid

Rf値: 0.70 (reverse phase prepared D1 (: piece (Ε· Merck), acetonitrile/water/trifluoroacetic acid = 50:50: 1), mass spectrum (ESr): m/z = 238 [M- Η]-. (6) 2-Amino-4-hydroxy-5-[(S)-(tetrahydrofuran-2-yl)methoxy]benzoic acid

Rr値: 〇·5 9 (reverse phase prepared TLC sheet (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50: 1), mass spectrum (ESI) ·· m/z = 252 [M -Η]·. Example vm 5-cycloindole-methyl 4-hydroxy-2-nitro-p-formic acid 15.37 g of 4,5-methyldioxy-2-nitrobenzoic acid and 51.84 ml of cyclopentylmethanol dissolved in 100 ml The dimethyl hydrazine was cooled in an ice bath under nitrogen. Then 3.90 g of sodium was added in portions. The reaction mixture was stirred for 3 minutes while being cooled in an ice bath, then simply heated to 35-40 ° C and then allowed to cool for 3 hours in an ice bath. The ice bath was then removed and the reaction mixture was stirred overnight at ambient temperature. The red dark brown reaction solution was poured into about 800 ml of acetone to form a dark smear. The precipitate was filtered off with suction, washed with acetone, dissolved in 30 mL of 4 ml of water and adjusted to pH about 2 with 60 ml of 2 HCl. The aqueous solution was extracted several times with digas methane. The extract was washed with a saturated sodium carbonate solution, dried over sodium sulfate and evaporated. The dark brown oil residue in the bottle was dissolved in 8 ml of di-methane and purified by feeding the methylene chloride/methanol (9:1). A brown oil was obtained which was stirred with water while being crystallized by cooling in an ice bath. The formed color sag is filtered by suction, washed with a small amount of water - and dried in a hollow dryer. Yield: 9.55 grams (47% of theory), -38-

1294422 A7 __B7 V. Description of invention (36~~~"

Rf値: 0.67 (Shixi gum, benzene/dioxane/ethanol/glacial acetic acid=9〇: 1〇: 1〇:6), mass spectrum (ESr): m/z = 280 [M-H]-. The following compounds were prepared in analogy to Example VIII: (1) 5-cyclopropyl decyloxy-4-hydroxy-2-nitrobenzoic acid 1 値: 0.61 (Shixi gum 'toluene / dioxane / ethanol / glacial acetic acid = 9 〇: 1〇: 1〇·· 6), Mass spectrum (ESI·): m/z = 252 [M-Η]-. , (2) 5-cyclopentyloxy-4-hydroxy-2-nitrobenzoic acid

Rt•値: 0.62 (Shixi gum, toluene/dioxane/ethanol/glacial acetic acid=9〇: 1〇: 1〇:6), mass spectrum (ESI·): m/z = 266 [M-Η]- . (3) 5-Methoxy-4-hydroxy-2-nitrobenzoic acid Melting point: 176-178 ° C, mass spectrum (ESI): m/z = 288 [M-Η]-. (4) 4-Hydroxy-2-nitro-5-((S)-tetrahydroindan-3-yloxy)benzoic acid

Rt. 値: 0.58 (reverse phase prepared TLC sheet (E· Merck), acetonitrile/water/trifluoroacetic acid = 50:50: 1), mass spectrum (ESI·): m/z = 268 [MH] 3 (5) 4-Hydroxy-2-nitro-5-[(S)-(tetrahydrofuran-2-yl)methoxy]benzoic acid IM straight: 0.53 (reverse phase prepared TLC sheet (E. Merck) , acetonitrile / water / trifluoroacetic acid = 50 : 50 : 1), mass spectrum (ESI·): m/z = 282 [M-Η]-.

Example IX -39- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294422 A7 _______B7 V. Description of invention (37 ) 11-_, hydroxy·2_methyl I propylamine) After 100.00 g of the side of the crucible, the sodium salt was added to a solution of 50.00 g of ethyl glycinate hydrochloride in 100 ml of a saturated potassium carbonate solution under cooling. The resulting mass was extracted several times with a total amount of about 0.6 ml of acetic acid. The combined ether extracts were dried over sodium sulfate and evaporated to dryness. Leave 28.60 grams of ethyl glycinate. It was mixed with 26 ml of epoxy isobutane and 4 ml of absolute ethanol and heated to 9 ° C for 6 hours in a Roth ball. After cooling to ambient temperature, the reaction mixture was concentrated by evaporation to leave a flowing oil. Yield: 45.80 g (73% of theory), mass spectrum (ESI+): m/z = 17 έ [M + H]+.

Example X 4-Methylaminodihydrofuran-2-_ 2.00 g of 4-(N-fluorenyl-N-decylamino)dihydrofuran-2-one in 25 ml of methanol at 250 g ( 10% on activated carbon) was hydrogenated at ambient temperature for 5 hours at 5 〇 pSi hydrogen pressure until a calculated amount of hydrogen was consumed. After the reaction was terminated, the catalyst and filtrate were filtered off and evaporated in the air. A colorless oil was left which was directly reacted without further purification. Production: 1.20 grams,

Rt, 値: 0.13 (gelatin, ethyl acetate) mass spectrum (ESr): m/z = 1 16 [M + H broad.

Example XI - mercaptomethylamino) diaminocarbamate-2-indole 23.20 ml of N-methyldecylamine was added to 15.00 g of 5H-furan-2-one in 150 ml of dioxane. The reaction mixture was stirred at ambient temperature for about 48 hours. After termination, the reaction mixture is concentrated by evaporation and the contents are on the second hose column -40- This paper scale is the National Standard (CNS) A4 specification (21GX297 public) ^ "

1294422 A7 B7 V. Description of invention (38)

Ethyl acetate/petroleum ether (3:1) was chromatographed as a solution. The desired product of the yellow oil was obtained. Yield: 19.77 grams (54% of theory),

Rf値: 0.67 (gelatin, ethyl acetate), ^(ESI): m/z = 228 [Iyi+Na]+.

Example XII 4-[(3-Chloro-4-fluorophenyl)amine-based μ7-cyclobutanyl-6-light-based 4-oxaline 10 ml of trifluoroacetic acid was added dropwise to 5 60 g of 6-benzyl group with stirring Oxy-4_[(3_qi_4-fluorophenyl)amino]-7-cyclobutoxyquinazoline. The reaction mixture was heated to about 40 C. After mixing for 20 hours at ambient temperature, add 3 ml of trifluoroacetic acid. Since the reaction was hardly carried out even after stirring for 3 hours at ambient temperature, the reaction mixture was heated to 50 °C. After 4 hours, the reaction was complete and the excess of three acetic acid was essentially distilled off using a rotary evaporator. The residue is mixed with water and made alkaline with concentrated aqueous ammonia solution. The resulting pale brown precipitate was filtered off with suction, washed with a large amount of water and dried in a dryer. The resulting product still contained trifluoroacetic acid. Yield: 5.82 g, 1 値: 0.61 (silicone, di- methane/methanol = 9: 1) Mass spectrum (ESr): m/z = 360, 362 [IVT+ΗΓ. The following compounds were prepared in a similar manner to Example XII: (1) 4-[(3-Vinyl-4-fluorophenyl)amino]-7-cyclopropylmethoxy-6-light-based 0 kujunlin 1 値: 0.65 ( Silicone, di-methane/decanol = 9 : 1) Mass spectrometry (ESP) L m/z = 360, 362 [Μ + ΗΓ. (2) 4-[(3-Chloro-4-fluorophenyl)amino]-7-cyclodecyloxy-6-hydroxyquinazole 4 -41 - This paper size is applicable to China National Standard (CNS) A4 specification ( 210 X 297 mm)

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1294422 A7 ___B7 V. Description of invention (39)

Rti : 0.65 (silicone, methylene chloride / methanol = 9 : ^ mass spectrum (ESI: m/z = 374, 376 [M + H] +. (3) 4_[(3_chloro-4-fluorophenyl) Amino]·6-hydroxy_7_((r)·tetrahydrofuranyloxy)4 Junkoulin

Rti : 0.3 2 (silicone, two gas / methanol = 9 : 1). (4) 4-[(3-Chloro-4-fluorophenyl)amino]-6-#mercapto-7-[(R)_(tetrahydrofuran-2-yl)methoxyquinazole 4 Mass Spectrum (ESP): m/z = 388,390 [M-Η]-.

Example XIII k-methoxy-4-indole-3-(3-fluoro-4-fluorophenyl)amino 1-7-cyclobutane-based bite 4. 7.50 g of potassium carbonate and 4.50 g of cyclobutyl methanesulfonate were added to 7 . 6-N-oxy-4-[(3-lactic-4-fluorophenyl)amino]-7-light base in 60 ml of N,N-dimethylformamide. The reaction mixture was stirred at 80 ° C for 2 hours. Further, 2.00 g of cyclobutyl methanesulfonate and 3.00 g of potassium carbonate and a mixture were added and stirred at 60 ° C for one weekend. Since the reaction was not complete, 3.50 g of cyclobutyl methanesulfonate and 5.00 g of potassium carbonate were further added. After another 20 hours at 80 ° C, the reaction was almost complete. After termination, the reaction mixture was combined with 300 ml of ethyl acetate and washed with water and saturated sodium chloride. The organic phase was dried over magnesium sulfate and concentrated by evaporation. The residue was stirred with methanol to give a brown precipitate. The mixture was suction filtered, washed with methanol and dried in a desiccator. Production: 5.10 grams (64% of theory),

Rt•値: 0.69 (silicone, di-methane/methanol = 9: 1) Mass spectrum (ESI·) m/z = 448, 450 [Μ-ΗΓ. Similar examples ΧΙΠ Preparation of the following compounds: -42- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1294422 A7 B7 V. Description of invention (40) (1) 6-methoxy-4- [(3-Gas-4-fluorophenyl)amino]-7-cyclopropylmethoxyquinazoline (using bromodecylcyclopropane)

Rt, 値: 0.72 (silicone, methylene chloride / methanol = 9 : 1) Mass Spectrum (ESI): m/z = 448, 450 [M-Η]-. (2) 6-Methoxy-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopentyloxyquinazoline (using bromocyclopentane)

Rf 値,: 0.78 (矽, methane / methanol = 9 : 1) Mass Spectrum (ESI + ) : m/z = 464, 466 [M + H]+.

Example XIV Hydroxypropylamino)acetic acid tert-butyl ester 15.00 g (S)-( + )-l-amino-2-propanol was dissolved in 100 ml of N,N-dimethylformamide and 6.97 ml of diiso was added. Propylethylamine. Then, 5.9 1 ml of tributyl bromoacetate was added dropwise under ice cooling for 30 minutes. The cooling bath was removed and the reaction mixture was stirred overnight at ambient temperature. After termination, the reaction mixture was evaporated to dryness. The bottle residue was dissolved in 50 ml of water and saturated with 15 g of sodium chloride. The aqueous solution was extracted several times with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium sulfate, dried over magnesium sulfate and evaporated to afford a yellow oil. Yield: 7.36 grams (97% of theory),

Rt, 値: 0.46 (gelatin, ethyl acetate / methyl alcohol = 9 : 1) Mass Spectrum (ESI + ) ·· m/z = 190 [M + H]+. The following compounds were prepared analogously to Example XIV: (1) (RH2·hydroxypropylamino)acetic acid tert-butyl ester

Rf 値: 0.46 (gel, ethyl acetate / methanol = 9 : 1) Mass Spectrum (ESI + ) : m/z = 190 [M + H]+. -43- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm)

Binding 1294422 A7 B7 V. INSTRUCTIONS (41) (2) (1,1-Dimercapto-2-3⁄4-ethylethylamino)acetic acid T-butadiene mass spectrometry (ESI+) : m/z = 204 [M+ H] + R,: 0.47 (silicone, methylene chloride / methanol / concentrated aqueous ammonia = 90: ι: 0.1).

Example XV 4_ "(3-Chloro-4-fluorophenyl)amino]-6-(3 - 曱 确 确 酿 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In the presence of an amine, 4-[(3- gas-4-fluorophenyl)amino]]-6-(3- sylpropoxy)-7-cyclobutoxy 0 quinone 4 and arsenic are placed at ambient temperature. The chlorine reaction is continued to obtain the compound. R,: 〇·3 7 (silicone, dichloromethane/methanol = 95: 5), mass spectrum (ESI·): m/z = 494, 496 [M-Η]. The following compounds were prepared in a similar manner to XV: (1) 4-[(3-Chloro-4-fluorophenyl)amino]-6-(3-methylpropenyloxypropoxy)-7-cyclopropyl Oxygen 4 Jun Lin

Rt, 値: 0.65 (silicone, dioxin/methanol = 9 〇: 1 〇), mass spectrum (ESI·): m/z = 494, 496 [M-Hf. (2) 4-[(3-Chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(3-decanesulfonyloxypropoxy) Jun 4 -

Rt-値: 0.73 (矽, 二气甲垸/methanol = 9〇: 1〇), mass spectrum (ESI: m/z = 496, 498 [M + H]+. (3) 4-[(3- Gas-4-fluorophenyl)amino]_6·(4·methanesulfonyloxybutoxycyclopentyloxy 11 kujun ru

Rf値: 0.76 (silicone, methylene chloride/methanol = 9〇: 1〇), -44- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 dongdong) 1294422 A7 B7 V. Description of invention (42 Mass Spectrum (ESI+): m/z = 524, 526 [M + H]+.

Example XVI 4 - "(3 -Chloro-4-a)-amino 1-6-trans-yl-7-cyclopropylmethoxyg-glycolin in a mixture of dichloromethane, ethanol and concentrated hydrochloric acid ( 500: 210 : 3.5) in a Parr apparatus, 6-benzyloxy-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropyl in the presence of 10% Pd/C Methoxy 4: hydrazine is hydrogenated to obtain the compound. Yield: 73% of theory, mass spectrum (ESI: m/z = 360, 362 [M + H]+.

EXAMPLE XVII 5-Ethyloxy-4-whenylpentyl-2-n-benzoic acid cyclopentyl g is intended to act as a secondary test in the presence of a carbonic acid clock, in a dimethyl sub-atmosphere at ambient temperature to make 5-anthracene The compound is obtained by reacting -4-hydroxy-2-nitrobenzoic acid with 2.2 equivalents of bromocyclopentane. Yield: 87% of theory,

Rt. 値: 0.92 (gel, ethyl acetate / cyclohexane: hydrazine, mass spectrum (ESF): m/z = 426 [M + H]+.

Example XVIII 4-[(3-oxo-4-fluorocapry-indole)amine-based 6-fluorenyl-7-(〇1)-tetraxin|pyran-3-yloxy) A 5.033⁄4 liter of diene dimethyl fe two ethyl @ 滴 drops to 8 gram heart [(3-chloro-4-fluorophenyl)amino]-6-decyloxy _7- via the base side saliva 4 (See w〇0055141 A1) and 2.42 ml of (S)-(+)-3-hydroxytetrahydrofuran and 7.95 g of triphenylphosphine in 160 ml of tetrahydrofuran solution. The reaction was stirred overnight at ambient temperature and evaporated using a rotary evaporator. Residue in the bottle and then on the hose column with dichloromethane/ethyl acetate-45 - This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1294422 A7 B7 V. Invention description (43) (2 : 1 to 1 ··· 2 gradient) Purified as a solution chromatography. Yield: 7.34 g (78% of theory), m.p.: 165-168 Ό, mass spectrum (ESP): m/z = 466,468 [M + H]+. The following compounds were prepared in analogy to Example XVIII: (1) 4-[(3-Gas-4-fluorophenyl)amino]-6-yloxy-7-[(R)-(tetrahydrofuran-2-yl) Methoxy]p quinone-mass mass spectrometry (ESI: m/z = 480,482 [M + H]+, 1 値:0.38 (矽, methane/methanol = 15:1). (2) 4 -[(3-chloro-4-fluorophenyl)amino]-7-(2-bromoethoxy)-6-((S)-tetrahydrofuran-3-yloxy)P-quinone sitting p-forest

Rt, 値: 0.35 (silicone, two gas methane / methanol = 20: 1). Preparation of the final compound: Example 1 --(3-chloro-4-fluorophenyl)amino 1-6-cyclopentylmethyl -7-f2-(2,2-dimethyl-oxo p林林-4-yl)ethoxy 1 pkudip 250 mg 4-[(3-Ga-4-fluorophenyl)amino]-6-cyclopentylmethoxy-7-(2- Bromoethoxy)quinazoline and 341 mg of (2-hydroxy-2-methylpropylamino)acetate in 20 ml of acetonitrile and with 50 mg of sodium iodide - 275 mg of potassium carbonate and 0.7 ml Diisopropylethylamine is mixed. The reaction mixture was refluxed for about 9 hours. After cooling to ambient temperature, the reaction mixture was filtered and the filtrate was evaporated. The residue in the flask was chromatographed on a silica gel column with petroleum ether/ethyl acetate (5 〇: 50, then 0: 1 〇〇). A cyclized product of a gray-brown solid was obtained. Yield · · 62 mg (23% of theory), -46- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

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1294422 A7 B7 V. Description of invention (44)

Rf値: 0.29 (Shixi gum, ethyl acetate), quality 1 Jin (ESI·): m/z = 541,543 [M-Η]-. The following compounds were prepared in the same manner as in Example 1: (1) 4-[(3-Ga-4-fluorophenyl)amino]cyclopropylmethoxy-yl-6-oxomorpholin-4-yl)ethoxylate ] 喹 唑 甲 甲 値 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (2) 4-[(3'-Ga-4-fluorophenyl)amino]_7-cyclobutoxy-6-[3-(2,2,- 'methyl-6-oxomorpholin-4-yl) ) propoxy] 4 oxazoline' melting point: 2 12-214 ° C, mass spectrum (ESI·): m/z = 527, 529 [M-Η]. (3) 4-[(3-Chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-6-[3_〇. , Ά dimethyl-6-oxomorpholin-4-yl)propoxy] quinazoline melting point: 200-202 ° C, negative ^ (ESI ) · · m / z = 527,529 [M-Η ]. (4) 4_[(3_Chloro-4-fluorophenyl)amino]-6-[3-(2,2·dimethyloxyxohexan-4-yl)propoxy]-7-anthracene ϋ 峻 峻 ρ 林 熔点 melting point: 222-224 ° C, mass spectrometry (ESI.): m / z = 487, 489 [M: H] _. Example 2 4-丨(3-Gas-4-fluorophenyl)aminodiphenyl 6-cyclopropylmethylcarbyl-7-indoletetrahydropyran-4-yl)-N-methylamino 1 ethoxy Base p Kui Junlin 300 mg 4-[(?-Ga-4-fluorophenyl)amino]-6-cyclopropyl oxime-7-(κ odor ethoxy) oxazoline and 400 mg 4- Methylaminodihydrofuran-2-one 2〇ml-47- This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1294422 A7 B7 V. Invention Description (45

Acetonitrile was mixed with 240 mg of potassium carbonate and 70 mg of sodium iodide and refluxed for 24 hours. After the cold name is reached to the ambient temperature, the filtration, the reaction mixture and the mash are evaporated. In the bottle, the field was chromatographed on the Shishijiao column with a gas-burning/a drunk/concentrated ammonia solution (9 7 · 3:0.05) as a solution. Obtained title character of light gray-brown solid 0 Yield: 70 mg (22% of theory), IM straight,: 0.47 (silicone, dichloromethane/methanol/concentrated aqueous solution = 9 〇: 1 〇: 0.1), mass spectrometry ( Esr) : m/z = 501,503 [Μ + ΗΓ. The following compounds were obtained in analogy to Example 2: (1) 4-[(3-chloro-4-phenyl)amino]-6-cyclopentyloxy-7-{2-[N-(2-oxotetrahydrofuran- 4-yl)methylamino]ethoxy}oxazoline R〆 straight: 0·42 (gelatin, di-hydrogen methane/nonanol/concentrated ammonia solution = 90: 1〇: 0.1), mass spectrum (ESr): m/z = 515, 517 [Μ + Η]+. (2) 4-[(3-Gas-4-fluorophenyl)amino]-6-{3-[N-(2-oxotetrahydropyran-4-yl)-N-methylamino ]propoxy}-7-cyclobutoxyquinazoline melting point: 147.5-151 ° C, mass spectrum (ESP): m/z = 5 15, 5 17 [M-+H]+. Example 3 4-((3-Bromophenyl)aminomercapto-2-oxomorpholine-4-) Λf-based 1 - 7-methoxy methoxy quinone bite forest 90 μl of formazan acid Add to 380 mg of 4-[(3-bromophenyl)amino]-6-(2-{N-[(tatabutoxycarbonyl)methyl]-N-((S)-2-hydroxypropyl Amino}ethoxy-48-

Air

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294422 A7 B7 V. Inventive Note (46) Base) 7-methoxyquinazoline in 8 ml of acetonitrile. The reaction mixture was refluxed for about 3 hours, then another equivalent of decanesulfonic acid was added and reflux was continued until the reaction was complete. After the termination, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate and saturated sodium sulfate. The organic phase was dehydrated with magnesium sulfate and evaporated in vacuo. The contents of the bottle were stirred and filtered with ether. The title compound was obtained as a white solid. Yield · · 280 mg (85% of theory),

Melting point: 190 ° C, mass spectrum (ESI·): m/z = 485, 487 [M-Η]·. Similar to Example 3, the following compounds were obtained: (1) 4-[(3-Bromophenyl)amino]-6-[2-((R)-6-methyl-2-oxomorpholin-4-yl) Oxymethoxy-p-pyrazole 4 mp. 193 ° C, mass ESI (ESI+): m/z = 487, 489 [M + H]+. (2) 4-[(3-Air-4-disorganophenyl)amino]-6-[2-((R)-6-methyl-2-oxo-4- 4-yl)ethoxy - 7-Methoxy η quinazoline (reaction with trifluoroacetic acid in acetonitrile) m.p.: 208 ° C, mass spectrum (ESI·) ·· m/z = 459, 461. (3) 4-[(3-Vinyl-4-fluorophenyl)amino]-6-[3-((R)-6-fluorenyl-2-oxo-indol-4-yl)propoxy ]-7-methoxyquinazoline (reaction with trifluoroacetic acid in acetonitrile)

Rt. 値: 0.33 (gelatin, ethyl acetate), mass spectrum (ESI): m/z = 473, 475 [Μ-ΗΓ. -49-

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294422

V. INSTRUCTIONS (47) (4) 4-[(RHl-Phenylethyl)amino]_6-[3-((S)-6-methyl-2-oxo? 4, 4-yl) Propyl]-7·methoxy π 奎 淋 ( (reaction with trifluoroacetic acid in B guess)

Rf 値: 0.41 (gelatin, ethyl acetate / methanol = 9 : 1), mass spectrum (ESI): m/z = 449 [Μ-ΗΓ. (5) 4-[(R)-(l-Phenylethyl)amino]-6-[2-((S)-6-methyl-2-oxo-4-yl)ethoxy] -7-methoxyquinazoline (reaction with trifluoroacetic acid in acetonitrile)

Rt. 値: 0.49 (silicone, ethyl acetate / methanol / concentrated aqueous ammonia = 9:1: 〇. 1), mass spectrum (ESI): m/z = 435 [M-Η]. (6) 4-[(3-Gaxo-4-fluorophenyl)amino]-6-[3-((R)-6-methyl-2-oxo-indol-4-yl)propoxy ]-7-cyclobutoxyquinazoline (reaction with trifluoroacetic acid in acetonitrile) m.p.: 1 85.5 - 189.5 ° C, mass spectrum (ESI+) ·· m/z = 515,517 [M + H]+ . (7) 4-[(3-Chloro-4-phenylphenyl)amino]-6·[3-(5,5-dimethyl-2-oxo-, lin-4-yl)propoxy]-7 - cyclobutoxyquinazoline (reaction was carried out in trifluoroacetic acid in B.). melting point · 214-216 ° C, - mass spectrum (ESI): m/z = 527, 529 [Μ-ΗΓ. (8) 4-[(3- gas-4-phenylphenyl)amino]-6-[3-((R)-6-methyl-2-oxo-4- 4-4-yl)propoxy ]-7-cyclopropyl decyloxy 4 oxazoline (reaction with trifluoroacetic acid in acetonitrile) _ Melting point: 160.5- 163 Ό, -50- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 gong) PCT)

12 1294422 A7 B7__ V. INSTRUCTIONS (48) Mass Spectrometry (ESP): m/z = 515, 517 [Μ + ΗΓ. (9) 4-[(3-Chloro-4-phenylphenyl)amino]-6-[3-((S)-6-methyl-2-oxo-indol-4-yl)propoxy - 7-cyclopropyl methoxy quinazoline (reaction with trifluoroacetic acid in acetonitrile) m.p.: 160-162 C, MS (ESI): m/z = 515, 517 [ Μ + ΗΓ. (1〇) 4.-[(3-Chloro-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxomorpholin-4-yl)B Oxy]-7-cyclopentyloxyquinazoline (reaction with trifluoroacetic acid in acetonitrile)

Rt. 値: 0.3 1 (gelatin, ethyl acetate), mass spectrum (ESI+): m/z = 5 15, 517 [M + H]+. (11) 4-[(3-Gas-4-fluorophenyl)amino]-6-[2-((R)-6-methyl-2-oxomorpholin-4-yl)ethoxy -7-cyclopentyloxyoxazoline (reaction with trifluoroacetic acid in acetonitrile) m.p.: 176-178 ° C, mass spectrum (ESI f) ·· m/z = 5 15, 517 [M + H] +. (12) 4-[(3-Vinyl-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxo-endoline-4-yl)ethoxylate ]-7-cyclopropylmethoxyquinazoline (reaction with trifluoroacetic acid in acetonitrile) - R t .値: 0 · 3 7 (Shixi gum, acetic acid ethyl acetate), mass spectrometry (ESP): m/z = 501,503 [Μ+ΗΓ. (13) 4-[(3-Gas-4-fluorophenyl)amino]-6-[2-((R)-6-methyl-2-oxomorpholine-4-yl)ethoxy H7-cyclopropylmethoxyquinazoline (reaction with trifluoroacetic acid in acetonitrile) 1-51 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1294422 A7 ______ B7 ___ , invention description (49)

Rt, 値: 0.3 7 (gelatin, ethyl acetate), overflow ^ (ESr): m/z = 501, 503 [M+H]+. (14) 4-[(3-Chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-[2-((S)-6-decyloxymorpholine-4 -yl)ethoxy]quinazoline (reaction with trifluoroacetic acid in acetonitrile) 値·· 0.48 (gelatin, ethyl acetate/methanol = 9 ··1), mass 4 (ESI'): m/z = 501,503 [M + H]+. (15) 4-[(3-Ga-4-fluorophenyl)amino]·6_cyclopropylmethoxy-7-[2-((R)-6-methyl-2-oxo? Phenyl)ethoxy]quinazoline (reaction with trifluoroacetic acid in acetonitrile) Mass Spectrum (ESI): m/z = 501, 503 [M + H]+. (16) 4-[(3-Gas-4-fluorophenyl)aminopyridin 6·cyclopropylmethoxy-7-[3-((R)-6-methyl-2-oxomorpholine -4-yl)propoxy]quinazoline (reaction with trifluoroacetic acid in acetonitrile) R: Straight: 0.67 (gel, ethyl acetate / methanol = 9 : 1), mass spectrum (ESI): m/z = 513, 515 [M-Hf. (17) 4-[(3-Ga-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-[3-((S)-6-methyl-2-oxo?琳-4-yl)propoxy]p kujun P (reaction with tri-acetic acid in acetonitrile) ~ 1 値: 0.67 (gelatin, ethyl acetate / methanol = 9: 1), mass spectrometry (ESI·) : m/z = 513,515 [M-Η]- ° (18) 4-[(3 -Ga-4-fluoroindolyl)amino]-6-[2-(2,2-dimethyl- 6-oxo-indol-4-yl)ethoxy; 1-_7-cyclopentyloxyoxazoline (reaction with trifluoroacetic acid in acetonitrile) • 52- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 public 7' 1294422 A7 ___B7__ V. Description of invention (50) n ·· 0.5 6 (silicone, ethyl acetate), mass spectrum (ESI+): m/z = 529, 53 1 [Μ + ΗΓ. 19) 4-[(3-Gas-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-((S)-6-methyl-2-oxomorpholine-4 -yl)ethoxy]quinazoline (reaction with trifluoroacetic acid in acetonitrile)

Rt, 値: 0.60 (gelatin, ethyl acetate / methanol = 9: 1), mass spectrum (ESI): m/z = 515, 517 [M + H]+. (20) 4-[(3-Chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-[2-((R)-6-mercapto-2-oxomorpholine- 4-yl)ethoxy]oxazoline (reaction with trifluoroacetic acid in acetonitrile) mass spectrum (ES1 + ) : m/z = 515, 517 [Μ + ΗΓ. (21) 4-[(3-Gas-4-fluorophenyl)amino]-6-[4-((S)-6-methyl-2-oxomorpholine-4-yl)butoxy ]-7 -Pentapentyloxy p-ku ρ sit ρ Lin (reaction is carried out in the second gas and B guess)

Rti : 0.5 1 (gelatin, ethyl acetate), mass spectrum (ESI+) ·· m/z = 543, 545 [Μ+ΗΓ. (22) 4·[(3-Ga-4-fluorophenyl)amino]-6-[4-((R)-6-methyl-2-oxomorpholine-4-yl)butoxy ]-7-cyclopentyloxyquinazoline (reaction with trifluoroacetic acid in acetonitrile). Mass Spectrum (ESP): m/z = 543, 545 [Μ+ΗΓ ° (23) 4-[(3- 4-fluorophenyl)amino]-6-[3-((S)-6-methyl-2-oxomorpholin-4-yl)propoxy]-7-methoxy p-kujun 4 (Reaction with trifluoroacetic acid in acetonitrile) - Melting point: 1 83- 186 ° C, -53- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) Binding 1294422 A7 B7 V. Description of the invention (51) Mass spectrum (ESI+): m/z = 475, 477 [M+H]+. (24) 4-[(3-Chloro-4-fluorophenyl)amino]-6-[3-(5,5-dimethyl-2-oxo-indol-4-yl)propoxy] -7-methoxy quinazoline (reaction with trifluoroacetic acid in acetonitrile)

Rt, 値: 0.43 (gelatin, ethyl acetate), mass spectrum (ESI): m/z = 487, 489 [Μ-ΗΓ. (25) 4-[(3-Gas-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxo? 4-4-yl)ethoxy -7-methoxy quinazoline (reaction with trifluoroacetic acid in acetonitrile) m.p.: s. (26) 4-[(3-Ga-4-fluorophenyl)amino]-6-{2-[N-(carboxymethyl)-N-((S)-2-hydroxypropyl)amino Ethoxy}·7-methoxyoxazoline (produces 3 (25) by-product) Melting point: 187-190 ° C, mass spectrum (ESI f ): m/z = 479, 481 [M + H]+ . (27) 4-[(3-Chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimercapto-6-oxomorpholin-4-yl)ethoxy] -7-Methoxyquinazoline (reaction with trifluoroacetic acid in acetonitrile) m.p.: 229-232 C, mp (ESI): m/z = 473, 475 [M-Η]-. (28) 4-[(3-Gas-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-4-yl)ethoxy] -7-((R)-Tetrahydrofuran-3-yloxy)carbazole 4 (Reaction with trifluoroacetic acid in acetonitrile _ melting point: 195-196 ° C, -54 -

Binding

This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 1294422 A7 B7 V. Description of invention (52) Mass spectrometry (ESI+): m/z = 531,533 [M + H]+. (29) 4-[(3_Gas-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-poline-4-yl)ethoxy] -7-[(HH-tetrahydrofuran-2-yl)methoxy]quinazoline (reaction with trifluoroacetic acid in acetonitrile) solv.: 184 ° C, MS (ESI+): m/z = 545, 547 [ M + H]+. (30) 4-[(3-Chloro-4-fluorophenyl)amino]-7-[2-(2,2-dimethyl-6-oxoline- 4-yl)ethyl lactyl] -6-((S)-Tetrachato-3-based gas base) p Kui-Lin melting point: 202-205 ° C, mass spectrum (ESP): m/z = 53 1,533 [M + H]+ . (31) 4-[(3-Gas-4-fluorophenyl)amino]-7-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)ethoxy] -6-[(S)-(Tetrahydrofuran-2-yl)methoxy]quinazoline melting point: 182°C, MS (ESI+): m/z = 545, 547 [M + H]+. Example 4 4-((3-Bromophenyl)aminophenyl 6-(2-{N-"(Tertidinoxycarbonyl)methyl2-3⁄4ylpropyl)aminopurine ethoxy)-7- Methoxy p-quinazoline 4 wood 0.25 ml of diisopropylethylamine was added to 650 mg of 4-[(3-bromophenyl)amino]-6-(2-bromoethoxy)-7-methoxy Thoroughly drenched with 1.1 g of (S)-(2-3⁄4 propylamino) acetic acid tert-butyl ester in 15 ml of acetic acid. The reaction mixture was stirred at 50 ° C overnight. Since no reaction was detected, the reaction mixture was concentrated by evaporation, mixed with 20 ml of N,N-dimethylformamide and stirred at 60 ° C for 8 hours. The temperature then rises to 80 °C. After _8 hours, the reaction was completed. The reaction mixture was concentrated by evaporation and chromatographed on a silica gel column using ethyl acetate as a solvent to obtain a white solid. -55- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1294422 A7 __B7 V. Invention Describe the desired product of (53). Yield: 410 mg (51% of theory),

Rf値·· 0.2 7 (gelatin, ethyl acetate), mass spectrum (ESI·): m/z = 559, 561 [M-Η]. The following compounds were prepared in analogy to Example 4: (1) 4-[(3-bromophenyl)amino]-6-(2_{N-[(t-butoxycarbonyl)methyl]-indole ((R)-2-hydroxyl) Propyl)amino}ethoxy bromide 7-methoxyoxazoline melting point: 130 ° C, mass spectrum (ESI·) ·· m/z = 559, 561 [M-Η]-. (2) 4- [(3-Chloro-4-fluorophenyl)amino]·6-(2-{Ν-[(Tertidinoxycarbonyl)methyl]-N-((R)*"2-^-propyl Amino)ethoxy}-7-decyloxyquinone ρ (in reaction with N,N-dimethylformamide) Heart palpitations: 0·40 (gelatin, ethyl acetate/oil Ether = 4 ·· 1). (3) 4-[(3-Gas-4-fluorophenyl)amino]-6-(3·{Ν-[(Tertidinoxycarbonyl)methyl]-N -((R)-2-hydroxypropyl)amino}propoxy)-7-methoxyquinazoline (reaction in hydrazine, hydrazine-dimercaptocaramine)

Rt, 値·· 0.37 (silicone, ethyl acetate/petroleum ether = 4 ··1), mass spectrum (ESI·): m/z = 547, 549 [Μ-ΗΓ. (4) 4-[(R)-(l-Phenylethyl)amino]-6--(3-{N-[(t-butoxycarbonyl)methyl]-N-((S)- 2-hydroxypropyl)amino}propoxy)-7-decyloxyquinazoline (reaction in N,N-dimethylformamide)

Rt•値: 0.65 (silicone, ethyl acetate/methanol = 9 ··1), mass spectrum (El): m/z = 524 [M]+. (5) 4-[(R)-(l-Phenylethyl)amino]-6-(2-{N-[(Tertidinoxycarbonyl)---- This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1294422 A7 _____ B7 V. Description of invention (54) Group]-N-((S)-2-hydroxypropyl)amino}ethoxy quinoxyquinazoline (Reaction in N,N-dimethylformamide) 1値:0.57 (矽, ethyl acetate / methanol / aqueous ammonia solution = 9 : 1 : 0.1) 〇 (6) 4-[(3-chloro 4-fluorophenyl)amino]-6-(3_{N-[(tatabutoxycarbonyl)methyl]-N-((R)-2-hydroxypropyl)amino}propoxy) -7-cyclobutoxyquinazoline

Rt-値: 0.3 1 (Shi Xijiao, two gas toluene / methanol = 95: 5). (7) 4-[(3-Gas-4-fluorophenyl)amino]-6-(3-{N-[(Tertiary)-yl)-N-(l, dimethyl 2-hydroxyethyl)amino}propoxycyclobutoxyquinazoline

Rt, 値·· 0.2 9 (silicone, dichloromethane/methanol = 95: 5), mass spectrum (ESI+): m/z = 603, 605 [M + H]+. (8) 4-[(3-Chloro-4-fluorophenyl)amino]-6-(3-{N-[(t-butoxycarbonyl)methyl]-N-((R)-2- Hydroxypropyl)amino}propoxy)-7-cyclopropylmethoxyquinazoline

Rt. 値: 0.37 (silicone, dichloromethane / methanol = 95: 5). (9) 4-[(3-Chloro-4-fluorophenyl)amino]-6-(3-{N-[(t-butoxycarbonyl)methyl]-N-((S)-2- Hydroxypropyl)amino}propoxy)-7-cyclopropylmethoxyoxazoline

Rt. 値: 0.50 (gelatin, ethyl acetate). (10) 4-[(3-Gas-4-fluorophenyl)amino]-6-(2-{N-[(t-butoxycarbonyl)methyl]-N-((S)-2- Hydroxypropyl)amino}ethoxy)-7-cyclopentyloxyquinazoline

Rt. 値: 0.54 (gelatin, ethyl acetate / cyclohexane = 9: 1). (11) 4-[(3-Gas-4-fluorophenyl)amino]-6-(2-{N-[(t-butoxycarbonyl)methyl]-N-((R)-2- Hydroxypropyl)amine.yl}ethoxycyclopentyloxyquinazoline 1値: 0.66 (gelatin, ethyl acetate). (12) 4-[(3-Ga-4-phenylphenyl)amino] -6-(2-{N-[(Secondoxybutyryl)methyl-57- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 public) 1294422 A7 B7 V. Description of invention ( 55)]-N-((S)-2-Hydroxypropyl)amino}ethoxy)-7-cyclopropylmethoxyquinazoline, 値: 0.60 (gelatin, ethyl acetate). 13) 4-[(3-Gas-4-fluorophenyl)amino]-6-(2-{N-[(t-butoxycarbonyl)indenyl]-N-((R)-2-hydroxyl Propyl)amino}ethoxy)-7-cyclopropylmethoxy-4-oxazoline

Rt, 値: 0.60 (gelatin, ethyl acetate). (14) 4-[(3-Gas-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(2-{Ν·[(Tertidinoxycarbonyl)methyl]- N-((S)-2-Hydroxypropyl)amino}ethoxyphenylquinazoline 1 値: 0·30 (gelatin, ethyl acetate). (15) 4-[(3-Chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(2-{Ν-[(t-butoxycarbonyl)methyl]- N-((R)-2-hydroxypropyl)amino}ethoxy)oxazoline

Rt, 値: 0·30 (gelatin, ethyl acetate). (16) 4-[(3-Gas-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(3-{Ν-[(t-butoxycarbonyl)methyl]- N-((R)-2-hydroxypropyl)amino}propoxy)oxazoline

Rt·値: 0.35 (gelatin, ethyl acetate). (17) 4-[(3-Chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(3-{N-[(t-butoxycarbonyl)methyl]- N-((S)-2-Hydroxypropyl)amino}propoxy)quinazoline 1 値: 0.35 (gelatin, ethyl acetate). (18) 4-[(3-Gas-4-fluorophenyl)amino]-6-(2-{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxy-2-methyl) Propyl)amino}ethoxy)-7-cyclopentyloxyquinazoline

Rr値············································ (19) 4-[(3-Chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-{N-[(t-butoxycarbonyl)methyl]-> L-((S)-2-hydroxypropyl)amino}ethoxy)oxazoline

Rt, 値: 0·5 1 (gelatin, ethyl acetate). -58- This paper size is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) binding

1294422 A7 B7 V. INSTRUCTIONS (56) (20) 4-[(3-Chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-{N-[(third Butoxycarbonyl)methyl]-N-((R)-2-hydroxypropyl)amino}ethoxy)quinazoline

Rt. 値: 0.51 (gelatin, ethyl acetate). (21) 4-[(3-Gas-4-fluorophenyl)amino]-6-(4-{N-[(t-butoxycarbonyl)methyl]-N-((S)-2- Hydroxypropyl)amino}butoxy)-7-cyclopentyloxyoxazoline 1 値: 0.61 (gelatin, ethyl acetate). (22) 4-[(3-Chloro-4-fluorophenyl)amino]_6-(4-{N-[(dioxabutoxy)methyl]-N-((R)-2- Propyl propyl)amino}butoxy)-7-cyclopentyloxyp-quineline: 0.61 (gelatin, ethyl acetate). (23) 4-[(3-Gas-4-fluorophenyl)amino]-6-(3-{N-[(t-butoxycarbonyl)indenyl]-N-((S)-2- Hydroxypropyl)amino}propoxy)-7-methoxyoxazoline heart: 0.46 (gelatin, ethyl acetate), mass spectrum (ESI·) ·· m/z = 547, 549 [MH]_ . (24) 4-[(3-Chloro-4-fluorophenyl)amino]-6-(3-{N-[(t-butoxycarbonyl)methyl]dimethyl-2-3⁄4ylethyl Amino}propoxy)-7-methoxy P quinone-mass mass spectrometry (ESI+) ·· m/z = 563, 565 [M + H]+. (25) 4-[(3-Gas-4-ylphenyl)amino]-6-(2-{N-[(Tertidinoxycarbonyl)methyl]-N-((S)-2- Hydroxypropyl)amino}ethoxy}-7-methoxyoxazoline

Rt.値·· 0.66 (gelatin, ethyl acetate/increol = 9:1), mass spectrum (ESP): m/z = 535, 537 [M + H]+. (26) 4-[(3-Gas-4-fluorophenyl)amino]-6-(2-{N-[(ethoxybenzyl)methyl]-N·(2-light-based-2- Methylpropyl)amino}ethoxy}-7-methoxy p-Quinolin (as a mixture with the cyclized material) 1値: 0.44 (gelatin, ethyl acetate), -59- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1294422 A7 B7 V. Description of invention (57) Quality 1 Jin (ESr): m/z = 521,523 [M + H]+. (27) 4-[(3-Gas-4-fluorophenyl)amino]-6-(2_{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxy-2-methylpropane Amino}ethoxy}7-((R)-tetrahydrofuranyloxy) quinazoline (as a mixture with the cyclized material)

Rt, 値: 0.3 0 (silicone, dichloromethane/methanol = 9:1). (28) 4-[(3-Chloro-4)fluorophenyl)amino]-6-(2-{N-[(ethoxycarbonyl)methyl]-N-(2-3⁄4-yl-2-yl) Propyl)amino}ethoxy)_7-[(R)-(tetrahydrofurfuryl)methoxy]p-quinone-ion mass spectrometry (ESI·) : m/z = 589, 591 [M-Η ]-. (29) 4-[(3-Ga-4-fluorophenyl)amino]-7-(2-{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxy-2-methyl Propyl)amino}ethoxy}_6_((5)·tetrahydrofuran_3_yloxy)rrkui P

Mii: 0·16 (silicone, gas-burning/methanol = 20:1). (3 0) 4-[(3-Chloro-4-fluorophenyl)amino]-7-(2-{N-[(ethoxycarbonyl)methyl]·N-(2-3⁄4yl-2- Methylpropyl)amino}ethoxy)_6-[(S)-(tetrahydrofuran-2-yl)methoxy]4 σ Gu Lin

Rt-値: 0.68 (gelatin, ethyl acetate / methanol = 15: 1). Similar to the foregoing examples and other methods known in the literature, the following compounds can be prepared: - (1) 4-[(3-Chloro-4-fluorophenyl)amino]-7-[2-(6-methyl-2) - oxo-based) ethoxy]-6-methoxyoxazoline, (2) 4-[(j-gas-4-qi; ^yl)amino]-7-[3-(6 -methyl-2-oxo- phenoline-a) propoxydi 6-methoxyquinazoline, (3) 4-[(3-chloro.4.fluorophenyl)aminophenyl 6-[2 -((S)-6-Methyl-2-oxo-dailin-60- This paper scale applies Chinese National Standard (CNS) A4 specification (210X 297 dongdong) "^ -- 1294422 A7 B7 V. Invention Description (58) yl)ethoxy]-7-methoxyquinazoline, (4) 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-((S)-6- Methyl-2-oxo-allinyl)propoxy]_7-methoxyquinazoline, (5) 4_[(3_气气木基)amino]-6-[3_(5,5 - Monomethyl-2-oxo-oxan 4-yl)propoxy]-7-methoxyquinazoline, (6) 4-[(3-Ga-4-fluorophenyl)amino]-6-[2 -(5,5-dimethyl-2-oxomorphin 4-yl)ethoxy]-7-methoxyquinazoline, (7) 4-[(3-chloro-4-fluorobenzene) Amino]-6-[3-(3-methyl-2-oxo- phenan-yl)propyl propyl]-7-methoxy p-kurine, (8) 4 -[(3- gas-4-fluorophenyl)amino]-6-[2-(3-methyl-2-oxo- phenanthrene H, yl) ethoxy]-7-methoxy p-quinion Junlin, (7) 4-[(R)-(l-phenylethyl)amino]-6-[3_((R)-6-methyloxo-indenyl 4-yl)propoxy]-7 -Methoxy sulphate p, (10) 4-[(R)-(l-phenylethyl)amino]-6-[2-((R)-t-methyl- 2 oxo? 4-yl)ethoxy]-7-methoxyoxazoline, (11) 4-[(3-Ga-4-fluorophenyl)amino]-7-[4-(6-methyl- 2-oxomorpholine _4, butoxy]-6-methoxy P quetiapine P, (12) 4-[(j-gas-4-fluoro)amino]-7-[3 -(6-methyl-2-oxo- phenanthine-methyl) propoxy]-6-methoxy P-kujun P, - (13) 4-[(3-Ga-4-Denyl) Amino]-6-[4-(6-methyl-2-oxo-t-butyl]--butoxy]-7-methoxy-p-Quin-Pu Lin, (14) 4-[(3- Gas-4-fluorophenyl)amino]-6-[2-(6-methyl-2-oxomorpholine_4, I> ethoxy]-7-(tetra-n-furan-3-yl Oxy) quinazoline, (15) 4-[(3- gas-4-fluorophenyl)amino group;]_6-[2-(6-methyl-2-oxomorpholine_4, VIII) -61 -

1294422 A7 __B7 V. INSTRUCTIONS (59) Ethoxy]-7-(tetrazinium-pyran-3-yloxy)p-kujunlin, (16) 4-[(3-Ga-4-t-benzene) Amino]-6-[2-(6-methyl-2-oxoline 4) ethoxy]-7-(tetrazo-pyran-4-yloxy) τι奎Lin, (17) 4-[(3-Ga-4-phenylene)amino]_6-[2-(6.methyl-2-oxo-phenanthine 4) Ethoxy]-7-( Tetrahydromethane-2-ylmethoxy) π 奎 琳, (18) 4-[(3-Gas-4-fluorophenyl)amino]-6-[2-(6-methyl-2) - oxo- 〃 〃 4 4) ethoxy]-7-(tetrachloro-p-pyran-4-ylmethoxy) ρ 奎 琳, (19) 4-[(3-chloro-4-fluorobenzene Amino]-6-[2-(6,6-dimethyl-2-oxomorpholine-4-yl)ethoxy]-7-(tetra-n-butyl-3-yloxy)奎奎σ坐琳, (20) 4-[(3 -Ga-4-fluorophenyl)amino]-6-[3-(6,6-dimethyl-2-oxomorphin-4-yl Propyloxy-7-(tetrahydrofuran-3-yloxy) quinazoline, (21) 4-[(3- gas-4-orthophenyl)amino]-6-[4 -(6,6-dimethyl-2-oxomorphin-4-yl)butoxy]-7-(tetrahydrofuran-3-yloxy)p-quinegrin, (22) 4- [(3- gas-4-fluorophenyl)amino]-6-[2-(6,6-dimethyl-2-oxo? 4-yl)ethoxy]-7-(tetrahydrofuran-2-ylmethoxy)oxazoline, (23) 4-[(3-chloro-4-fluorophenyl)amino]-6-[3 -(6,6-dimethyl-2-oxomarin-4,yl)propoxy]-7-(tetrahydrofuran-2-yloxy)quinazoline, (24) 4-[(3 - gas-4-fluorophenyl)amino]-6-[4-(6,6-dimethyl-2-oxomarin-4,yl)butoxy]-7-(tetrahydrofuran-2-yl Methoxy)α quinazoline, (25) 4-[(3-Ga-4-fluorophenyl)amino]-7-[2-(6-methyl-2-oxomorpholine_4臬乙乳基]-6-(tetrahydrofuran-3-yloxy) ρ Π Π Τ 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 [2-(6-Methyl-2-oxomorpholine·4 Fu) Ethoxy]-6-(tetra-ammonium 0-pyran-3-yloxy) α Kui-Lian, (27) 4- [(3-Gas-4-fluorophenyl)amino]-7-[2-(6-methyl-2-oxomorpholine·4_) -62- This paper scale applies to Chinese national standards (CNS ) Α 4 specifications (210X297 mm) ---, -- 1294422 A7

Ethoxy]-6-(tetrahydrop-pyran-4-yloxy) π quetal,

(28) 4_[(3_Chloro-4-fluorophenyl)aminophenyl 7_[2-(6-methyl-2-oxoethoxy)-6-(tetrahydrofuran-2-ylmethoxy) Quinazoline, (29) 4-[(3-chloro-4-fluorophenanyl)amino]-7-[2·(6-methyl·2-oxo-la-la·4 guang] > Ethoxy]-6-(tetrahydropyran-4-ylmethoxy)quinazoline, (3〇) 4-[(3_chloro-4-fluorophenyl)amino]-7-[2 -(6,6-Dimethyl-2-oxo-indolyl 4-yl)ethoxy]-6·(tetrahydrocarbamate-3-yloxy quetiapine, (31) 4-[( 3-gas _4·fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-4-yl)propoxy]-6-(tetrahydroanthracene- 3-(yloxy)p-Quin-Prin, (32) 4-[(3-Ga-4-fluorophenyl)amino]-7-[4-(6,6-dimethyl-2-oxo代 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- ]-7-[2-(6,6-Dimethyl-2-oxomorphin-4-yl)ethoxy]-6-(tetrazole-2-ylmethoxy) ττ奎君, (34) 4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(6,6-dimethyl-2-oxo-4-yl)propoxy] -6-(tetrahydrofuran-2-ylmethoxy)p-ku jun p, (35) 4-[(3- gas-4-fluorophenyl)amino]-7-[4-(6 ,6-dimethyl Benzyl-2-oxo-indolyl 4-yl)butoxy]-6-(tetrahydro-n-yl-2-yloxy)p-kulin p-lin. Example 5 package containing 75亳 active substance Lozenge - 1 core bond contains: Active substance 75.0 mg phosphoric acid #5 93.0 mg corn starch _ 35.5 mg polyvinylpyrrolidone 10.0 mg-63-

1294422 A7 B7

150 g of 230.0 g of hydroxypropyl methylcellulose magnesium stearate preparation: active substance with calcium phosphate, corn starch, polyethylene flat pyrrolidone, hydroxypropyl methylcellulose and specific amount of magnesium stearate Half of the mix, match. An ingot of 13 mm in diameter was obtained by the ingot making mechanism and it was then rubbed with a mesh of 1-5 turpentine < mesh screen using an appropriate device and mixed with the remaining amount of magnesium stearate. Slightly right to the tablet machine, it is compressed to form a tablet of the desired shape.核心 Core weight: 230 mg Mold: 9 mm, rounded The resulting core is coated with a μ consisting essentially of hydroxypropyl methylcellulose. The finished film coated lozenge is polished with beeswax. Coated tablet weight: 245 mg. Example 6 Composition of a tablet containing 1 mg of active substance: 1 tablet contains: active substance Ί 00.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidinium with 4.0 mg magnesium stearate _ 2.0 mg 220.0 mg-64 - The paper size is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) 1294422 A7 ____ B7______ V. Description of invention (62) Preparation method: Active substance, lactose and starch are mixed together and water is dropped by polyvinylpyrrolidone Evenly humidified. The wet composition was then sieved (2. glutinous rice mesh) and dried in a 5 °C mesh dryer, sieved again (1.5 mil mesh) and added with a lubricant. The redundant mixture is compressed to form a marine agent. Lozenge weight · · 2 2 0 mg Diameter · · 10 mm, double-layered double-section and one side has a score. Example 7 Contains 15 mg of active substance to make the composition of the reamer: 1 ingot contains: active substance 150.0 mg of powdered lactose 89.0 mg of corn starch 4 〇. 〇 胶 胶 胶 胶 胶 ο ο 毫克 毫克 毫克 比 比 比 比 比 比〇 〇 〇 mg magnesium stearate U mg 300·0 mg Preparation method: - The active substance is mixed with lactose, corn starch and cerium oxide, and is uniformly wetted with an aqueous solution of polyvinylpyrrolidone, which is a network of 15 mm mesh. Screened) sieve. The granules were dried at 45 ° C and passed through the same mesh and mixed with the specific magnesium oleate. j The mixture is compressed into a tablet. Lozenge weight · 300 mg

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1294422 A7 B7 V. Description of invention (63) Mold: 10 mm, flat. Example 8 Hard gelatin capsule containing 150 mg of active substance 1 capsule containing: active substance 50.0 mg corn starch (dry) about 80.0 mg lactose (powder) about 87.0 mg magnesium stearate 3.0 mg about 420.0 mg active substance and excipient Mix, pass through a mesh of 0.75 mm mesh and mix evenly using suitable equipment. The finished mixture is filled with size 1 hard gelatin capsules. Capsule filling: approx. 320 mg Capsule shell: Size 1 gelatin capsule. Example 9 Suppository containing 150 mg of active substance 1 Suppository contains: 150.0 mg 550.0 mg 460.0 mg 840.0 mg of active substance-polyethylene glycol 1500 polyethylene glycol 6000 polyoxyethylene sorbitan monostearate 200.0 mg preparation : -66- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1294422 A7

After the suppository block is melted, it is cooled in the mold. f Example 10 The active substance is evenly distributed therein and the cans are poured into the box of milligrams of active substance in the county yinyuan 1 〇〇 ml suspension containing: active substance carboxymethyl cellulose-Na salt p-hydroxybenzoic acid methyl ester pair - Preparation of glyceryl benzoate, glucose glycerol 70% sorbitol solution flavoring agent Luohe water to prepare: 1.00 g 0.10 g 0.05 g 0.01 g 10.00 g 5 · gram 20.00 g 0.30 g 100 ml steaming water heated to thief. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Bu „ dissolves in it. The solution is cooled to the ambient temperature and the active substance is added and stirred in the mixture. After the sugar is added, the sorbitol solution and the flavoring agent are added and dissolved (four) and the gas is extracted to eliminate the gas 〇. _ 5 ml suspension contains 50 mg of active substance. Example 1 I Contains 10 mg of active _ substance composition: -67- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1294422 A7 B7 V. Invention Description (65) Active substance 10.0 mg 0.01 N hydrochloric acid An appropriate amount of double distilled water was added to the preparation: 2.0 ml of the active substance was dissolved in a necessary amount of 0.01 N HCl, adjusted to an isotonic state with a general salt, sterilized by filtration and transferred into 2 ml of ampoule. Example 12 Ampoule composition containing 50 mg of active substance: Active substance 50.0 mg of 0.01 N hydrochloric acid, an appropriate amount of double distilled water was added to the preparation: 10.0 ml of the active substance was dissolved in a necessary amount of 0.01 N HCl, and the salt was adjusted to be isotonic, filtered and sterilized. And transferred into 10 ml ampoules. Example 13 Powder inhalation capsule containing 5 mg of active substance 1 capsule containing: Active substance 1.0 mg Inhalation lactose 15.0 mg Preparation: 20.0 mg of active substance is mixed with _ inhalation lactose. The mixture is filled into capsules in a capsule making machine (empty capsule weight is about 50 mg) -68- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297) 1294422 A7 B7 V. INSTRUCTIONS (66) Capsule weight: 70.0 mg capsule size = 3 Example 14 Inhalation solution for hand-held spray containing 2.5 mg of active substance Spray: Active substance 2.500 mg of gasified hydrazine Alkyl ammonium 0.001 mg 1 N hydrochloric acid amount of ethanol / water (50 / 50) added to 15.000 Aike preparation: Active substance and chlorinated sulphur is dissolved in ethanol / water (5 0/5 0). Solution p Η to 1 Adjust the hydrochloric acid solution. The resulting solution is filtered and transferred to a suitable container for hand-held spray. Container contents: 4.5 g-69- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)

Claims (1)

1294^) Patent application No. 2320905 Chinese patent application scope replacement (July 1996) Patent application Fans Supplementary WpILuj 1 · A bicyclic heterocyclic compound of the formula I Ra, Η '(I) wherein Ra represents 1-phenylethyl, 3-bromophenyl or 3-amino-4fluorobenzene, and Rb represents R3-(CH2)m-fluorenyl, wherein ''R3 stands for and can pass 1 Or 2 methyl substituted 2-oxomorpholin-4-yl, m represents 2 or 3; Rc represents methoxy, cyclobutoxy, cyclopentyloxy, cyclo &#二基甲轰I tetrahydrofuran _3· yloxy or tetrahydrofuranyl methoxy; except for the following compounds: 4-[(3-bromophenyl)amino]-6-[2·(6,6-dimethyl-2- Oxygen-producing octaphylline _4_ylethoxy]-7-methoxyquinazoline, ethyl 4-[(3-bromophenyl)amino]-6-[2-(3-methyl -2_oxo?^株株·基) oxy]-7-methoxyquinazoline '4-[(3_bromophenyl)amino]-6-[2-(5,5- Dimethyl-2-oxo ethoxy]-7-methoxyquinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(6, 6-Dimethyl-2-oxo-[xylo]4-yl)ethoxy]-7-methoxyquinazoline, '4-[(3-chloro-4-fluorophenyl)amino]- 6-[2-(6,6-Dimethyl-2-oxo-endolin-4-yl)ethoxy]-7-cyclobutoxyquinazoline, 72914-960712.doc This paper scale applies to China Standard (CNS) Α4 Specifications (210X2 97 mm) 1294422 4_[(3_murine fluorophenyl)amino]-6-[2»·(656-dimethyl-2-oxo-4-yl)ethoxy]-7-cyclopropylmethoxy oxime Oxazoline, ~lin-4_[(3ϋfluorophenyl)amino]-6-[3-(6,6-dimethyl-2«oxo1 4 -yl)propoxy]-7 曱 oxime基ρ奎嗤琳, '4-[(3_Chloro-4-phenyl)amino]-6_[2_(6,6-dimethyl-2-oxo-4-yl)ethylidyl]_ 7-cyclopentyloxy π quetium, '4_[(3ϋfluorophenyl)amino] winter [3_(6,6-dimethyl-2-oxo? 4-yl)propoxy]-7 -cyclopentyloxy ρ 奎 ρ 林, and ' (R)-4_[(l_phenylethyl)amino]_6_[3-(6,6-dimethyl- 2 oxoline-4 -yl)propoxy]_7_cyclopentyloxyquinazoline, horse or a physiologically acceptable salt thereof. A chelating agent selected from the group consisting of (4a) 4-[(3-chloro-4-fluorophenyl)amino]>7-cyclobutoxy-6-indole (6 6_methyl-2) -oxomorpholin-4-yl)propoxy]quinazoline, ~ (b) '[(3-chloro-4-fluorophenyl)amino]_7-cyclopropylmethoxy_heart [3_ (6 6 dimethyl-2-oxomorpholin-4-yl)propoxy]oxazoline, 5 (4)4-[(3-bromophenyl)amino]6-[2-((8) -6-Methyl-2-oxo- phenothiyl)ethoxy]-7-methoxyquinazoline, (4) Ben [(3_bromophenyl)amino] winter [2-((R)_6) _Methyl-2_oxo- oxaline^-yl)ethoxy]-7-methoxyp-quine-p-lin, (e)4-[(3-mur-4-fluorophenyl)amino]- 6-[2-((R)-6-methyl"·2_oxo- phenanthrene-4-yl)ethoxy]_7-methoxyquinazoline, (1)4_[(3_chloro-4-fluoro Phenyl)amino]-6-|>((R)-6-methyl-2-oxo-4-methyl)propoxy]-7-methoxy P-quinazoline 4, 72914 -960712.doc _2_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294422 A8 B8 C8 D8, Patent Application Park (g) 4-[(R)-(l-phenylethyl)amino group] Winter [3_((8) Winter methyl-2-oxomorpholin-4-yl)propoxyb 7-methoxyquinazoline, (h) 4_[(R)-(l-phenylethyl) Amino] winter [2_((8) winter methyl 2 oxo. 淋 _ 4-yl) ethoxy]_7_methoxy quinazoline, and (1) 4-[(3-chloro-4- Fluorophenyl)amino]_6_[2_((s)-6-methyl|oxo-endoline-4-yl)ethoxy]_7-methoxy-junine, or a physiologically acceptable salt thereof . 3. A physiologically acceptable salt of a compound according to claim 1 or 2 with an inorganic or organic acid or base. 4. A pharmaceutical composition as an inhibitor of signal transduction of tyrosine kinase, comprising a compound according to the scope of the patent application or a physiologically acceptable salt according to claim 3 of the patent application and a pharmaceutically acceptable carrier or Thinner. 5. A pharmaceutical composition for treating respiratory and pulmonary diseases caused by an increase or change in mucosa caused by tyrosine kinase stimulation, comprising a compound as claimed in claim 1 or 2 or as in claim 3 Physiologically acceptable salts and pharmaceutically acceptable carriers or diluents. 6. The pharmaceutical composition of claim 5, wherein the disease is selected from the group consisting of chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, Cystic fibrosis, α丨_anti-proteolysis, cough, pulmonary sputum, pulmonary fibrosis and respiratory allergies. 72914-960712.doc , _ 3 - This paper size applies to the Chinese National Standard (CNS) Α4 specification (21〇Χ297 mm)