CN1058265C

CN1058265C - Quinazoline derivatives

Info

Publication number: CN1058265C
Application number: CN94105724A
Authority: CN
Inventors: 李钟郁; 金在圭; 孙文奎; 蔡正锡; 林大圣; 赵大雄; 金昌燮; 李正源
Original assignee: Yuhan Corp
Current assignee: Yuhan Corp
Priority date: 1994-05-16
Filing date: 1994-05-16
Publication date: 2000-11-08
Anticipated expiration: 2014-05-16
Also published as: CN1113912A

Abstract

The present invention relates to a Quinazoline compound represented in a general formula (I) and acceptable pharmacology salt thereof. In the general formula, R1 and R2 is hydrogen or C1-C4 alkyl, and R3 is hydrogen or halogen; R4, R5, R6, R7, R8 and R9 can be the same or different and are hydrogen or C1-C4 alkyl and cyclopropyl respectively; R5 and R6 can form cyclopentane or a cyclohexan ring; R10 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkoxy or methylthio methoxy.

Description

Quinazoline derivant, its preparation method and comprise the composition of this material

The present invention relates to acceptable salt on a kind of novel quinazoline quinoline derivant and the pharmacology thereof, it has good secretion inhibitor activity, also relate to its pharmaceutical composition as active constituent, and the intermediate that it is new, and prepare these compound methods.

For the peptic ulcer treatment of diseases, adopted various medicines, such as antacid, anti-choline agent and H ₂Receptor antagonist.Recently, studying the Australia U.S.A that is used from proton pump inhibitor again draws azoles (omeprozole) active next in this field.

Yet the someone points out that it is irreversible that Yi Aomei draws azoles to do proton pump inhibitor, and it may cause some side effect.Therefore, people attempt to develop a kind of reversible proton pump inhibitor (proton pump inhihitor) now, and for example, European patent 322133 and 404322 discloses the quinazoline derivant that relates to a kind of reversibility proton pump inhibitor.

The inventor has carried out extensive studies to develop a kind of reversibility proton pump inhibitor with improvement effect; The result finds that also the 4th at quinazoline nuclear has the quinazoline derivant of a tetrahydroisoquinoline group to demonstrate good proton pump restraining effect, and this derivative can obtain reversible proton pump restraining effect.

The object of the present invention is to provide a kind of novel quinazoline derivant, have a tetrahydroisoquinoline group on the 4th of its quinazoline nuclear, and acceptable salt on a kind of its pharmacology is provided.

Another object of the present invention is to provide the method for the described compound of preparation.

Another object of the present invention is to provide and contain the pharmaceutical composition of this compound as activeconstituents.

Further purpose of the present invention is to be provided for preparing the new intermediate compound of quinazoline derivant of the present invention.

Brief Description Of Drawings

Can further understand the present invention in conjunction with the following drawings, wherein:

Fig. 1 to Fig. 3 represents that compound, Australia U.S.A of obtaining draw azoles and SK﹠amp from embodiments of the invention; The Lineweaver-Burk trace figure of the sp act that obtains among the F96067.

According to the present invention, provide acceptable salt on the novel quinazoline quinoline derivant of a kind of general formula (I) and the materia medica thereof:

Wherein: R₁And R₂, independently be hydrogen or C respectively₁-C ₄Alkyl;

R ₃It is hydrogen or fontanel element;

R ₄，R ₅，R ₆，R ₇，R ₈, and R₉, they can be identical or not identical, is hydrogen or C₁-C ₄Alkyl, cyclopropyl, perhaps R₅And R₆Can form together a cyclopenta or cyclohexyl;

R ₁₀Be hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, hydroxyl C ₁-C ₄Alkoxyl group or methyl sulphur methoxyl group (methylthiomethyloxy group).

In these compounds of the present invention, wherein preferably:

R ₁And R ₂Be C ₁-C ₄Alkyl;

R ₃It is the fontanel element;

R ₄, R ₅, R ₆, R ₇, R ₈, and R ₉, can be identical or inequality, be hydrogen or C ₁-C ₄Alkyl;

R ₁₀Be C ₁-C ₄Alkoxyl group.

Preferred compound of the present invention is special list as follows:

2-(phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(N-aminotoluene base)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-N-methyl-phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(2-methylbenzene amino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methyl-phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoroanilino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(N-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoroanilino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methyl-phenylamino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methyl-phenylamino)-4-(1,8-ethano-(ethano)-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-(N-methylbenzene amino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(4-fluoroanilino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(4-fluoro-2-methyl-phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(4-fluoro-N-methyl-phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(4-fluoroanilino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(4-fluoro-2-methyl-phenylamino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

(R)-8-methoxyl group-2-(4-fluoro-2-methyl-phenylamino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

(S)-8-methoxyl group-2-(4-fluoro-2-methyl-phenylamino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-(2-hydroxyl-oxethyl)-2-(4-fluoro-2-methyl-phenylamino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-oxyethyl group-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-(methyl sulphur methoxyl group)-4-(1-methyl isophthalic acid, 2,3,4-four ammonia isoquinoline 99.9-2-yl) quinazoline;

8-methoxyl group-2-(N-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(4-fluoro-N-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoroanilino)-8-methoxyl group-4-(1-methyl fluoride-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1-methyl fluoride-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(4-fluoroanilino)-4-(1-ethyl-1,2,3,4 ,-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(2-methyl-4-fluoroanilino)-4-(1-ethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoroanilino)-8-methoxyl group-4-(3-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(3-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoroanilino)-8-methoxyl group-4-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoroanilino)-8-methoxyl group-4-(1,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoroanilino)-8-methoxyl group-4-(1,6-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1,6-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoroanilino)-8-methoxyl group-4-(1,4-dimethylbenzene-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(4-fluoroanilino)-4-(1,8-ethano-(ethano)-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(4-fluoro-2-methylbenzene amino)-4-(1,8-ethano--1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline; With

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline.

The quinazoline derivant of general formula of the present invention (I) can optically active isomer (R) (S) or the form of its mixture exist.Find that two kinds of isomeric compounds all show good secretion inhibitor activity.

The method of compound of preparation general formula (I) can comprise: the compound reaction of the compound of general formula (II) and general formula (III), generate the compound of general formula (IV), and this compound reacts with the compound of logical formula V more then,

Wherein:

R ₁And R ₂Independent respectively, be hydrogen or C ₁-C ₄Alkyl;

R ₃Be hydrogen or fontanel element;

R ₄, R ₅, R ₆, R ₇, R ₈, and R ₉, can be identical or inequality, be hydrogen or C ₁-C ₄Alkyl, cyclopropyl, perhaps R ₅And R ₆Can form a ring penta or a hexamethylene ring together;

R ₁₀Be hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, hydroxyl C ₁-C ₄Alkoxyl group or methyl sulphur methoxyl group;

X is the fontanel element.

Can prepare general formula (II) compound, for example disclosed method among the EP0322133 with known method.Logical formula V is that the commercially available prod is (as Aldrich Co., USA)

General formula (II) compound and general formula (III) compound reacted in suitable solvent and alkali 1 to 24 hour, generated general formula (IV) compound.The suitable solvent that adopts in the reaction can comprise methylene dichloride, acetone, acetonitrile, dimethyl formamide, the mixture of tetrahydrofuran (THF) and they and water.Temperature of reaction is preferably between between the room temperature to 150 ℃.The suitable alkali that uses in this reaction can comprise triethylamine, N, accelerine and pyridine.

The general formula that obtains thus (IV) compound then with logical formula V compound suitable solvent internal reaction 2 to 4 hours, generate general formula of the present invention (I) compound.The suitable solvent that uses in the reaction can comprise dimethyl formamide, P-diox, methyl-sulphoxide etc.Temperature of reaction is preferably 80～120 ℃.

Through the above-mentioned general formula of preparing (IV) compound is the new of preparation general formula (I) quinazoline compound, useful as intermediates.Therefore, the present invention comprises the novel cpd and its preparation method of general formula (IV) in this field.

The compounds of this invention can oral or subcutaneous injection, and the effective dose that the patient uses is preferably 1.0mg/kg to 100mg/kg every day as 0.1mg/kg to 500mg/kg every day.

The present invention also further comprises upward acceptable salt of general formula (I) compound medicine.The non-toxic salt that the present invention adopts can comprise inorganic acid salt, example hydrochloric acid salt, vitriol, phosphoric acid salt and nitrate, and organic acid salt, tartrate for example, fumarate, Citrate trianion, metilsulfate (mesylate) and acetate.

Can prepare acceptable salt on the pharmacology by known method, for example, general formula (I) compound and above-mentioned acid be reacted in solvent, described solvent is, as methane, and ethane, methylene dichloride, acetic acid ethyl ester and ether.

The present invention also comprises the pharmaceutical composition in this field, and said composition contains one or more the present invention's compound as activeconstituents, if desired, and with pharmacology on acceptable carrier, vehicle and/or other additives are formed pharmaceutical composition together.Activeconstituents in the said composition can be 0.1% to 99.9% of its weight.

Following embodiment only is explanation the present invention's a purpose, and unrestricted protection domain of the present invention.

1,2,3 of the general formula (III) that preparation 1 replaces, the preparation of 4-tetrahydroisoquinoline

Preparation 1-1:1-methyl isophthalic acid, 2,3, the 4-tetrahydroisoquinoline

The preparation of step 1:N-(2-styroyl) ethanamide

12.6ml phenylethylamine (0.1M) and 14ml triethylamine (0.1M) are dissolved in the methylene dichloride of 100ml; (0.1M) splashes into wherein with the 6.9ml Acetyl Chloride 98Min., keeps the temperature of reaction system to be lower than 0 ℃ simultaneously, and stirring at room is 10 minutes subsequently.Water flushing reaction soln, anhydrous magnesium sulfate drying, concentrating under reduced pressure gets 14.23 gram white solid title compounds.

Step 2:1-methyl-3, the preparation of 4-dihydro-isoquinoline

8.43 digest compound (51.6mM) and add in the Tripyrophosphoric acid of 84.36 grams what above-mentioned steps 1 made, 160 ℃ of stirring reactions 1.5 hours.Reaction soln impouring frozen water with the ammoniacal liquor neutralization, is used ethyl acetate extraction.The extract anhydrous magnesium sulfate drying, concentrating under reduced pressure.Therefore the residuum that obtains is used methyl alcohol in silica gel column chromatography: the mixing solutions of methylene dichloride (1: 20 (v/v)) obtains oily title compound 6.48 grams as eluting solvent.

Step 3:1-methyl isophthalic acid, 2,3, the preparation of 4-tetrahydroisoquinoline

1.76 gram sodium borohydrides (46mM) are suspended in the ethanol of 80ml, will 6.48 digest compound (44.6mM) and add wherein by what step 2 made.The mixture that stirring at room temperature obtains 1 hour, and be cooled to below 5 ℃, add dilute hydrochloric acid subsequently and make its acidifying.Add sodium hydroxide and make reaction soln be alkalescence, use ethyl acetate extraction.Use the anhydrous sodium sulfate drying ethyl acetate layer, and concentrating under reduced pressure, oily title compound 6.17 grams obtained.

Preparation 1-2:(R)-and the 1-methyl isophthalic acid, 2,3, the 4-tetrahydroisoquinoline

Step 1:(R)-and 1-methyl-4-methyl sulphur-1,2,3, the preparation of 4-tetrahydroisoquinoline-3-ketone.

27.85ml (R)-1-phenylethylamine (0.21M) and 30ml triethylamine (0.21M) be dissolved in the methylene dichloride of 200ml, is cooled to 0 ℃.0 ℃ to wherein splash into 37.8 the gram α-chloro-α (methyl sulphur)-Acetyl Chloride 98Min.s (0.21M).Stirring at room resultant 30 minutes adds tin chloride (IV), and stirring at room is 30 minutes again.

Reaction soln impouring frozen water washes with water.Dehydration concentrates organic layer, gets the solid title compounds of 32.5 grams.

Step 2:(R)-and the 1-methyl isophthalic acid, 2,3, the preparation of 4-tetrahydroisoquinoline-3-ketone

The 150g Raney nickel is suspended in the ethanol of 300ml, to wherein adding the 32.5g compound (0.16M) that makes through above-mentioned steps 2.This mixture of stirring at room removed by filter described Raney nickel after 3 days, and concentrated filtrate gets 20 gram solid title compounds.

Step 3:(R)-and the 1-methyl isophthalic acid, 2,3, the preparation of 4-tetrahydroisoquinoline

10.0 digest compound (62mM) and mix what above-mentioned steps 2 made, to the 10.2M borane-methyl-sulfide mixture that wherein splashes into 9ml with the 20ml tetrahydrofuran (THF).This mixture of back flow reaction 1 hour, and be cooled to room temperature.By add 10ml 6NHCl in this reaction soln, remaining borane-methyl-sulfide mixture is destroyed, and resultant neutralizes with 10% NaOH.Use the ethyl acetate extraction resultant, dehydration and concentrate 8.8 gram oily title compounds.

Preparation 1-3:(S)-and the 1-methyl isophthalic acid, 2,3, the 4-tetrahydroisoquinoline

By with preparation among the 1-2 identical step carry out, just with α-chloro-α-(methyl the sulphur)-Acetyl Chloride 98Min.s (0.22M) of 25.6ml (S)-1-phenylethylamine (0.20M) and 34.8 grams as initiator, 8.8 restrain the oily title compounds.

Preparation 1-4:1,8-ethano--1,2,3,4-tetrahydroisoquinoline

Step 1:3, the preparation of 4-dihydro-isoquinoline

18.8

ml

1,2,3,4-tetrahydroisoquinoline (0.15M) is dissolved in the methylene dichloride of 400ml; 29.4 gram N-bromo-succinimides (0.165M) are at room temperature added to wherein at leisure, stirred subsequently 30 minutes.Add 100ml aqueous sodium hydroxide solution (30%) again, and further stirred 1 hour.Isolate organic layer, wash with water, from aqueous hydrochloric acid solution, extract organic layer.Add ammoniacal liquor pH is transferred to 9; Use dichloromethane extraction, wash with water, use anhydrous sodium sulfate drying again, concentrate 18.5 gram oily title compounds.

Step 2:1,2,3, the preparation of 4-tetrahydroisoquinoline-1-acetate

Stir down to contain at 120 ℃ and 18.5 digest the mixture 1 hour that compound (0.14M) and 14.5 restrains propanedioic acid (0.14M), and be cooled to room temperature through what above-mentioned steps 1 made.To the mixing solutions that wherein adds first alcohol and water (4: 1), stir, filter, get 11.2 gram title compounds.

Step 3:N-(methoxy carboxyl)-1,2,3,8a-four hydroxyl chlorine penta [ij] isoquinoline 99.9-7 (8H)-ketone [N-(methoxycarbonyl)-1,2,3,8a-tetrahydroxychl or opent[ij] isoquinoline-7 (8H)-one] preparation

11.16 restrain in the methylsulfonic acid that five phosphorus oxide are dissolved in 75.35ml, and be heated to 150 ℃; To wherein adding the 11.16g compound (58.3mM) that makes through step 2.150 ℃ of following stirring reaction solution 30 minutes is cooled to room temperature with it then, and the 1N sodium hydroxide to wherein adding 1.5 liters extracts with methylene fluoride.The extract that obtains salt of wormwood drying, the methyl-chloroformate of adding 8.94ml stirred 1 hour, concentrated, and used silica gel chromatography, got 7.2 gram title compounds.

Step 4:N-(methoxy carboxyl)-1, the inferior second-1,2,3 of 8-bridge, the preparation of 4-tetrahydroisoquinoline.

The compound (31.3mM) that 7.2 grams are made by step 3 is dissolved in the 100ml acetate, makes its hydrogenation with 1 gram 10% palladium/gac as catalyzer.Elimination palladium/gac, concentrating under reduced pressure filtrate, with silica gel chromatography it, 5.7 the gram title compounds.

Step 5:1,8-ethano--1,2,3, the preparation of 4-tetrahydroisoquinoline

To contain the compound that 5.7 grams make through step 4,100 ℃ of heating of the mixture of 340ml aqueous potassium hydroxide (10%) and

340ml

1,2 ethylene glycol 14 hours make it to be cooled to room temperature, use ethyl acetate extraction.Wash extract with water, use dried over mgso, concentrating under reduced pressure gets 3.7 gram title compounds.

Preparation 1-5:1-Trifluoromethyl-1,2,3, the 4-tetrahydroisoquinoline

Undertaken by the step identical, just use 25ml phenylethylamine (0.2M) and the anhydrous trifluoroacetic acid of 30ml (0.21M), make 5.4 gram title compounds as initiator with preparation 1-1.

Preparation 1-6:1-methyl fluoride-1,2,3, the 4-tetrahydroisoquinoline

The preparation of step 1:N-(2-styroyl) monofluoroacetamide

In the mixture of dicyclohexylcarbodiimide (0.17M) that contains 11.7 gram gifblaar poison (0.15M) 27.3ml and 200ml methylene dichloride, drip the phenylethylamine (0.17M) of 17ml, stirred 12 hours, filter the solids that generates, water flushing filtrate is with anhydrous sodium sulfate drying and concentrated.Use the silica gel chromatography resistates, get 11.9 gram white solid title compounds.

Step 2:1-methyl fluoride-3, the preparation of 4-dihydro-isoquinoline

By with preparation 1-1 in the identical step of step 2 carry out, what just above-mentioned steps 1 made 11.9 digests compound (65mM) and is used as initiator, 7.7 gram title compounds.

Step 3:1-methyl fluoride-1,2,3, the preparation of 4-tetrahydroisoquinoline

By with preparation 1-1 in the identical step of step 3 carry out, just 7.6 digest compound (46mM) and be used as initiator through what above-mentioned steps 2 made, 7.0 gram title compounds.

Preparation 1-7:1-ethyl-1,2,3, the 4-tetrahydroisoquinoline

Be prepared by the step identical with preparation 1-1, just the propionyl chloride (90mM) with 11.3ml phenylethylamine (90mM) and 7.8ml is a starting raw material, gets 8.48 gram title compounds.

Preparation 1-8:1-cyclopropyl-1,2,3, the 4-tetrahydroisoquinoline

Being prepared by the step identical with preparation 1-1, is starting raw material with 12.5ml phenylethylamine (0.1M) and 10ml cyclopropane carbonyl chloride (0.11M) just, gets 2.5 gram title compounds.

Preparation 1-9:3-methyl isophthalic acid, 2,3, the 4-tetrahydroisoquinoline

With 3.0 gram 3-methylisoquinolinium (21mM) and 50ml methanol mixed, again to the platinum oxide that wherein adds 0.84 gram.Under the pressure of 40psi, make this mixture carry out hydrogenation and filtration.Concentrating under reduced pressure filtrate gets 3.3 gram title compounds.

Preparation 1-10:1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline

Step 1:1-methyl-N-phenyl methyl-3, the preparation of 4-dihydro-isoquinoline father-in-law bromide

What will contain that the step 2 for preparing 1-1 makes 20 digests compound (0.14M, the mixture heating up of 18ml bromotoluene (0.15M) and 150ml acetonitrile refluxed 12 hours, and was cooled to room temperature.Filter the solids that generates, the dry 22 gram title compounds that get.

Step 2:1,1-dimethyl-N-phenyl methyl-1,2,3, the preparation of 4-dihydro-isoquinoline

20 digest compound (0.06M) and 80ml anhydrous diethyl ether and mix what above-mentioned steps 1 made, to wherein splashing into 60ml methyl-magnesium-bromide (3.0M diethyl ether solution).This mixture of reflux 6 hours is cooled to room temperature, stirs then 12 hours.In reaction soln, add aqueous ammonium chloride solution, separate organic layer, use anhydrous sodium sulfate drying, concentrating under reduced pressure.The resistates that silica gel chromatography generates gets 11.4 gram title compounds.

Step 3:1,1-dimethyl-1,2,3, the preparation of 4-tetrahydroisoquinoline

The compound (44mM) that 11 gram above-mentioned steps 2 make mixes with 80ml acetate, to wherein adding 10% palladium/gac, makes it carry out hydrogenation and filtration under 40psi pressure.Concentrating under reduced pressure filtrate makes its alkalization with NaOH solution.After going out resultant with dichloromethane extraction, use the anhydrous sodium sulfate drying extract, concentrate, get 6.78 gram title compounds.

Preparation 1-11:1,8-dimethyl-1,2,3,4-tetrahydroisoquinoline

The preparation of step 1:1-(2 '-aminomethyl phenyl) ethamine

26ml 2-methyl acetanilide (0.2M) mixes with 32ml methane amide and 7.5ml formic acid, and 160 ℃ of reactions boiled off water in 5 hours simultaneously.Resultant is cooled to room temperature, uses extracted with diethyl ether.Wash extract with water, concentrating under reduced pressure adds the 20ml concentrated hydrochloric acid again, reflux 1 hour.Reaction soln is cooled to room temperature, with the ether flushing, with the neutralization of the NaOH aqueous solution.Behind the extracted with diethyl ether resultant, use the anhydrous sodium sulfate drying extract, concentrating under reduced pressure gets 16.9 gram title compounds.

The preparation of step 2N-(oxyethyl group carboxymethyl)-1-(2 '-aminomethyl phenyl) ethamine

Compound (0.124M), 17.3ml triethylamine that 16.8 above-mentioned steps 1 that restrain are made mix with the 100ml tetrahydrofuran (THF), and to the ethyl bromoacetate that wherein splashes into 13.8ml (0.124M), postheating refluxed 1 hour.Stirring at room resultant 12 hours adds ether again, behind the solids that filter to generate, water flushing filtrate, with anhydrous sodium sulfate drying it, concentrating under reduced pressure.Use the silica gel chromatography resistates, get 23.3 gram title compounds.

The preparation of step 3:N-(2-hydroxyethyl)-1-(2 '-methyl-phenyl) ethamine

With splashing under 23.3 compound (1.105M) room temperatures that make of gram above-mentioned steps 2 in the mixture of tetrahydrofuran (THF) of 3.8 gram lithium aluminium hydride (0.1M) and 150ml, stirred 30 minutes.Water is joined in the resultant, filter the solids that generates.Use anhydrous sodium sulfate drying filtrate, concentrating under reduced pressure it, 13.8 the gram title compounds.

The preparation of step 4:N-(2-bromotrifluoromethane)-1-(2 '-methyl-phenyl) ethylamine hydrochloride

The 48%HBr of 77ml is cooled to 0 ℃, in the time of 0 ℃, it is splashed into 13.8 grams in the compound (77mM) that above-mentioned steps 3 makes.Then, the reaction soln of distillation 50ml is cooled to room temperature with resistates.The solids that recrystallization obtains in the mixed solvent of ethanol and ether generates 14.75 gram title compounds.

Step 5:1,8-dimethyl-1,2,3, the preparation of 4-tetrahydroisoquinoline

Add aluminum chloride to 14.7g in the mixture of compound (45.5mM) that above-mentioned steps 4 makes and 100ml dicaine (decarine), reaction is 1.5 hours in the time of 140 ℃～150 ℃, is cooled to 0 ℃ again.Reaction mixture is poured into makes its dilution in the frozen water, and wash with ether.In reaction mixture, add the NaOH aqueous solution and make its alkalization.Filter the solids that generates.Also use the anhydrous sodium sulfate drying extract with extracted with diethyl ether filtrate.Concentrating under reduced pressure gets 3.16 gram title compounds.

Preparation 1-12:1,6-dimethyl-1,2,3,4-tetrahydroisoquinoline

Be prepared by the step identical, just restrain 4-methyl acetanilides (0.2M) as starting raw material, make 2.8 gram title compounds with 13.41 with preparation 1-11.

Preparation 1-13:1,4-dimethyl-1,2,3,4-tetrahydroisoquinoline

By being prepared with the identical step of preparation 1-1, just (β-methylphenethylamine) (0.1M) and 7.8ml Acetyl Chloride 98Min. (0.11M) make the title compound of 6.6g as starting raw material with 14.5ml Beta-methyl phenylethylamine.

Preparation 2: 2 of the general formula of replacement (II), the preparation of 4-two chloro-quinazolines

Preparation 2-1:2,4-two chloro-quinazolines

Step 1:2, the preparation of 4-two oxyquinazolines

Dropwise 54 gram potassium cyanates are dissolved in the solution that forms in the 200ml water in the mixture that contains 41 gram 2-benzaminic acid (0.3M) and 2 premium on currency and 34ml acetate.Stirred resultant 1 hour, the aqueous sodium hydroxide solution that adds 60 gram 0.3M at leisure makes temperature of reaction be no more than 40 ℃.Solution is being heated in 90 ℃, was stirring 30 minutes, be cooled to 0 ℃ then.In resultant, add the concentrated hydrochloric acid acidifying it, filter the solids that generates, the title compounds of 43.7 grams.

Step 2:2, the preparation of 4-two chloro-quinazolines

In the compound (0.5M) that above-mentioned steps 1 makes, add 200ml phosphoryl chloride and 28ml xylidine to 81 grams; Reflux resultant 5 hours.The concentrating under reduced pressure reaction mixture gets 40.2 gram light yellow solid title compounds.

Preparation 2-2:8-methoxyl group-2,4-two chloro-quinazolines

Be prepared by the step identical, just, get 36 gram title compounds with 57 gram 2-amino-3-methoxyl group-phenylformic acid (0.43M) conduct reaction starting raw material with preparing 2-1.

2-chloro-4-(-1,2,3 of replacement, the 4-tetrahydroisoquinoline-2-yl) quinazoline that in the following example 1 to 17, has prepared general formula (IV).

The preparation of embodiment 1:2-chloro-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

10 digest compound (50.2mM) and mix what preparation prepared among the 2-1, be lower than in 10 ℃, slowly splash into 6.4ml 1 in the maintenance temperature of reaction with 70ml methylene dichloride and 7.8ml triethylamine (56mM), 2,3,4-tetrahydroisoquinoline (50.2mM), stirring at room 2 hours.Use the anhydrous sodium sulfate drying reaction mixture, concentrating under reduced pressure it.Crystalline residue gets 14.6 title compounds that restrain.

The preparation of embodiment 2:2-chloro-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical with embodiment 1, just will prepare make among the 2-1 10 digest the 7.4ml compound (50.2mM) that makes among compound (50.2mM) and the preparation 1-1 as starting raw material, make the title compounds of 13.5 grams.

The preparation of embodiment 3:2-chloro-4-(1,8-ethano--1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical with embodiment 1, just will prepare make among the 2-1 2.31 digest make among compound (11.6mM) and the preparation 1-4 1.85 digest compound (11.6mM) as starting raw material, make the title compounds of 3.0 grams.

The preparation of embodiment 4:2-chloro-8-methoxyl group-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical with embodiment 1, just will prepare make among the 2-2 11.2 digest compound and 6.2

ml

1,2,3,4-tetrahydroisoquinoline (48.8mM) makes the title compounds of 14.2 grams as starting raw material.

The preparation of embodiment 5:2-chloro-8-methoxyl group-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical with embodiment 1, just will prepare make among the 2-2 3.35 digest make among compound (14.6mM) and the preparation 1-1 2.15 digest compound (14.6mM) as starting raw material, make 3.5 gram title compounds.

Embodiment 6:(R)-preparation of 2-chloro-8-methoxyl group-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical with embodiment 1, will prepare just that 2-2 makes 3.0 digest make among compound (15.1mM) and the preparation 1-2 2.22 digest compound (15.1mM) as starting raw material, make 3.64 gram title compounds.

Embodiment 7:(S)-preparation of 2-chloro-8-methoxyl group-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

By with embodiment 1 in identical step carry out, just will prepare make among the 2-2 3.0 digest make among compound (15.1mM) and the preparation 1-3 2.22 digest compound (15.1mM) as starting raw material, make 3.5 gram title compounds.

The preparation of embodiment 8:2-chloro-8-methoxyl group-4-(1-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

To preparation make among the 2-2 3.05 digest add in the mixture of dimethyl formamide of compound (13.3mM) and 20ml that preparation 1-5 makes 2.68 digest compound (13.3mM), 110 ℃ were reacted 1 hour.Reaction mixture with the methylene dichloride dilution, and washes with water, uses anhydrous sodium sulfate drying, concentrating under reduced pressure.With the resistates that silica gel chromatography generates, get 2.1 gram title compounds.

The preparation of embodiment 9:2-chloro-8-methoxyl group-4-(1-methyl fluoride-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical, just restrain and be equipped with compound (22mM) and 4 that 2-2 makes and restrain and be equipped with compound (24mM) that 1-6 makes, make 6.8 title compounds that restrain as starting raw material with 5.0 with embodiment 1.

The preparation of embodiment 10:2-chloro-8-methoxyl group-4-(1-ethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical, just restrain and be equipped with compound (15.3mM) and 2.46 that 2-2 makes and restrain and be equipped with compound (15.3mM) that 1-7 makes, make 4.07 title compounds that restrain as starting raw material with 3.5 with embodiment 1.

The preparation of embodiment 11:2-chloro-8-methoxyl group-4-(1-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical, just restrain and be equipped with compound (6.30mM) and 1.15 that 2-2 makes and restrain and be equipped with compound (6.9mM) that 1-8 makes, make 2.25 title compounds that restrain as starting raw material with 1.44 with embodiment 1.

The preparation of embodiment 12:2-chloro-8-methoxyl group-4-(3-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical, just restrain and be equipped with compound (21.8mM) and 3.3 that 2-2 makes and restrain and be equipped with compound (22.4mM) that 1-9 makes, make 2.0 title compounds that restrain as starting raw material with 5.0 with embodiment 1.

The preparation of embodiment 13:2-chloro-8-methoxyl group-4-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical, just restrain and be equipped with compound (34mM) and 6.50 that 2-2 makes and restrain and be equipped with compound (40mM) that 1-10 makes, make 4.9 title compounds that restrain as starting raw material with 7.70 with embodiment 1.

The preparation of embodiment 14:2-chloro-8-methoxyl group-4-(1,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical, just restrain and be equipped with compound (16mM) and 3.10 that 2-2 makes and restrain and be equipped with compound (19mM) that 1-11 makes, make 5.2 title compounds that restrain as starting raw material with 3.6 with embodiment 1.

The preparation of embodiment 15:2-chloro-8-methoxyl group-4-(1,6-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical, just restrain and be equipped with compound (16mM) and 2.80 that 2-2 makes and restrain and be equipped with compound (19mM) that 1-12 makes, make 5.2 title compounds that restrain as starting raw material with 3.6 with embodiment 1.

The preparation of embodiment 16:2-chloro-8-methoxyl group-4-(1,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical, just restrain and be equipped with compound (20mM) and 3.60 that 2-2 makes and restrain and be equipped with compound (22mM) that 1-13 makes, make 4.5 and restrain title compounds as starting raw material with 4.65 with embodiment 1.

The preparation of embodiment 17:2-chloro-8-methoxyl group-4-(1,8-ethano--1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

Undertaken by the step identical, just restrain and be equipped with compound (11.6mM) and 1.85 that 2-2 makes and restrain and be equipped with compound (11.6mM) that 1-4 makes, make 3.5 title compounds that restrain as starting raw material with 2.64 with embodiment 1.

Acceptable salt is made by the following example 18 to 61 on the quinazoline derivant of general formula (I) and its pharmacology.

The preparation of embodiment 18:2-(anilino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

2.0 digest and add 1.25ml aniline (13.6mM) in the mixture of compound (6.8mM) and 15ml dimethyl formamide to what embodiment 1 made, 110 ℃-120 ℃ reactions 2 hours.Resultant is cooled to room temperature, adds the NaOH aqueous solution and neutralize it, and with the dichloromethane extraction of 50ml.

Use the anhydrous sodium sulfate drying extract, concentrating under reduced pressure.Resistates with the silica gel chromatography generation.The white solid that generates is dissolved in the ether of 100ml, adds with the saturated diethyl ether solution of hydrochloric acid.The solid filtering that obtains thus, vacuum-drying gets 0.6 gram title compound.Productive rate is 23%.

M.P.：246-248℃ ¹H-NMR(DMSO-d ₆)：δ3.1(bs，2H)，4.18(bs，2H)，5.16(s，2H)，7.14-7.34(m，

5H)，7.47(t，3H)，7.62(t，3H)，7.86(t，1H)，8.22(d，1H)

10.64(s，1H)

The preparation of embodiment 19:2-(methylphenylamine base)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

Undertaken by the step identical with embodiment 18, just to 0.9 gram embodiment 1 make 0.9 digest in the mixture of compound (3mM) and 15ml dimethyl formamide add 0.4ml methylphenylamine (3.6mM)), make 0.51 and restrain title compound.

Productive rate: 42%

M.P.：206-208℃ ¹H-NMR(CDCl ₃)：δ2.90(t，2H)，3.91(t，2H)，

4.00(s，3H)，4.82(s，2H)，6.98(d，

1H)，7.14-7.54(m，9H)，7.75(t，1H)，7.86(d.1H)，8 96(d，1H)，

13.8(s，1H)

The preparation of embodiment 20:2-(4-fluoro-N-aminomethyl phenyl amino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

Undertaken by the step identical, just 1.9 gram 4-fluoro-methylphenylamines (15mM) are added in the mixture of compound (7mM) that 2.2 gram embodiment 1 make and 15ml dimethyl formamide, make 2.45 and restrain title compounds with embodiment 18.

Productive rate: 81%

M.P.：242-244℃ ¹H-NMR(DMSO-d ₆)：δ2.96(t，2H)，3.71(s，3H)，4.01(t，2H)，5.03(s，2H)，7.23

(m，4H)，7.25-7.62(m，5H)，7.84(t，1H)，8.20(t，2H)，12.70

(bd，1H)

The preparation of embodiment 21:2-(2-aminomethyl phenyl amino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

Undertaken by the step identical, just 2.2ml 2-aminotoluene (20.6mM) is added in the mixture of compound (10.3mM) that 3.05 gram embodiment 1 make and 15ml dimethyl formamide, make 0.9 and restrain title compound with embodiment 18.

Productive rate: 22%

M.P.：206-209℃ ¹H-NMR(DMSO-d ₆)：δ2.35(s，3H)，3.30(bs，2H)，4.17(bs，2H)，5.17(s，2H)，7.1

7.8(m，10H)，7.9(t，1H)，8.3(t，1H)，10.1(s，1H)

The preparation of embodiment 22:2-(4-fluoro-2-aminomethyl phenyl amino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

Undertaken by the step identical, just the 4-fluoro-2-aminotoluene (15mM) of 1.7ml is added in the mixture of compound (7mM) that 2.2 gram embodiment 1 make and 15ml dimethyl formamide, make 1.35 title compounds that restrain with embodiment 18.

Productive rate: 46%

M.P.：210-212℃ ¹H-NMR(DMSO-d ₆+TFA-d)：δ2.33(s，3H)，3.02(t，2H)，4.10(t，2H)，5.09(s.2H)，

7.25(m，6H)，7.47(t，1H)，7.58(m，2H)，7.86(t，1H)，8.20(d，

1H)，10.10(s，1H)，13.25(bd，1H)

The preparation of embodiment 23:2-(4-fluoroanilino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just the 4-fluoroaniline (20.2mM) of 1.9ml is added in the mixture of compound (10.1mM) that 3.0 gram embodiment 1 make and 20ml dimethyl formamide, make 1.05 and restrain title compounds.

Productive rate: 26%

M.P.：269-271℃ ¹H-NMR(DMSO-d ₆)：δ3.06(t，2H)，4.15(t，2H)，5.14(s，2H)，7.16-7.40(m，6H)，

7.46(t，1H)，7.63(m，3H)，7.85(t，1H)，8.21(d，1H)，10.70(s，1H)

The preparation of embodiment 24:2-(N-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just the methylphenylamine (10.1mM) of 1.1ml is added in the mixture of the compound (4.52mM) of 1.4 gram embodiment, 2 preparations and 15ml dimethyl formamide, make 1.02 and restrain title compounds.

Productive rate: 54%

M.P.：213-215℃ ¹H-NMR(DMSO-d ₆)：δ1.23-1.64(m，2H)，2.69-3.30(m，2H)，3.44-3.75(m，1H)，

3.98(s，3H)，4.26-4.47(m，1H)，5.23-5.40(m，1H)，7.17-7.56

(m，2H)，7.70-7.83(m，9H)，8.94(d，1H)，13.88(s，1H)

The preparation of embodiment 25:2-(4-fluoroanilino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just the 4-fluoroaniline (8.54mM) of 0.81ml is added in the mixture of compound (4.07mM) that 1.26 gram embodiment 2 make and 15ml dimethyl formamide, make 1.59 and restrain title compounds.

Productive rate: 93%

M.P.：250-252℃ ¹H-NMR(CDCl ₃)：δ1.68-1.87(m，3H)，2.96-3.42(m，2H)，3.74-3.88(m，1H)，

4.64-4.72(m，1H)，5.67-5.73(m，1H)，7.03-7.96(m，12H)，

10.65(s，1H)，13.84(s，1H)

The preparation of embodiment 26:2-(4-fluoro-2-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 14, just the 4-fluoro-2-aminotoluene (10.9mM) of 0.89ml is added in the mixture of compound (5.20mM) that 1.61 gram embodiment 2 make and 15ml dimethyl formamide, make 1.76 and restrain title compounds.

Productive rate: 78%

M.P.：260-263℃ ¹H-NMR(CDCl ₃)：δ1.54-1.82(m，3H)，2.43(s，3H)，2.85-3.38(m，2H)，3.61-3.37

(m，1H)，4.52-4.65(m，1H)，5.60(q，1H)，6.90-7.07(m，3H)，

7.17-7.27(m，3H)，7.34-7.50(m，2H)，7.67-7.78(m，2H)，

7.89(d，1H)，10.02(s，1H)，14.18(s，1H)

Embodiment 27:2-(the preparation of 4-fluoro-2-methylbenzene amino-4-(1,8-ethano--1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just the 4-fluoro-2-aminotoluene (9.79mM) of 0.80ml is added in the mixture of compound (4.46mM) that 1.50 gram embodiment 3 make and 15ml dimethyl formamide, make 1.64 and restrain title compounds.

Productive rate: 79%

M.P.：248-250℃ ¹H-NMR(CDCl ₃)：δ1.55-1.78(m，1H，)，2.33(s，3H)，2.53-2.99(m，4H)，3.82-

4.02(m，1H)，4.37-4.50(m，1H)，5.02-5.30(m，1H)，6.60-7.01

(m，5H)，7.43(t，1H)，7.59-7.67(m，2H)，7.86(t，1H)，8.14(d，

1H)，10.13(s，1H)，13.40(s，1H)

The preparation of embodiment 28:8-methoxyl group-2-(phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 0.65ml aniline (6.9mM) is added in the mixture of compound (4.6mM) that 1.5 gram embodiment 4 make and 15ml dimethyl formamide, make 1.40 and restrain title compounds.

Productive rate: 73%

M.P.：181-183℃ ¹H-NMR(DMSO-d ₆)：δ3.14(t，2H)，4.06(s，3H)，4.23(t，2H)，5.14(s，2H)，7.05-7.40

(m，9H)，7.50(d，1H)，7.74(d，2H)，11.90(s，1H)，12.89(s，1H)

The preparation of embodiment 29:8-methoxyl group-2-(N-aminomethyl phenyl amino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just the methylphenylamine (12.28mM) of 1.46ml is added in the mixture of compound (6.14mM) that 2.0 gram embodiment 4 make and 15ml dimethyl formamide, make 1.5 and restrain title compounds.

Productive rate: 56%

M.P.：90-92℃ ¹H-NMR(DMSO-d ₆)：δ3.12(t，2H)，3.83(s，3H)，3.96(s，3H)，4.24(t，2H)，5.15(s，

2H)，7.10-7.26(m，5H)，7.28-7.72(m，7H)

The preparation of embodiment 30:8-methoxyl group-2-(4-fluorophenyl amino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just the 4-fluoroaniline (9.2mM) of 0.85ml is added in the mixture of compound (4.6mM) that 1.5 gram embodiment 4 make and 15ml dimethyl formamide, make 1.3 title compounds that restrain.

Productive rate: 65%

M.P.：239-241℃ ¹H-NMR(DMSO-d ₆)：δ3.12(t，2H)，4.07(s，3H)，4.20(t，2H)，5.12(s，2H)，6.98-7.49

(m，3H)，7.40-7.68(m，8H)，11.80(bs，1H)

The preparation of embodiment 31:8-methoxyl group-2-(4-fluoro-2-methylbenzene amino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 1.7ml 4-fluoro-2-aminotoluene (20mM) is added in the mixture of compound that 3.26 gram embodiment 4 make and 15ml dimethyl formamide, make 2.5 gram title compounds.

Productive rate: 55%

M.P.：195-197℃ ¹H-NMR(DMSO-d ₆)：δ2.42(s，3H)，3.01(t，2H)，4.09(t，2H)，4.10(s，3H)，5.00(s，

2H)，6.80-7.56(m，11H)，11.20(s，1H)

The preparation of embodiment 32:8-methoxyl group-2-(4-fluoro-N-methylbenzene amino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 1.5 gram 4-fluoro-methylphenylamines (12.2mM) are added in the mixture of compound that 2.0 gram embodiment 4 make and 15ml dimethyl formamide, make 1.05 gram title compounds.

Productive rate: 38%

M.P.：93-95℃ ¹H-NMR(DMSO-d ₆)：δ3.08(t，2H)，3.88(s，3H)，4.01(s，3H)，4.16(t，2H)，5.06(bs，

2H)，7.08-7.60(m，11H)

The preparation of embodiment 33:8-methoxyl group-2-(4-fluoroanilino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just the 4-fluoroaniline (9.27mM) of 0.88ml is added in the mixture of compound (4.4mM) that 1.50 gram embodiment 5 make and 15ml dimethyl formamide, make 0.97 and restrain title compound.

Productive rate: 49%

M.P.：155-157℃ ¹H-NMR(CDCl ₃)：δ1.58-1.98(m，3H)，2.85-3.46(m，2H)，3.73-3.97(m，1H)，

4.07(s，3H)，4.64-4.77(m，1H)，5.73(q，1H)，7.03-7.67(m，

11H)，11.85(s，1H)，12.82(s，1H)

The preparation of embodiment 34:8-methoxyl group-2-(4-fluoro-2-methylbenzene amino-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just the 4-fluoro-2-aminotoluene (9.27mM) of 0.75ml is added in the mixture of compound (4.41mM) that 1.50 gram embodiment 5 make and 15ml dimethyl formamide, make 0.78 and restrain title compound.

Productive rate: 38%

M.P.：231-233℃ ¹H-NMR(CDCl ₃)：δ1.51-1.90(m，3H)，2.42(s，3H)，2.84-3.35(m，2H)，3.57-3.81

(m，1H)，4.10(s，3H)，4.51-4.66(m，1H)，5.58(q，1H)，6.89-7.44

(m，11H)，11.12(s，1H)，13.16(s，1H)

Embodiment 35:(R)-preparation of 8-methoxyl group-2-(4-fluoro-2-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just the 4-fluoro-2-aminotoluene (16.3mM) of 1.33ml is added in the mixture of compound (7.77mM) that 2.64 gram embodiment 6 make and 15ml dimethyl formamide, make 1.50 and restrain title compounds.

Productive rate: 42%

M.P.：230-233℃ ¹H-NMR(CDCl ₃)：δ1.51-1.90(m，3H)，2.42(s，3H)，2.84-3.35(m，2H)，3.57-3.81

(m，1H)，4.10(s，3H)，4.51-4.66(m，1H)，5.58(q，1H)，6.89-7.44

(m，11H)，11.12(s，1H)，13.16(s，1H)

Embodiment 36:(S)-preparation of 8-methoxyl group-2-(4-fluoro-2-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just the 4-fluoro-2-aminotoluene (16.3mM) of 1.33ml is added in the mixture of compound (7.77mM) that 2.64 gram embodiment 7 make and 15ml dimethyl formamide, make 1.60 title compounds that restrain.

Productive rate: 44%

M.P.：230-232℃ ¹H-NMR(CDCl ₃)：δ1.51-1.90(m，3H)，2.42(s，3H)，2.84-3.35(m，2H)，3.57-3.81

(m，1H)，4.10(s，3H)，4.51-4.66(m，1H)，5.58(q，1H)，6.89-7.44

(m，11H)，11.12(s，1H)，13.16(s，1H)

The preparation of embodiment 37:8-(2-hydroxyl-oxethyl)-2-(4-fluoro-2-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

The preparation of step 1:8-hydroxyl-2-(4-fluoro-2-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

In the time of 0 ℃, 48ml tribromo borane (tribromoboran) is added in the mixture of compound (9.6mM) that 4.1 gram embodiment 34 make and 50ml methylene dichloride.Stirring at room resultant 14 hours is then with in its impouring frozen water.Filter the solid that generates, and it is dissolved in the methylene dichloride, add the NaOH aqueous solution and neutralize it.The separate dichloromethane layer, anhydrous sodium sulfate drying it.Concentrate and obtain 2.4 gram title compounds.

Productive rate: 60% ¹H-NMR (DMSO-d ₆): δ 1.48 (m, 3H), 2.07 (s, 3H), 2.59 (t, 1H), 3.00 (m, 1H), 3.42 (t,

1H)，5.58(q，1H)，6.80-7.20(m，9H)，7.40(d，1H)，9.40(s，1H)，

11.40(s，1H)

The preparation of step 2:8-(ethoxycarbonyl methoxy)-2-(4-fluoro-2-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

In the time of 0 ℃, compound (5.8mM) 2.4 grams that above-mentioned steps 1 is made splash in the mixture of 0.2 gram 65% sodium hydride (5.8mM) and 15ml dimethyl formamide, stir subsequently 30 minutes.And then, stirred 1 hour to wherein splashing into 0.65ml ethyl bromoacetate (5.8mM).Add water in the resultant, and the adding sodium bicarbonate neutralizes it.After going out resultant with dichloromethane extraction,, concentrate the dichloromethane layer dehydration.Use ether: hexane (1: 2), purifying resistates on the exsiccant silica gel column chromatography gets 2.0 gram title compounds.

Productive rate: 70% ¹H-NMR (DMSO-d ₆): δ 1.30 (t, 3H), 1.48 (m, 3H), 2.07 (s, 3H), 2.59 (t, 1H), 3.00 (m,

1H)，3.42(t，1H)，4.30(q，2H)，4.85(s，2H)，5.58(q，1H)，6.80-

7.20(m，9H)，7.40(d，1H)，9.40(s，1H)，

The preparation of step 3:8-(2-hydroxyl-oxethyl)-2-(4-fluoro-2-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline

At 0 ℃, compound (3.0mM) that make with above-mentioned steps 2 and that be dissolved in the gram of 1.5 in the tetrahydrofuran (THF) splashes in the mixture of 0.12 gram lithium aluminium hydride (3.0mM) and 30ml tetrahydrofuran (THF), stirs 1 hour.In reaction soln, add water and use dichloromethane extraction.Dehydration concentrates dichloromethane layer, and uses silica gel chromatography, gets 0.80 gram title compound.

Productive rate: 58%

M.P.：120-122℃ ¹H-NMR(DMSO-d ₆)：δ1.48(m，3H)，2.07(s，3H)，2.59(t，1H)，3.00(m，1H)，3.42(t，

1H)，3.90-4.20(m，4H)，5.58(q，1H)，6 80-7.20(m，9H)，7.40(d，

1H)，9.40(s，1H)

The preparation of embodiment 38:2-(4-fluoro-2-aminomethyl phenyl amino)-8-oxyethyl group-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

Compound (4.8mM) with 2.0 gram embodiment, 37 steps 1 make splashes in the time of 0 ℃ in the mixture of 0.2 gram 65% sodium hydride (5.8mM) and 15ml dimethyl formamide, stirs subsequently 30 minutes.Then to the mixture that wherein adds 0.4ml iodoethane (4.8mM) and 5ml dimethyl formamide again, stirring at room 2 hours.In resultant, add water, and the adding sodium bicarbonate neutralizes it.Behind the ethyl acetate extraction resultant, dehydration concentrates this ethyl acetate layer.Use the silica gel chromatography resistates, and be dissolved in the ether; Again to wherein adding hydrochloric acid.Filter the solid that generates, vacuum-drying gets 0.52 gram title compound.

Productive rate: 22%

M.P.：165-170℃1H-NMR(CDCl3)：δ1.54-1.76(m，6H)，2.40(s，3H)，2.80-3.32(m，2H)，3.54-3.80

(m，1H)，4.28(q，2H)，4.48-4.62(m，1H)，5.52(q，1H)，6.92-7.04(m，3H)，

7.15-7.41(m，7H)，11.22(s，1H)，13.00(s，1H)

The preparation of embodiment 39:2-(4-fluoro-2-methylbenzene amino)-8-(methylthio group methoxyl group)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 38, just with 0.2 gram 65% sodium hydride (5.8mM), compound (4.8mM) that 2.0 gram embodiment, 37 steps 1 make and 0.4ml methylthio group methyl chloride (4.8mM) make 0.52 and restrain title compound as starting raw material.

Productive rate: 7.1%

M.P.：94-96℃1H-NMR(CDCl3)：δ1.65-1.76(d，3H)，2.32(s，6H)，2.76(d，1H)，3.30(m，1H)，3.60(t，1H)，

4.38(m，1H)，5.42(m，3H)，6.68(s，1H)，6.90(d，2H)，7.00-7.20(m，5H)，

7.50(d，1H)，7.92(m，1H)

The preparation of embodiment 40:8-methoxyl group-2-(N-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 2.00ml methylphenylamine (18.45mM) is added in the mixture of compound (8.82mM) that 8.00 gram embodiment 5 make and 15ml dimethyl formamide, 0.85 restrain title compound.

Productive rate: 22%

M.P.：93-95℃ ¹H-NMR(CDCl ₃)：δ1.63(bs，3H)，2.80-3.36(m，2H)，3.50-4.00(m，1H)，4.47-

4.57(m，1H)，5.59-5.69(m，1H)，7.21-7.68(m，12H)，10.44(s，

1H)

The preparation of embodiment 41:8-methoxyl group-2-(4-fluoro-N-methylbenzene amino)-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 0.77 gram 4-fluoro-methylphenylamine (6.18mM) is added in the mixture of compound (2.94mM) that 1.00 gram embodiment 5 make and 15ml dimethyl formamide, make 0.66 and restrain title compound.

Productive rate: 44%

M.P.：100-103℃ ¹H-NMR(CDCl ₃)：δ1.58-1.82(m，1H)，2.82-3.61(m，2H)，3.67-4.05(m，1H)，

4.51-4.64(m，1H)，5.51-5.63(m，1H)，7.00-7.13(m，11H)，

9.80(bs，1H)

The preparation of embodiment 42:2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 0.82ml 4-fluoro-2-aminotoluene (10.1mM) is added in the mixture of compound (4.82mM) that 1.9 gram embodiment 8 make and 15ml dimethyl formamide, make 1.32 and restrain title compounds.

Productive rate: 53%

M.P.：158-160℃1H-NMR(CDCl3)：δ2.38(s，3H)，2.97-3.30(m，2H)，3.98-4.18(m，4H)，4.65-4.82(m，1H)，

6.301(q，1H)，6.85-7.00(m，2H)，7.15-7.38(m，7H)，7.50(d，1H)，

11.40(s，1H)，14.40(s，1H)，14.55(s，1H)

The preparation of embodiment 43:2-(4-fluoroanilino)-8-methoxyl group-4-(1-methyl fluoride-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 1.9ml 4-fluoroaniline (20.0mM) is added in the mixture of compound (9mM) that 3.3 gram embodiment 9 make and 15ml dimethyl formamide, 0.61 restrain title compound.

Productive rate: 14.5%

M.P.：208-211℃1H-NMR(CDCl3)：δ3.02(bd，1H)，3.25(m，1H)，3.94(bd，1H)，4.06(s，3H)，4.74(d，2H)，

5.00(m，1H)，6.02(tt，1H)，7.08(t，2H)，7.20(m，6H)，7.58(m，3H)，

11.90(s，1H)，12.96(s，1H)

The preparation of embodiment 44:2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1-methyl fluoride-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 2.2ml 4-fluoro-2-aminotoluene (20mM) is added in the mixture of compound (9.0mM) that 3.3 gram embodiment 9 make and 15ml dimethyl formamide, make 0.65 and restrain title compound.

Productive rate: 15%

M.P.：122-130℃1H-NMR(CDCl3)：δ2.40(s，3H)，2.84-2.95(bd，2H)，3.15(bd，1H)，4.86(bd，1H)，4.10(s，3H)，

4.62(bd，1H)，4.64-4.88(dd，2H)，5.80(tt，1H)，6.90-7.08(m，3H)，

7.19-7.40(m，6H)，7.62(d，1H)

The preparation of embodiment 45:8-methoxyl group-2-(4-fluoroanilino)-4-(1-ethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 0.65m1 4-fluoroaniline (6.95mM) is added in the mixture of compound (4.63mM) that 1.50 gram embodiment 10 make and 15ml dimethyl formamide, make 1.20 and restrain title compounds.

Productive rate: 56%

M.P.：187-189℃ ¹H-NMR(DMSO-d ₆)：δ0.82(t，3H)，1.90(bs，1H)，2 08(m，1H)，3.10(m，3H)，4.02(s，

3H)，4.15(bs，1H)，4.51(m，1H)，5.70(t，1H)，7.20-7.80(m，

11H)，11.20(s，1H)，12.05(s，1H)

The preparation of embodiment 46:8-methoxyl group-2-(2-methyl-4-fluoroanilino)-4-(1-ethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 0.80ml 2-methyl-4-fluoroaniline (9.73mM) is added in the mixture of compound (4.63mM) that 1.5 gram embodiment 10 make and 1.5ml dimethyl formamide, make 0.70 and restrain title compound.

Productive rate: 32%

M.P.：145-147℃ ¹H-NMR(DMSO-d ₆)：δ0.66(t，3H)，1.72(bs，1H)，1.94(m，1H)，2.32(s，3H)，3.06

(m，3H)，3.96-4.20(bs+s，4H)，4.40(m，1H)，5.45(t，1H)，7.00-

7.80(m，10H)，10.58(bs，1H)，12.42(bs，1H)

The preparation of embodiment 47:2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1-cyclopropyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By preparing, just in the mixture of compound (6.15mM) that 1.05ml 4-fluoro-2-aminotoluene (12.9mM) adding 2.25 gram embodiment 11 are made and 15ml dimethyl formamide, make 2.5 gram title compounds with embodiment 18 described same steps as.

Productive rate: 71%

M.P.：134-136℃1H-NMR(CDCl3)：δ0.10-0.50(m，3H)，0.52-0.66(m，1H)，1.16-1.36(m，1H)，2.39

(s，1H)，3.00-3.40(m，2H)，4.08-4.25(m，4H)，4.50-4.70(m，

1H)，5.36(d，1H)，6.87-7.05(m，3H)，7.16-7.36(m，6H)，7.48

(d，1H)，11.10(d，1H)，13.04(s，1H)

The preparation of embodiment 48:2-(4-fluoroanilino)-8-methoxyl group-4-(3-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 0.7ml 4-fluoroaniline (6.6mM) is added in the mixture of compound (4.4mM) that 1.5 gram embodiment 12 make and 15ml dimethyl formamide, make 0.7 and restrain title compound.

Productive rate: 35%

M.P.：150-153℃1H-NMR(CDCl3)：δ1.38(d，3H)，2.80(d，1H)，3.37(d，1H)，4.08

(s，3H)，4.92(d，1H)，5.30(m，2H)，6.90-7.40(m，

8H)，7.40-7.70(m，3H)，11.90(s，1H)，12.80(s，1H)

The preparation of embodiment 49:2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(3-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 1.1ml 4-fluoro-2-aminotoluene (8.9mM) is added in the mixture of compound (5.9mM) that 2.0 gram embodiment 12 make and 15ml dimethyl formamide, make 0.8 and restrain title compound.

Productive rate: 29%

M.P.：214-217℃1H-NMR(CDCl3)：δ1.30(d，3H)，2.40(s，3H)，2.70(d，1H)，3.22

(d，1H)，4.10(s，3H)，4.86(m，1H)，5.10-5.30(m，

2H)，6.90-7.50(m，10H)，11.20(s，1H)，13.20(s，1H)

Embodiment 50:2-(4-fluoroanilino)-8-methoxyl group-4-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) preparation of quinazoline hydrochloride is by the step preparation identical with embodiment 18, just in the mixture of compound (5.0mM) that 1.10ml 4-fluoroaniline (11mM) adding 1.80 gram embodiment 13 are made and 10ml dimethyl formamide, make 1.14 gram title compounds.

Productive rate: 49%

M.P.：134-138℃1H-NMR(CDCl3)：δ1.75(s，6H)，3.22(t，2H)，4.00(t，2H)，4.09(s，3H)，7.13(m，

6H)，7.25(m，2H)，7.40(m，3H)，11.62(s，1H)，13.08(s，1H)

The preparation of embodiment 51:2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 1.20ml 4-fluoro-2-aminotoluene (11mM) is added in the mixture of compound (5.0mM) that 1.80 gram embodiment 13 make and 10ml dimethyl formamide, make 0.81 and restrain title compound.

Productive rate: 34%

M.P.：176-180℃1H-NMR(CDCl3)：δ1.56(s，6H)，2.36(s，3H)，3.21(t，2H)，3.98(t，2H)，4.11(s，

3H)，6.94(m，2H)，7.16-7.38(m，8H)，11.22(s，1H)，13.40(s，

1H)

The preparation of embodiment 52:2-(4-fluoroanilino)-8-methoxyl group-4-(1,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 1.9ml 4-fluoroaniline (20mM) is added in the mixture of compound (9mM) that 3.3 gram embodiment 14 make and 15ml dimethyl formamide, make 1.14 and restrain title compounds.

Productive rate: 49%

M.P.：134-138℃1H-NMR(CDCl3)：δ1.74(s，3H)，1.23(d，3H)，2.82-3.37(m，2H)，3.68-3.84(m，

1H)，4.05(s，3H)，4.58-4.80(m，1H)，5.66(q，1H)，6.90-7.32

(m，7H)，7.45(d，1H)，7.58-7.66(m，2H)，11.20(s，1H)

The preparation of embodiment 53:2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 1.21ml 4-fluoro-2-aminotoluene (14.9mM) is added in the mixture of compound (7.06mM) that 2.50 gram embodiment 14 make and 15ml dimethyl formamide, make 0.70 and restrain title compound.

Productive rate: 21%

M.P.：128-131℃1H-NMR(CDCl3)：δ1.56(s，3H)，2.22(s，3H)，2.31(s，3H)，2.74-3.20(m，2H)，

3.62-3.79(m，1H)，3.98(s，3H)，4.36-4.52(m，1H)，5.50(q，

1H)，6.80-7.25(m，5H)，7.38-7.50(m，2H)，7.53-7.77(m，

2H)，10.28(s，1H)，12.35(s，1H)

The preparation of embodiment 54:2-(4-fluoroanilino)-8-methoxyl group-4-(1,6-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 1.40ml 4-fluoroaniline (14.8mM) is added in the mixture of compound (7.06mM) that 2.50 gram embodiment 15 make and 10ml dimethyl formamide, make 2.0 and restrain title compounds.

Productive rate: 61%

M.P.：124-128℃1H-NMR(CDCl3)：δ1.73(bs，3H)，2.32(s，3H)，2.88-3.38(m，2H)，3.66-3.86(m，

1H)，4.07(s，3H)，4.60-4.74(m，1H)，5.70(q，1H)，6.96-7.18

(m，6H)，7.31(t，1H)，7.45(d，1H)，7.60-7.77(m，2H)，11.80

(s，1H)，12.76(s，1H)

The preparation of embodiment 55:2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1,6-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 1.21ml 4-fluoro-2-aminotoluene (14.9mM) is added in the mixture of compound (7.06mM) that 2.50 gram embodiment 15 make and 10ml dimethyl formamide, make 1.10 and restrain title compounds.

Productive rate: 33%

M.P.：130-135℃1H-NMR(CDCl3)：δ1.63(bs，3H)，2.42(s，3H)，2.70-3.30(m，2H)，3.31(s，3H)，

3.62-3.79(m，1H)，3.50-3.85(m，1H)，4.09(s，3H)，4.50-4.62

(m，1H)，5.55(q，1H)，6.80-7.22(m，6H)，7.28(t，1H)，7.37-

7.46(m，2H)，11.11(m，2H)，13.12(s，1H)

The preparation of embodiment 56:2-(4-fluoroanilino)-8-methoxyl group-4-(1,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 1.90 milliliters of 4-fluoro-2-aminotoluenes (20mM) are added in the mixture of compound (8.40mM) that 3.00 gram embodiment 16 make and 10ml dimethyl formamide, make 1.10 and restrain title compounds.

Productive rate: 30%

M.P.：145-149℃1H-NMR(CDCl3)：δ1.42(d，3H)，1.83(bd，3H)，3.24(bd，2H)，4.08(s，3H)，4.60

(bd，1H)，5.72(q，1H)，6.84(t，1H)，7.10(m，2H)，7.30(m，

6H)，7.63(m，1H)，11.80(s，1H)，12.78(bd，1H)

The preparation of embodiment 57:2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 2.20ml 4-fluoro-2-aminotoluene (20mM) is added in the mixture of compound (8.76mM) that 3.10 gram embodiment 16 make and 10ml dimethyl formamide, make 1.40 and restrain title compounds.

Productive rate: 34%

M.P.：135-139℃1H-NMR(CDCl3)：δ1.12-1.37(bd，3H)，2.40(s，3H)，3.20(bd，2H)，4.12(s，3H)，

4.43(q，1H)，5.57-5.76(qq，1H)，6.95(m，3H)，7.30(m，5H)，

7.42(m，2H)，10.82(bd，1H)

The preparation of embodiment 58:8-methoxyl group-2-(4-fluoroanilino)-4-(1,8-ethano--1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 0.5ml 4-fluoroaniline (4.6mM) is added in the mixture of compound (3.10mM) that 1.10 gram embodiment 17 make and 15ml dimethyl formamide, make 0.9 and restrain title compound.

Productive rate: 63%

M.P.：186-196℃ ¹H-NMR(CDCl ₃)：δ1.78(m，1H，)，2.70-3.05(m，4H)，3.90(m，1H)，4.06(s，3H)，

4.48(d，1H)，5.38(m，1H)，7.09-7.40(m，6H)，7.52(d，1H)，7.70

(d，3H)，11，18(s，1H)，12.10(bs，1H)，

The preparation of embodiment 59:8-methoxyl group-2-(4-fluoro-2-methylbenzene amino)-4-(1,8-ethano--1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline hydrochloride

By the step preparation identical with embodiment 18, just 0.80ml 4-fluoro-2-aminotoluene (9.79mM) is added in the mixture of compound (4.46mM) that 1.50 gram embodiment 17 make and 15ml dimethyl formamide, make 1.64 and restrain title compounds.

Productive rate: 37%

M.P.：195-197℃ ¹H-NMR(CDCl ₃)：δ1.60(m，1H，)，2.33(s，3H)，2.42-2.93(m，4H)，3.90(m，1H)，

4.06(s，3H)，4.48(m，1H)，5.10(m，1H)，7.10-7.80(m，9H)，

10.40(bs，1H)，12.40(bs，1H)

The preparation of embodiment 60:2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline mesylate

0.2ml mesylate (3.08mM) is splashed in the mixture of 1.20 compounds (2.80mM) that make of gram embodiment 34 and 50ml methylene dichloride stirring at room resultant 30 minutes, concentrating under reduced pressure.Add the resistates that the ether recrystallization generates, get 1.32 gram title compounds.

Productive rate: 90%

M.P.：109-115℃1H-NMR(CDCl3)：δ1.40-1.80(m，3H)，2.35(s，3H)，2.93-3.40(m，5H)，3.58-3.90

(m，1H)，4.11(s，3H)，4.48-4.63(m，1H)，5.53(q，1H)，6.89-

7.04(m，3H)，7.17-7.25(m，4H)，7.31-7.46(m，3H)，10.08(s，

1H)，12.43(s，1H)

The preparation of embodiment 61:2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1-methyl isophthalic acid, 2,3,4-tetrahydroisoquinoline-2-yl) quinazoline malate

The compound (2.80mM) that 1.20 gram embodiment 34 are made splashes in the oxysuccinic acid (2.33mM) and 50ml alcoholic acid mixture of 0.27 gram.Stirring at room resultant 12 hours, and concentrating under reduced pressure.Add the resistates that ether and re-crystallizing in ethyl acetate generate, get 1.15 gram title compounds.

Productive rate: 75%

M.P.：190-192℃1H-NMR(CDCl3)：δ1.44-1.70(m，3H)，2.32(s，3H)，2.80-3.28(m，2H)，3.55-3.75

(m，1H)，4.11(s，3H)，4.43-4.60(m，1H)，5.53(q，1H)，6.35

(s，3H)，6 89-7.04(m，3H)，7.17-7.35(m，6H)，7.43(d，1H)，

12.00(s，1H)，13.10(s，1H)

Experimental example proton pump (H ⁺/ K ⁺The ATP enzyme) active inhibition

1-1: the preparation in proton pump enzyme source

Knock head and kill new zealand white rabbit, take out its stomach.Remove stomach content normal saline washing coat of the stomach.With pulling out sheet scraping stomach inwall, with Te Fulong-glass homogenizer cell that homogeneous obtains in 0.25M sucrose damping fluid.With 10, the centrifugal homogeneous solution of the speed of 000g 10 minutes, again with 20, the further centrifuged supernatant of the speed of 000g 20 minutes.With 180, the centrifugal supernatant liquor that obtains of the ultra-high speed of 000g 1 hour.Abandon supernatant collecting precipitation thing, this throw out suspends in the Tris-HCl damping fluid of pH 7.2 at 50mM.With the described suspension of identical damping fluid (1,000 times of volume) dialysis 3 hours, and in liquid nitrogen, preserve.

Carry out above-mentioned centrifugal and dialysis at 4 ℃.De microbody (microsomes) is as the enzyme source of vitro enzyme repercussion study proton pump thus.

1-2: the active mensuration of proton pump

Adopt the vitro enzyme repercussion study to measure the present invention's compound to the active inhibition effect of proton pump.Use Mg ⁺⁺The proton pump that stimulates is active in negative comparative group, and uses Mg ⁺⁺And K ⁺The activity that stimulates is with making positive comparative group.Control compounds is that azoles draws in Australia U.S.A.

Test tube is divided into 4 groups: organize 1 negative comparative group (n=3), organize 2 positive comparative group (n=3), the group of group 3 (n=5) for taking The compounds of this invention, and organize 4 for taking the control compounds group.Employing is drawn azoles mensuration group 3 and is organized 4 the active inhibition effect of proton pump through compound and Australia U.S.A that embodiment 34 makes, and each group all is dissolved in the methyl-sulphoxide with 5 different concentration.

In

group

1,2,3 and 4 every group, add 0.1ml and be dissolved in the enzyme source that the experiment 1-1 of the magnesium chloride (40mM) of 50mM Tris-HCl damping fluid (pH 7.2) and 50 μ g makes.Then, the ammonium chloride (100mM) that is dissolved in Repone K (500mM) in the 50mM Tris-HCl damping fluid (pH 7.2) and 0.1ml with 0.1ml adds in organizing each group 1.

With 0.1ml methyl-sulphoxide adding group 1 and group 2; Add the compound that embodiment 34 makes in the group 3, this compound is dissolved in methyl-sulphoxide with 5 kinds of different concns and makes the solution use.Add 0.01ml in the group 4 and be dissolved in the solution that the Australia U.S.A in the methyl-sulphoxide draws azoles to make with 5 kinds of different concns, these 5 kinds of concentration are respectively 37.6,21.4,12.2,7.0 and 4.0 μ M.In the middle of them, add 50mM Tris-HCl damping fluid again so that cubic capacity reaches 0.4ml.

After, each group test tube is placed 37 ℃ of following pre-reactions 15 minutes.Add 0.1ml ATP solution (33.3mM) and reach 0.5ml until reaction volume, this ATP solution is Tris-ATP (50mM) to be added in the Tris-HCl damping fluid of pH.7.2 make.MgCl ₂, KCl, NH ₄, ATP, the ultimate density of enzyme and Tris-HCl is respectively 8mM, 100mM, 20mM, 6.7mM, 100 μ g/ml and 50mM., add 25% cold trichoroacetic acid(TCA) and stop enzyme reaction after 30 minutes 37 ℃ of reactions.(SBA 300, Gilford) measure the inorganic phosphate that discharges with automatic analyser.

Group 1 is represented just K with group 2 different significancees ⁺The activity of activated proton pump.Inhibition percentage through Litchfield-wilcoxon equation (referring to J.Pharmacol.Exptl.Ther.96,99 (1949)) calculating group 3 and group 4.Table 1 is represented IC ₅₀The time suppress the liquid degree of the test compound of proton pump activity.

The inhibition of experimental example 2 stomachial secretions

Press people's disclosed methods such as Shay (et al., Gastroenterology 5,43-61 (1945) for Shay, H.) and experimentize 2.

With body weight is that 170 ± 10 Spragae-Dawley rats that restrain are divided into 3 groups (n=5), and fasting is 24 hours before the experiment, freely drinks water.The etherization hara kiri pulls away pylorus.Group 1 as comparative group feeds 0.5ml/200g 30% polyethylene glycerine 400 (polyethyleneglyceol 400) aqueous solution through duodenum.Group 2 and group 3 are drawn azoles through composition and Australia U.S.A that duodenum feeds embodiment 34 respectively, and the both is suspended in respectively in 30% polyethylene glycerine, 400 aqueous solution, and its concentration is 20mg/kg.After closing the abdominal cavity, rat was left standstill 5 hours, killed it through disconnected neck then.Take out stomach and get gastric juice.

Remove precipitation with the centrifugal gastric juice of the speed of 1000g.Measure gastric juice amount and acidity.With formula (I), (II) and (III) calculate the relative capacity that test compound causes, relative acid concentration and relative sour discharge, it the results are shown in Table 2.

The average gastric juice amount relative capacity of the average gastric juice amount-group 2 of group 1=

(I)

The average gastric juice amount of the average gastric juice amount-group 3 of group 1

The relative acid concentration of average acidity of the average acidity-group 2 of group 1=

(II)

The average acidity of the average acidity-group 3 of group 1

The acid outflow total amount acid relatively of the acid outflow total amount-group 2 of group 1=

(III) the acid outflow total amount experimental example 3 secretion inhibitor effects of total amount-group 3 are flowed out in the acid of discharge group 1

Press people's such as Ghosh and Shild method (Ghosh ﹠amp; Shild, et al., BritishJournal of Pharmacology13:54-61 (1958)), the secretion inhibitor effect of research trial material in this experiment.

3-1: the secretion inhibitor effect of substances when stimulating stomachial secretion with histamine (histamine)

With body weight is that 200 ± 20 Sprague-Pawley male rats that restrain are divided into 3 groups, and the 1st group of compound of giving embodiment 34 given SK﹠amp for the 2nd group; F96067 (referring to Keeling, D.J.et al., Biochemical Pharmacology 42,1,123-130 (1991)), and the 3rd group given Australia U.S. azoles.Fasting is 24 hours before every group the rat experiment, freely drinks water.Intraperitoneal anaesthetizes for the 20% urethane aqueous solution of ester of 1.5g/kg, rat is placed on to heat on the test board keep 37 ℃.Its right jugular vein intubate of rat of anesthesia is to feed test compound, and left jugular vein intubate is to feed excitor substance.Behind the abdominal incision, will manage and insert oesophagus and duodenum, physiological saline is connected in each pipe and thermostatted and the composition collector.Pour into the physiological saline that picks up from thermostatted with peristaltic pump in oesophagus and duodenum, its filling rate is 1ml/ minute.

Jugular vein feeds the compound that embodiment 34 makes to the right, and as the SK﹠amp of comparative compound; Azoles draws in F96067 and Australia U.S.A, and every kind of compound is dissolved in ethanol respectively, in 40% polyethylene glycerine or the physiological saline.Jugular vein feeds histamine as the stomachial secretion stimulator left.

At first pouring into physiological saline in stomach collected with per 10 minutes through the composition collector at interval with the perfusion thing that contains gastric juice.When stomachial secretion reaches equilibrium state, approximately need more than 60 minute, to stimulate stomachial secretion, collected perfusion liquid 60 minutes at interval with per 10 minutes with 4mg/2ml/200g/ hour dosage perfused tissue amine simultaneously.

In the time of the continous pouring histamine, make compound, SK﹠amp with the embodiment 34 of the different concns shown in the table 3; F96067 and Australia U.S.A draw the azoles vein to inject the right jugular vein of the 1st, 2 and 3 group of rat; Collect perfusion liquid then.Measure to collect the capacity of composition and acidity to calculate μ M/ minute sour discharge.

The stomachial secretion of calculating test compound with following formula suppresses (%):

Wherein:

A is the hydrochloric acid in gastric juice discharge (μ mol/10 minute) that feeds the one-tenth branch of collecting in 60 minutes behind the histamine;

B is the hydrochloric acid in gastric juice discharge (μ mol/10 minute) that physiological saline pours into the one-tenth branch of collecting in back 60 minutes; And

C feeds behind the test compound minimum hydrochloric acid in gastric juice discharge (μ mol/10 minute) during 120 minutes.

It the results are shown in Table 3-1

Table 3-1: stomachial secretion suppresses (%)

Amount (mg/kg)	Azoles draws in Australia U.S.A	SK&F96067	The compound of embodiment 34
Amount (mg/kg)	Azoles draws in Australia U.S.A	SK&F96067	The compound of embodiment 34	0.1 0.3 0.5 1.0 3.0	8.0％ 49.4％ 102.3％	29.8％ 57.1％ 75.9％	44.4％ 52.0％ 76.5％
ED ₅₀	0.29mg/kg	0.96mg/kg	0.90mg/kg	0.1 0.3 0.5 1.0 3.0	8.0％ 49.4％ 102.3％	29.8％ 57.1％ 75.9％	44.4％ 52.0％ 76.5％

3-2: test compound is to the inhibition of stomachial secretion when stimulating stomachial secretion with pentagastrin (Pentagastrin)

By with experimental example 3-1 in identical step carry out, just with the left jugular vein of pentagastrin (Pentagastrin) as secretion excitor substance input rat, dosage is 24 μ g/2ml/200g/ hours.It the results are shown in Table 3-2.

Table 3-2: stomachial secretion suppresses (%) and ED when stimulating secretion with histamine ₅₀

Amount (mg/kg)	Azoles draws in Australia U.S.A	SK&F96067	The compound of embodiment 34
Amount (mg/kg)	Azoles draws in Australia U.S.A	SK&F96067	The compound of embodiment 34	0.1 0.3 0.5 1.0 3.0 5.0	5.0％ 63.1％ 114.3％	32.6％ 64.0％ 77.3％	41.2％ 77.0％ 110.20％
ED ₅₀	0.47mg/kg	1.85mg/kg	1.31mg/kg	0.1 0.3 0.5 1.0 3.0 5.0	5.0％ 63.1％ 114.3％	32.6％ 64.0％ 77.3％	41.2％ 77.0％ 110.20％

The test of embodiment 4 reversibilitys

4-1: the preparation of magenblase

Method by people such as Saccomani G. prepares magenblase (Saccomani G., et al., J.Biol.Chem.250,4802-2809 (1975)) from the pig stomach.℃ preservation of freeze-drying this magenblase-70.Employing standard bSA is identified its protein content (referring to Lowry, D.H., Rosebrough, N.J.and Randall, R.J., J.Biol.Chem.193,265-275 (1951)) by people's such as Lowry method.

4-2:H ⁺/ K ⁺Atpase activity

Test tube is divided into 4 groups, and every group has 3 test tubes.The 1st group of DMSO that adds 10 μ l as control group.The 2nd group, the 3rd group and the 4th group of compound that uses embodiment 34, its ultimate density is respectively 0.17 μ M, 0.33 μ M and 0.67 μ M.Each group further is divided into 3 groups again, wherein uses ATP respectively; ATP and Mg ⁺⁺And ATP, Mg ⁺⁺And K ⁺, activating enzyme.

To all freeze-drying magenblases that in vitro adds 100 μ l, its concentration is the Pipes/Tris damping fluid of 25 μ g albumen/ml and 90 μ l5m Mp H7.0.The compound that embodiment 34 is made adds each group, is respectively 0.17,0.33 or 0.67 μ M until its final concentration.Preincubate l5 minute.

Each group in 4 groups all adds the ATP (3mM) of 50 μ l, and the 2nd and the 3rd group of each group adds the MgCl of 50 μ l ₂(2mM).The 3rd group of each group adds the KCl solution of the various concentration of 50 μ l (from 0.1mM to 30mM) again, adds the Pipes/Tris damping fluid of 150 μ l pH 7.0 then.In other each groups, add pH and be 7.0 Pipes/Tris damping fluid till reaching the identical capacity of the 3rd group to its capacity.

Hatch test tube 30 minutes for 37 ℃, add 25% cold trichoroacetic acid(TCA) solution termination reaction.Centrifugal with microcentrifuge, get supernatant liquor and measure the inorganic phosphate salts contg that discharges with automatic analyser (CIBA CORNING, Express 550).

By step preparation same as described above, just the SK﹠amp of azoles and 0.75,1.5 and 3.0 μ m draws in Australia U.S.A of 15 and 30 μ m; F96067 is used as the contrast material, measures the content of the inorganic phosphate that discharges.

The content that its three groups discharge inorganic phosphate is considered to all have H when each working concentration ⁺/ K ⁺The activity of ATP enzyme.Calculate H with following formula ⁺/ K ⁺The sp act of ATP enzyme:

Sp act=(A-C)-(B-C) (V)

Wherein:

A is ATP, Mg ⁺⁺And K ⁺The activity of activated enzyme;

B is ATP, Mg ⁺⁺The activity of activated enzyme;

C is the activity of ATP activated enzyme.

In accompanying drawing 1, relate to employing DMSO that the concentration of KCl provides and embodiment 34 the 1st group with three kinds of different concns, the sp act that calculates of the 2nd group and the 3rd group, adopt the Lineweaver-Bruk method on the method, wherein, ■, and zero represents respectively with 0.67 μ M, embodiment 34 compounds of 0.33 μ M and 0.17 μ M concentration; ● represent the DMSO compound concentrations.Shown in Figure 2 from SK﹠amp; The figure of the Lineweaver-Burk sp act that obtains among the F96067, wherein, on behalf of its concentration, ■, and zero be respectively 0.3 μ M, 1.5 μ M, 0.75 μ M; And ● expression DMSO compound concentrations.Fig. 3 represents that Australia U.S.A draws the Lineweaver-Burk figure of the sp act of azoles, wherein zero and to represent its concentration respectively be 15 μ M and 30 μ M; And ● the concentration of expression DMSO.

As Fig. 1,2 and Fig. 3 finding, The compounds of this invention and SK﹠amp; F96067 is at K ⁺Proton pump binding site place and K ⁺Competitive inhibition, and Australia U.S.A draws azoles competitive inhibition not occur, promptly for the present invention and SK﹠amp; The F96067 compound, V _MaxIn Lineweaver-Burk figure, do not change, and the Km value changes.The compounds of this invention and SK﹠amp; The Ki value of F96067 is respectively 0.04 μ M and 0.7 μ M.On the contrary, draw azoles for Australia U.S.A, when concentration was 15 and 30 μ M, speed of response reduced greatly: the concentration that increases KCl fails to overcome the inhibition of enzymic activity.From this point, provable Australia U.S.A draws azoles not exist and K ⁺The relation that competition suppresses.

4-3: the reversibility of inhibition

The method test The compounds of this invention is machine-processed to the active inhibition of proton pump by so-called dilution (Dilution) with (Washout), (referring to D.J.Keeling, et al., Biochemical Pharmacology 42 (1), 123-130 (1991).

That is, test tube is divided into two groups, first group and second group of compound of making for the DMSO and the embodiment of the invention 34 respectively separately.The compound (6 μ M) that DMSO and the embodiment 34 of 10 μ l made adds first group and second group respectively.

In all two groups, add 100 μ l by embodiment 4-1, the freeze drying bone magenblase that when concentration is 100 μ g albumen/1ml, makes.Then, in the 3rd group, add 5m MPipes/Tris damping fluid (pH 6.4), reach 150 μ l until its test tube volume.Behind the preincubate 15 minutes, press step measurements H identical among the embodiment 4-2 ⁺/ K ⁺The activity of ATP enzyme.The concentration of above-mentioned trier is final concentration.

After preincubate is finished, with 50 times of each group dilutions, use centrifugal 60 minutes of Beckman ultracentrifuge (L8-80 type) then with 5mM Pipes/Tris damping fluid (pH 6.4).Abandon supernatant liquor, throw out is suspended in (pH 6.4) reach identical with the volume of preincubate until its volume in the 5m MPipes/Tris damping fluid.After this, press the identical step measurements (H described in the embodiment 4-2 ⁺/ K ⁺The inhibition of)-atpase activity; Fixed by step 1 pacing same as described above again, just azoles and SK﹠amp are drawn in Australia U.S.A; F96067 is as the contrast material.Carry out before or after described dilution and the flushing; H ⁺/ K ⁺It is as shown in table 4 that atpase activity suppresses.

Table 4H ⁺/ K ⁺The inhibition of atpase activity

	Before dilution and the flushing	After dilution and the flushing
	Before dilution and the flushing	After dilution and the flushing	Azoles SK﹠F96067 draws in compound Australia U.S.A of embodiment 34	84％ 80％ 80％	16％ 67％ 0％

From table 4 as seen, dilute with rinse step before Australia U.S.A draw azoles to suppress 80% enzymic activity, and after diluting and washing, all have only enzymic activity restraining effect in 67%.As seen at dilution and rinse step, Australia U.S.A draws azoles not break away from the combining site of enzyme, shows that it is non-reversible that the inhibition of azoles is drawn by Australia U.S.A.

On the contrary, SK﹠amp; The inhibition of F96067 and The compounds of this invention enzymic activity behind dilution and rinse step is zero or 16%.This represents SK﹠amp; It is reversible that the enzymic activity of F96067 and The compounds of this invention suppresses.

Description of the invention only is above-mentioned specific embodiment, and those skilled in the art can carry out other modification or change in not exceeding essence that claim of the present invention limits and scope.

Table 1: the active inhibition of proton pump (50%)

Azoles draws in Australia U.S.A of test compound

The compound effect ratio

IC ₅₀(μM) IC ₅₀(μM)

Example 18 0.6 37.0 61.67

Example 19 5.2 9.5 1.83

Example 20 8.4 9.2 1.10

Example 21 1.2 7.4 6.17

Example 22 0.7 7.9 11.29

Example 23 2.0 8.6 4.30

Example 24 ～ 12.5 16.1 ～ 1.29

Example 25 2.7 16.1 5.88

Example 26 0.4 16.1 46.00

Example 27 2.9 5.7 1.97

Example 28 1.2 8.3 6.92

Example 29 4.9 7.2 1.47

Example 30 2.2 7.2 3.27

Example 31 2.0 10.1 5.13

Example 32 ＞ 16.0 9.3 ＜ 0.58

Example 33 2.3 2.8 1.22

Example 34 1.7 9.2 5.45

Example 35 1.8 5.1 2.83

Example 36 4.0 5.1 1.28

Example 37 ～ 12.5 7.5 ～ 0.60

Example 38 1.2 2.0 1.67

Example 39 4.0 2.8 0.70

Example 40 1.3 10.6 8.15

Example 41 3.8 7.6 2.00

Example 42 12.5 2.2 ＜ 0.18

Example 43 ＞ 12.5 12.1 ＜ 0.97

Example 44 ～ 12.5 12.1 ～ 0.97

Example 45 8.9 4.1 0.46

Example 46 ～ 6.0 4.1 0.68

Example 47 ～ 25 12.1 0.49

Example 48 ～ 25.0 6.3 ～ 0.25

Example 49 ＞ 25.0 6.3 ＜ 0.25

Example 50 6.05 7.4 1.22

Example 51 6.12 7.4 1.2l

Example 52 7.5 9.4 1.26

Table 1 (continuing)

Azoles draws in Australia U.S.A of test compound

The compound effect ratio

IC ₅₀(μM) IC ₅₀(μM)

Example 53 2.0 9.4 4.75

Example 54 ～ 12.5 8.0 ～ 0.64

Example 55 ～ 10.0 8.0 ～ 0.80

Example 56 ＞ 12.5 7.5 ＜ 0.60

Example 57 7.18 7.5 1.04

Example 58 13.5 8.8 0.65

Example 59 4.8 8.5 1.77

Example 60 1.8 9.2 5.20

Example 61 2.1 9.2 4.42

Annotate: " Example " expression " embodiment " in the table.

Table 2: the amount of gastric juice and acidity

Compound relative volume relative concentration is acid relatively

(%) (%) discharge

Example 18 0.38 0.02 0.29

Example 19 1.03 0.28 0.68

Example 20 1.28 0.64 0.92

Example 21 0.74 -0.04 0.38

Example 22 0.74 0.43 0.64

Example 23 0.39 0.42 0.44

Example 24 0.47 0.07 0.36

Example 25 0.69 0.14 0.50

Example 26 0.38 0.04 0.25

Example 27 0.29 0.12 0.30

Example 28 0.67 0.37 0.64

Example 29 0.87 0.67 0.84

Example 30 0.76 0.53 0.76

Example 31 0.86 0.74 0.79

Example 32 0.47 0.16 0.43

Example 33 1.09 0.34 0.79

Example 34 1.36 0.55 0.97

Example 35 0.92 0.58 0.79

Example 36 0.82 0.42 0.67

Example 37 0.37 0.15 0.37

Example 38 0.80 0.53 0.83

Example 39 0.66 0.22 0.57

Example 40 0.73 0.76 0.82

Example 41 0.63 0.15 0.48

Example 42 0.40 0.14 0.42

Example 43 0.81 0.44 0.76

Example 44 0.73 0.56 0.75

Example 45 0.20 -0.22 -0.06

Example 46 0.42 -0.21 0.1l

Example 47 0.45 0.15 0.33

Example 48 0.75 0.52 0.76

Example 49 0.59 0.12 0.42

Example 50 0 85 0.65 0.82

Example 51 0.86 0.64 0.82

Example 52 1.03 0.55 0.79

Table 2 (continuing)

Compound relative volume relative concentration is acid relatively

(%) (%) discharge

Example 53 1.01 0.65 0.92

Example 54 0.94 0.35 0.82

Example 55 0.57 0.50

Example 56 0.91 0.70 0.85

Example 57 0.92 0.35 0.67

Example 58 1.32 0.71 0.94

Example 59 1.53 0.47 0.83

Example 60 1.03 0.55 0.84

Example 61 0.73 0.51 0.76

Annotate: " Example " expression " embodiment " in the table.

Claims

1, by acceptable salt on the quinazoline derivant of general formula (I) expression and the pharmacology thereof:

Wherein:

R ₁And R ₂Represent hydrogen or C respectively independently ₁-C ₄Alkyl;

R ₃It is hydrogen or halogen;

R ₄, R ₅, R ₆, R ₇, R ₈And R ₉, can be identical or inequality, be hydrogen or C ₁-C ₄Alkyl, cyclopropyl, methyl fluoride or trifluoromethyl;

R ₁₀It is methoxyl group.

2, quinazoline derivant as claimed in claim 1, it can be by selecting in the following compound:

8-methoxyl group-2-(4-fluoro-N-methyl-phenylamino)-4-(1,2,3,4-first hydrogen isoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1,1 ,-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoroanilino)-8-methoxyl group-4-(1,6 ,-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

2-(4-fluoroanilino)-8-methoxyl group-4-(1,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-yl) quinazoline;

8-methoxyl group-2-(4-fluoroanilino)-4-(1,8-ethano--1,2,3,4-first hydrogen isoquinoline-2-yl) quinazoline;

2-(4-fluoro-2-methylbenzene amino)-8-methoxyl group-4-(1-methyl isophthalic acid, 2,3,4-first hydrogen isoquinoline-2-yl) quinazoline.

3, the pharmaceutically acceptable salt of quinoline as claimed in claim 1, they are selected from hydrochloride, vitriol, phosphoric acid salt, nitrate, tartrate, fumarate, Citrate trianion, mesylate and acetate.

4, the method for preparing the quinazoline derivant of general formula as claimed in claim 1 (I), be included in the compound of the compound that makes general formula (II) in first solvent and general formula (III) and the compound that alkali reaction generates general formula (IV), the compound of general formula (IV) subsequently in second solvent with the compound reaction of logical formula V:

R wherein ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₈, R ₉And R ₁₀Have the definition identical with claim 1, X is a chlorine.

5, method as claimed in claim 4, wherein said first solvent be methylene dichloride, acetone, acetonitrile, tetrahydrofuran (THF) with and with the mixture of water, and described alkali is triethylamine, N, accelerine and pyridine.

6, method as claimed in claim 4, wherein said second solvent are dimethyl formamide, p-diox or methyl-sulphoxide.

7, a kind of pharmaceutical composition for the treatment of stomach ulcer comprises acceptable salt on the quinazoline derivant as claimed in claim 1 for the treatment of effective dose or its pharmacology, and acceptable carrier on the pharmacology.