CN102659764A - Tyrosine kinase inreversible inhibitor, its preparation method and application - Google Patents
Tyrosine kinase inreversible inhibitor, its preparation method and application Download PDFInfo
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- CN102659764A CN102659764A CN2012101112452A CN201210111245A CN102659764A CN 102659764 A CN102659764 A CN 102659764A CN 2012101112452 A CN2012101112452 A CN 2012101112452A CN 201210111245 A CN201210111245 A CN 201210111245A CN 102659764 A CN102659764 A CN 102659764A
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Abstract
The invention provides a tyrosine kinases inreversible inhibitor of structural formula I and its preparation method and application in preparing antitumor drugs, belonging to the field of pharmaceutical chemistry. The tyrosine kinases inreversible inhibitor has extremely high activity for inhibiting tumor cell growth, especially has significant inhibition effect against the growth of tumor cells with high EGFR and HER2 expression.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, specifically, particularly relate to one type of dual irreversible inhibitor of new type tyrosine kinase and the application in preparation treatment or prevention of cell proliferation disorders medicine thereof.
Technical background
Under the normal circumstances, cell need obtain growth signals from the stationary state to the vegetative state.These growth signals change cell over to through the receptors bind on specific signal molecule and the cytolemma.EGF is one of wherein most important growth signals molecule.The EGF acceptor is the multi-functional transmembrane glycoprotein that is distributed widely on each histocyte of human body, belongs to one of ErbB family member, and this family has four members; Be respectively EGFR (HER1/erbB-1); HER2 (erbB-2/neu), HER3 (erbB-3), HER4 (erbB-4).They are the single polypeptide chain, relative molecular mass about 1.7 * 10
5～1.85 * 10
5, respectively by the coded by said gene that is positioned on the coloured differently body.Two kinds of acceptors of EGFR and HER2 in multiple human tumor cell, often occur and cross the expression phenomenon, generation, evolution that this mistake is expressed phenomenon and tumour have substantial connection.
Find in the clinical tumor research that the expression phenomenon excessively of one or more ErbB acceptors all can appear in known 70% malignant tumour.The expression amount of discovery EGFR is above 100 times of the normal cell level in kinds of tumor cells such as mammary cancer, bladder cancer, lung cancer, prostate cancer; In kinds of tumor cells such as mammary cancer, ovarian cancer, cervical cancer, prostate cancer, nonsmall-cell lung cancer, nasopharyngeal carcinoma, find the amplification of HER2 or cross the expression phenomenon.This phenomenon of expressing of crossing indicates the tumour patient prognosis mala usually, shows as weak point lifetime, the easy recurrence of tumour, is prone to far-end transfer etc. takes place, and insensitive to chemotherapy or hormonotherapy.
Because the tyrosine kinase mediated cell growth signals of ErbB plays important effect in the generation of tumour, development, blocking-up ErbB cell signal network can reach the purpose that suppresses tumour.With small molecules ErbB receptor tyrosine kinase inhibitors (Tyrosine kinase inhibitors; TKIs); Be incorporated into the ATP-binding domain of ErbB receptor tyrosine kinase with ATP competitiveness; Suppress kinase whose catalytic activity, thereby the conduction of blocking-up cell proliferation signal is blocking-up ErbB receptor signal path, suppresses one of valid approach of tumor growth.The Tyrosylprotein kinase micromolecular inhibitor of exploitation listing at present comprises ZD1939 (Iressa); Hydrochloric acid Tarceva (Te Luokai); Hydrochloric acid dust gram is for Buddhist nun (Kai Meina) lapatinibditosylate etc., ZD1939 wherein, hydrochloric acid Tarceva; Hydrochloric acid dust gram is the EGFR reversible inhibitor for the Buddhist nun, and lapatinibditosylate is the dual reversible inhibitor of EGFR/HER2.
But external clinical study result finds that only 10% left and right sides tumour patient has objective reaction to said medicine, and all the other are all reactionless or resistance arranged.In 10% left and right sides tumour patient that when the treatment beginning, responds, great majority also finally produce resistance to it, do not have obvious improvement on the life-span the prolongation patient.Trace it to its cause, be the rapid generation of drug resistance.EGFR T790M sudden change is the major reason that causes drug resistance; The change of the amino-acid residue skeleton that causes of sudden change makes reversible EGFR suppressor factor such as ZD1939, hydrochloric acid Tarceva break away from the ATP-binding domain of ErbB receptor tyrosine kinase, thus loss of activity.
In order to overcome drug resistance and the early stage big shortcoming of reversible inhibitor dosage, scholars begin to focus on the research of irreversible inhibitor.Utilize sulfydryl on Cys773 and the Cys805 amino-acid residue at EGFR and HER2 kinases ATP-binding domain edge to have the characteristics of stronger nucleophilicity; In drug molecule, introduce a Michael addition acceptor; Make drug molecule form covalent bonds, reach the purpose of irreversible inhibition with kinases.
A large amount of researchs show; The double inhibitor of development target property EGFR and HER2 Tyrosylprotein kinase has following advantage: 1. suppress two kinds of Tyrosylprotein kinases of EGFR and HER2 simultaneously, other members of EGFR family raise the redundant resistance that produces of the cell growth signals that causes when using single tyrosine kinase inhibitor thereby be easier to overcome; 2. because EGFR and HER2 heterodimer activity are the highest, the double inhibitor of EGFR and HER2 Tyrosylprotein kinase is effective to most cancer patientss.3. compare with single suppressor factor, double inhibitor suppresses effect to tumour cell and has synergistic effect.External and in vivo tests also show, to the anticancer effect of EGFR and HER2 Tyrosylprotein kinase double inhibition greater than inhibition to single receptor.Compare with using two medicines that act on single target spot respectively simultaneously in addition, the medicine patient who acts on two target spots uses more convenient, can also avoid the interaction of medicine and medicine.
In sum, the dual irreversible inhibitor of exploitation targeting EGFR and HER2 Tyrosylprotein kinase is rational selection.
At present, the irreversible dual tyrosine kinase inhibitor that gets into clinical study has BIBW2992, HKI-272 and PF299804, and the clinical experiment data show that this type suppressor factor has good DEVELOPMENT PROSPECT.
Recently disclosed tyrosine kinase irreversible inhibitor, its medical composition and its use of having following patent: CN101824029 announce relevant with EGFR and/or HER2 tyrosine kinase inhibitor; The preparation method of the quinazoline derivative that WO 2009012647 announces and in pharmaceutically application; CN102153544 has announced the preparation and the purposes of one type of novel tyrosine kinase inhibitor; Protein tyrosine kinase aryl and heteroaryl quinazoline compounds that CN1187129 announces with selective inhibition of HER-2-2 autophosphorylation properties; Human epidermal growth factor receptor 2's tyrosine kinase inhibitor that CN1651418 announces; Quinazoline compounds or its pharmacologically acceptable salt and its preparation method and pharmaceutical use that CN101003513 announces; The pharmaceutical applications of the 4-aniline quinazoline derivative that CN101347433 announces; CN101311166 tyrosine kinase inhibitor, its method for making and purposes; A kind of amido quinazoline derivatives and its esters that CN101367793 announces with anti-tumor activity.The summary of the invention of this patent all is different from above patent.The chemical structure that this patent is announced is not appeared in the newspapers through retrieval.
Summary of the invention
First purpose of the present invention provides a kind of tyrosine kinase irreversible inhibitor, and I is following for its general formula of molecular structure:
General formula 1
Wherein, Y restrains acceptor class and active alkyls compound for stepping,
X is for containing one or more heteroatomic ring compounds,
Ar is phenyl and substituted phenyl, and contains the also aryl and the heteroaryl compound of lopps,
R is H, C1-C6 alkyl and unsaturated alkyl,
W is C1-C6 alkyl and unsaturated alkyl or do not have,
R
6Be H, C1-C6 alkyl and unsaturated alkyl, C6-C10 substituted aralkyl, F, Cl, Br, I, CF
3, CHF
2, CH
2F, OR
7, NR
7R
8, CN, CO
2R
7, CONR
7R
8, SO
2R
7, SO
2NR
7R
8, NO
2, NCONR
7R
8, NCO
2R
7, OCONR
7R
8, CSNR
7R
8, NCSNR
7R
8
R
7, R
8Can separately or be respectively: the saturated and unsaturated alkyl of hydrogen, C1-6 and the substituted alkyl of heteroatoms;
Preferably, X general structure II is following:
General formula I I
Wherein, V, U, T, Q, Z can be simultaneously or are CH independently, O, S, N, NH group form particularly aryl-heterocyclic substituted radical of cyclic substituents,
Y is an acrylic, the propine acidic group, and vinyl sulfonic acid base and phosphate and corresponding substitutional crylic acid base, propynoic acid group, acrylic, propine acidic group come as stepping the gram acceptor.
Preferred, X is following group or substituted following group:
Wherein, R
2Saturated and unsaturated alkyl and the substituted alkyl of heteroatoms for hydrogen, C1-6;
Y is preferably following group:
Wherein, R
3, R
4, R
5Can be H independently perhaps simultaneously, F, Cl, C1-C6 alkyl or unsaturated alkyl contain O, N, S, heteroatomic C1-C6 alkyl such as P, cyclic alkyl or unsaturated chain and cyclic alkyl, R
3, R
4, R
5Two substituting groups also can Cheng Huan; W is C1-C6 alkyl and unsaturated alkyl, is preferably CH
2, CH
2CH
2, CH
2CH
2CH
2
R is H, and C1-C6 alkyl and unsaturated alkyl are preferably H, CH
3, CH
2CH
3
Ar is following group:
Be more preferably, X is preferably following group:
Wherein, R
2Saturated and unsaturated alkyl and the substituted alkyl of heteroatoms for hydrogen, C1-6;
Y is following group:
Wherein, R
3Be preferably H, F, Cl, C1-C6 alkyl or unsaturated alkyl,
R
9And R
10Can be simultaneously or independent be H, alkyl and substituted alkyl; R
9And R
10Also can form ring-type and contain heteroatomic ring texture.
Ar is preferably following group:
Preferably, Y is following group:
Wherein, R
3Be preferably H, the C1-C6 alkyl;
R
9And R
10Can be simultaneously or independent be H, alkyl and substituted alkyl, R
9And R
10Also can form ring-type and contain heteroatomic ring texture.
Most preferred, tyrosine kinase irreversible inhibitor provided by the invention is selected from one of following compound:
General formula I
The pharmacy acceptable salt of the tyrosine kinase irreversible inhibitor that second purpose of the present invention is to provide above-mentioned.
Preferably, the pharmacy acceptable salt of described tyrosine kinase irreversible inhibitor is the salt of said tyrosine kinase irreversible inhibitor and mineral acid or organic acid list or diacid addition.
The preparation method of the tyrosine kinase irreversible inhibitor that the 3rd purpose of the present invention is to provide above-mentioned, adopt following route:
Wherein, each general formula compound preparation method can be through following each flow preparation, comprising:
Flow process I: the preparation of intermediate compound I-6a to I-6d
In the formula, representational Ar comprises following group:
(1) intermediate compound I-3 is in inertia (polarity) solvent; Under the effect of appropriate bases, with POCl3 or thionyl chloride chlorination, reaction can get intermediate compound I-4 in 3-4 hour under 70～80 ℃; Cooling a little; Add corresponding amine in the reaction flask,, get final product a step to obtain intermediate compound I-5a-I-5d 75～80 ℃ of reactions 3-4 hour down.Polar solvent can be acetonitrile, DMF, toluene, acetone etc.Alkali can be selected from organic basess such as DBU, triethylamine, diisopropylethylamine, N-methylmorpholine.Optimum reaction condition is for being solvent with toluene.(2) raw material I-5a-I-5d is a catalyzer at Tong Shiji and sodium ascorbate in polar solvent, suitable copper part; Under alkaline condition; Under protection of inert gas, under suitable temperature, carry out the click reaction with sodium azide, propine amido t-butyl formate, generate intermediate compound I-6a-I-6d.Polar solvent can be selected from methylene dichloride, chloroform, THF, ether, methyl tert-butyl ether, 1,4-dioxane, DMF, DMSO 99.8MIN., acetonitrile isopolarity non-protonic solvent; Tong Shiji can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; The copper part can be selected from L-proline(Pro), N, N '-dimethyl amine; Alkali can be selected from organic basess such as DBU, triethylamine, diisopropylethylamine, N-methylmorpholine, quadrol; Temperature is 50～100 ℃, and the reaction times is 2-24 hour.Optimum reaction condition does, is solvent with DMSO, is catalyzer with cupric sulfate pentahydrate and sodium ascorbate, is part with the L-proline(Pro), with the diisopropylethylamine be alkali under argon shield, be heated to 60-80 ℃ the reaction 2-4 hour.
Flow process II: the preparation of intermediate II-3a to II-3d
(1) intermediate compound I-5a-I-5d is in polar aprotic solvent; Under suitable temperature; Rare gas element and suitable alkali exist down, obtain a series of trimethylsilyl acetylene bases with palladium/copper mixed catalyst catalysis trimethylsilyl acetylene and halogenide cross-coupling and replace midbody.Polar aprotic solvent is selected from THF, ether, methylene dichloride, toluene, 1,4-dioxane, DMF, acetonitrile etc.; TR is between 20-100 ℃; Alkali can be selected from yellow soda ash, cesium carbonate, salt of wormwood, triethylamine, Diisopropylamine, pyridine, N-methylmorpholine, morpholine, diisopropylethylamine etc.; Palladium catalyst optional two (triphenyl is seen) palladium chloride, three (dibenzalacetones), two palladiums, [1,1 '-two (phenylbenzene see base) ferrocene] palladium chloride, four (triphenyl is seen) palladium, palladium etc.; Copper catalyst is selected cuprous iodide for use.Optimum condition is: with two (triphenyl is seen) palladium chlorides and cuprous iodide is catalyzer, and Diisopropylamine is an alkali, and THF is that solvent at room temperature reacts and spends the night.The tetrahydrofuran solution that this serial trimethylsilyl acetylene replaces midbody in room temperature reaction 1 hour, obtains intermediate II-2a-II-2d directly in the presence of fluorine reagent.(2) raw material II-2a-II-2d is a catalyzer at Tong Shiji and sodium ascorbate in polar solvent, under protection of inert gas, under suitable temperature, carries out the click reaction with N-Boc-2-nitrine ethamine, generates the triazole compounds of Boc protection.Polar solvent can be selected from methylene dichloride, chloroform, THF, ether, methyl tert-butyl ether, 1,4-dioxane, DMF, DMSO 99.8MIN., acetonitrile isopolarity non-protonic solvent; Tong Shiji can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is 50～100 ℃, and the reaction times is 2-24 hour.Optimum reaction condition does, is solvent with DMSO, is catalyzer with cupric sulfate pentahydrate and sodium ascorbate, under argon shield, is heated to 60-80 ℃ of reaction 2-4 hour.The midbody of this serial Boc protection directly in the presence of trifluoroacetic acid or hydrochloric acid, in room temperature reaction 1 hour, obtains intermediate II-3a-II-3d at dichloromethane solution.
Flow process III: the preparation of intermediate III-5a to III-5d
(1) intermediate compound I-5a-I-5d in the presence of suitable alkali, obtains intermediate III-2a-III-2d with palladium catalyst catalysis carbon monoxide and halogenide cross-coupling under the suitable temperature in alcoholic solvent.Alcoholic solvent is selected from methyl alcohol, ethanol, the trimethyl carbinol etc.; TR is between 60-100 ℃; Reaction times is 8-15 hour; Alkali can be selected from yellow soda ash, cesium carbonate, salt of wormwood, triethylamine, Diisopropylamine, pyridine, N-methylmorpholine, morpholine, diisopropylethylamine etc.; Palladium catalyst optional two (triphenyl is seen) palladium chloride, [1,1 '-two (phenylbenzene see base) ferrocene] palladium chloride, three (dibenzalacetone) two palladiums, four (triphenyl is seen) palladium, palladium etc.Optimum condition is: with two (triphenyl is seen) palladium chloride is catalyzer, and Diisopropylamine is an alkali, and methyl alcohol is that solvent under refluxad reacted 10 hours.(2) raw material II I-2a-III-2d is hydrolyzed into IV-3a-IV-3d under the alkaline condition in the mixed solvent of polar aprotic solvent and water.Polar aprotic solvent can be selected from THF, methyl alcohol, ethanol, the trimethyl carbinol, acetonitrile etc.; Alkali can be selected from Lithium Hydroxide MonoHydrate, Pottasium Hydroxide, sodium hydroxide etc.Optimum condition is for being solvent with THF and water, and Lithium Hydroxide MonoHydrate is an alkali, and reaction is 1 hour under the room temperature.(3) raw material II I-3a-III-3d is in polar aprotic solvent; Under the suitable temperature; Under EDCI (1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride) and HOBt (I-hydroxybenzotriazole) acted on, the aminoacethydrazide generation peptide chain dehydration reaction of protecting with Cbz obtained III-4a-III-4d.Polar aprotic solvent can be selected from methylene dichloride, THF, DMF, DMSO 99.8MIN.; TR is between 25-50 ℃; Reaction times is 2-24 hour.Preferred condition is for being solvent at methylene dichloride, and reaction is 3 hours under the room temperature.(4) raw material II I-4a-III-4d is in non-protonic solvent, and suitable temperature and suitable alkali exist down, obtains Cbz protection De oxadiazole midbody with chlorination reagent reaction cyclization.Non-protonic solvent can be selected from methylene dichloride, THF, acetonitrile, 1,4-dioxane etc.; Alkali can be selected from triethylamine, Diisopropylamine, pyridine, N-methylmorpholine, morpholine, diisopropylethylamine etc.; Chlorination reagent can be selected from oxalyl chloride, thionyl chloride, POCl3 etc.; TR is between 0-30 ℃; Reaction times is 2-24 hour.Preferred condition is for being that alkali and oxalyl chloride reacted 4 hours between 0-30 ℃ with the triethylamine in methylene dichloride.This serial Cbz protection De oxadiazole midbody is in methanol solution, and hydrogen exists palladium carbon catalytic hydrogenation in room temperature reaction 5 hours, obtains intermediate III-5a-III-5d.
Flow process IV: the preparation of intermediate compound IV-4a to IV-4h
A is selected from O in the formula, S.
(1) intermediate compound I-5a-I-5d in the presence of suitable alkali, obtains intermediate compound IV-2a-IV-2d with palladium catalyst catalysis tributyl (vinyl ethyl ether base) tin and halogenide cross-coupling under the suitable temperature in polar aprotic solvent.Polar aprotic solvent is selected from THF, acetonitrile, 1,4-dioxane, DMF etc.; TR is between 60-100 ℃; Reaction times is 8-15 hour; Alkali can be selected from yellow soda ash, cesium carbonate, salt of wormwood, triethylamine, Diisopropylamine, pyridine, N-methylmorpholine, morpholine, diisopropylethylamine etc.; Palladium catalyst optional two (triphenyl is seen) palladium chloride, three (dibenzalacetones), two palladiums, [1,1 '-two (phenylbenzene see base) ferrocene] palladium chloride, four (triphenyl is seen) palladium, palladium etc.Optimum condition is: with two (triphenyl is seen) palladium chloride is catalyzer, and Diisopropylamine is an alkali, 1, and the 4-dioxane is that solvent reacted 10 hours down at 80 ℃.(2) intermediate compound IV-2a-IV-2d under the suitable temperature, can get midbody V-3a-V-3d through the bromide reagent bromination in non-protonic solvent.Non-protonic solvent can be selected from methylene dichloride, tetracol phenixin, 1,2-ethylene dichloride, ether, acetonitrile, 1,4-dioxane, DMF etc.; Bromide reagent is bromine, NBS etc.; Temperature of reaction is 0-100 ℃; Reaction times is 2-24 hour.Optimum condition is that ether is a solvent, and bromine is a bromide reagent, and reaction is 4 hours under the room temperature.(3) intermediate compound IV-3a-IV-3d can get intermediate compound IV-4a-IV-4h with thiocarbamide or urea cyclization under the suitable temperature in polar aprotic solvent.Polar aprotic solvent is selected from ethanol, methyl alcohol, Virahol, acetonitrile, toluene, DMF etc.; Temperature of reaction is 80-100 ℃; Reaction times is 2-5 hour.Priority condition is for being solvent with ethanol, back flow reaction 4 hours.
Flow process V: the preparation of midbody V-2a to V-2d
(1) intermediate compound IV-3a-IV-3d is in polar aprotic solvent, and under the suitable temperature, suitable alkali exists down, and the amino ethanamidine cyclization of protecting with Cbz can get the imidazole derivative of Cbz protection.Polar aprotic solvent is selected from DMF, THF, 1,2-dioxane, acetonitrile, ethanol etc.; Alkali can be selected from salt of wormwood, cesium carbonate, yellow soda ash, sodium hydroxide, triethylamine etc.; TR 80-100 ℃; Reaction times is 4-10 hour.Optimum condition is for being solvent with DMF, and salt of wormwood is alkali, and 100 ℃ were reacted 6 hours down.This serial Cbz protection De oxadiazole midbody is in methyl alcohol/hydrochloric acid soln, and hydrogen exists palladium carbon catalytic hydrogenation in room temperature reaction 5 hours, obtains midbody V-2a-V-2d.
Flow process VI: the preparation of midbody VI-5a to VI-5h
P represents O in the formula, S.
(1) intermediate compound I-5a-I-5d is in polar aprotic solvent, and in the presence of suitable alkali, suitable part obtains midbody VI-2a-VI-2h with substituted heterogeneous ring compound of palladium catalyst catalysis boric acid and halogenide cross-coupling under existing under the suitable temperature.Polar aprotic solvent is selected from THF, acetonitrile, 1,4-dioxane, DMF, methylene dichloride, 1,2-ethylene dichloride etc.; TR is between 60-100 ℃; Reaction times is g-24 hour; Alkali can be selected from yellow soda ash, cesium carbonate, salt of wormwood, triethylamine, Diisopropylamine, pyridine, N-methylmorpholine, morpholine, diisopropylethylamine etc.; Palladium catalyst optional two (triphenyl is seen) palladium chloride, three (dibenzalacetones), two palladiums, four (triphenyl is seen) palladium, palladium, [1,1 '-two (phenylbenzene see base) ferrocene] palladium chloride etc.; Part be selected from triphenyl see, 1,10-phosphorus phenanthroline, 2-cyclohexyl phosphorus-2,4,6-tri isopropyl biphenyl etc.Optimum condition is: be catalyzer with the palladium, seeing with triphenyl is part, and Diisopropylamine is an alkali, and DMF is that solvent reacted 10 hours down at 70 ℃.(2) raw material VI-2a-VI-2h is in the mixed solvent of alcohol and water, and suitable alkali exists down, mixes midbody oxime VI-3a-VI-3h with the oxammonium hydrochloride effect can get cis-trans isomerism under the suitable temperature.Alcohol can be selected from methyl alcohol, ethanol, Virahol etc.; Alkali can be selected from sodium-acetate, Potassium ethanoate etc.; TR is between 25-60 ℃; Reaction times 1.5-5 hour.Optimum condition be with second alcohol and water 3: 1 as solvent, sodium-acetate is an alkali, reaction is 2 hours under the room temperature; (3) raw material VI-3a-VI-3h under the suitable temperature, can get midbody VI-4a-VI-4h through appropriate reductant reduction oxime in non-protonic solvent.Non-protonic solvent can be selected from THF, ether, 1,4-dioxane, DMF, methylene dichloride, 1,2-ethylene dichloride etc.; Reductive agent is seen and is selected from Lithium Aluminium Hydride, Peng Qinghuana etc.; TR is between 0-30 ℃; Reaction times is 1-4 hour.Optimum condition is in tetrahydrofuran solvent, reacts 0.5 hour under zero degree with Lithium Aluminium Hydride, slowly rises to room temperature reaction then 2 hours.
The above-mentioned preparation method who describes general formula of the present invention (I) structural compounds particularly, but these concrete grammars do not constitute any restriction to the present invention.General formula of the present invention (I) structural compounds can make through aforesaid method, however the condition of this method, and for example the amount of reactant, solvent, alkali, compound used therefor, temperature of reaction, reaction required time etc. are not limited to above-mentioned explanation.The compounds of this invention can also be chosen wantonly various compound method that describe in this specification sheets or known in the art is combined and makes easily, and such combination can be easy to carry out by those skilled in the art in the invention.
The 4th purpose of the present invention is to provide the application of a kind of above-mentioned tyrosine kinase irreversible inhibitor in the preparation antitumor drug.
Compared with prior art, the beneficial effect that has of the present invention is: tyrosine kinase irreversible inhibitor provided by the present invention.Utilize sulfydryl on Cys773 and the Cys805 amino-acid residue at EGFR and HER2 kinases ATP-binding domain edge to have the characteristics of stronger nucleophilicity; In drug molecule, introduce a Michael addition acceptor; Make drug molecule form covalent bonds, reach the purpose of irreversible inhibition with kinases.Thereby have the following advantages: 1. suppress two kinds of Tyrosylprotein kinases of EGFR and HER2 simultaneously, other members of EGFR family raise the redundant resistance that produces of the cell growth signals that causes when using single tyrosine kinase irreversible inhibitor thereby be easier to overcome; 2. because EGFR and HER2 heterodimer activity are the highest, the double inhibitor of EGFR and HER2 Tyrosylprotein kinase is effective to most cancer patientss.3. compare with single suppressor factor, double inhibitor suppresses effect to tumour cell and has synergistic effect.External and in vivo tests also show, to the anticancer effect of EGFR and HER2 Tyrosylprotein kinase double inhibition greater than inhibition to single receptor.Compare with using two medicines that act on single target spot respectively simultaneously in addition, the medicine patient who acts on two target spots uses more convenient, can also avoid the interaction of medicine and medicine.
Embodiment
The compounds of this invention and salt thereof also can be through becoming known for preparing the method preparation of chemofacies related compounds, and the raw material that relates in an embodiment all can obtain through the similar approach of prior art.
Embodiment one
Synthesizing of compound 1.N-(2-(4-(4-(3-chloro-4-(3-fluorine benzyloxy) anilino) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl) acrylic amide
With compound I I-3a (49mg, 0.1mmol), EDCI (29mg, 0.15mmol); HOBt (3mg, 0.02mmol), (8.6mg 0.12mmol) adds in the 10mL reaction flask vinylformic acid; Airtight, nitrogen replacement adds two triethylamines and 4mL DCM, stirring reaction under the room temperature (TLC monitoring); Reaction finishes, and revolves dried solvent, and column chromatography purification gets title compound, yield 43%.
1H?NMR(400MHz，DMSO-d
6)6ppm?10.01(s，1H)，9.05(s，1H)，8.64(s，1H)，8.63(s，1H)，8.26-8.37(m，2H)，8.17(d，J＝2Hz，1H)，7.85(d，J＝8.8Hz，1H)，7.78(dd，J＝8.8，2.0Hz，1H)，7.47(dd，J＝14.0，8.0Hz，1H)，7.05-7.13(m，3H)，7.16(t，J＝8.0Hz，1H)，6.23-5.83(m，2H)，5.59(d，J＝2.4Hz，1H)，5.26(s，2H)，4.53(t，J＝5.6Hz，2H)，3.67(dd，J＝11.6，6.0Hz，2H).
ESI-MS?m/z：544.1(M+H)
+，542.1(M-H)
-
Embodiment two:
Synthesizing of compound 2. (E)-N-(2-(4-(4-(3-chloro-4-(3-fluorine benzyloxy) anilino) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl)-but-2-enamides
The preparation method is with compound 1, and different is that vinylformic acid is replaced with Ba Dousuan.Obtain light yellow solid, yield 56%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.01(s，1H)，9.05(s，1H)，8.64(s，1H)，8.63(s，1H)，8.27(dd，J＝8.8，1.6Hz，1H)，8.17(t，J＝6.4Hz，1H)，8.04(d，J＝2.4Hz，1H)，7.85(d，J＝8.8Hz，1H)，7.78(dd，J＝8.8，2.8Hz，1H)，7.45-7.50(m，1H)，7.20-7.35(m，3H)，7.16(t，J＝8.0Hz，1H)，6.58-6.67(m，1H)，5.86(dd，J＝15.2，2.0Hz，1H)，5.26(s，2H)，4.53(t，J＝6.0Hz，2H)，3.67(dd，J＝11.6，6.0Hz，2H)，1.77(dd，J＝6.8，1.2Hz，3H).
ESI-MS?m/z：558.1(M+H)
+，556.1(M-H)
-
Embodiment three:
Synthesizing of compound 3. (E)-N-(2-(4-(4-(3-chloro-4-(3-fluorine benzyloxy) anilino) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl)-4-morphine quinoline butyl-2-alkene acid amides
The preparation method is with compound 1, and different is vinylformic acid to be replaced with (E)-4-morphine quinoline butyl-2-olefin(e) acid, obtains light yellow solid, yield 45%.
1H?NMR(400MHz，DMSO-d
6)δppm?9.99(s，1H)，9.03(s，1H)，8.62(s，1H)，8.58(s，1H)，8.27(dd，J＝8.8，1.6Hz，1H)，8.17(t，J＝6.4Hz，1H)，8.03(d，J＝2.4Hz，1H)，7.85(d，J＝8.8Hz，1H)，7.78(dd，J＝8.8，2.8Hz，1H)，7.45-7.50(m，1H)，7.20-7.35(m，3H)，7.16(t，J＝8.0Hz，1H)，6.53-6.65(dt，J＝13.2，6Hz，1H)，6.02(d，J＝8.8Hz，1H)，5.74(d，J＝5.6Hz，2H)，5.26(s，2H)，4.56(t，J＝6.0Hz，2H)，3.57(t，J＝4.8Hz，4H)，3.06(d，J＝5.6Hz，2H)，2.35(s，4H).
ESI-MS?m/z：643.2(M+H)
+，641.2(M-H)
-
Embodiment four:
Synthesizing of compound 4. (E)-N-(2-(4-(4-(3-chloro-4-(3-fluorine benzyloxy) anilino) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl)-4-(dimethylamino)-butyl-2-alkene acid amides
The preparation method is with compound 1, and different is vinylformic acid to be replaced with (E)-4-(dimethylamino)-butyl-2-olefin(e) acid, obtains light yellow solid, yield 38%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.01(s，1H)，9.06(s，1H)，8.63(s，1H)，8.58(s，1H)，8.23-8.29(m，2H)，8.03(d，J＝2.8Hz，1H)，7.85(d，J＝8.8Hz，1H)，7.78(dd，J＝8.8，2.8Hz，1H)，7.45-7.50(m，1H)，7.20-7.35(m，3H)，7.16(t，J＝8.0Hz，1H)，6.53-6.60(m，1H)，6.00(d，J＝15.6Hz，1H)，5.27(s，2H)，4.57(t，J＝4.8Hz，2H)，3.66(dd，J＝11.6，6.0Hz，2H)，2.95(d，J＝6.4Hz，2H)，2.11(s，6H).
ESI-MS?m/z：601.2(M+H)
+，599.2(M-H)
-
Embodiment five:
Synthesizing of compound 5.N-(2-(4-(4-(3-chloro-4-(3-fluorine benzyloxy) anilino) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl)-2-propine acid amides
The preparation method is with compound 1, and different is that vinylformic acid is replaced with propynoic acid, obtains light yellow solid, yield 46%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.01(s，1H)，9.05(s，1H)，8.64(s，1H)，8.63(s，1H)，8.26-8.37(m，2H)，8.17(d，J＝2Hz，1H)，7.85(d，J＝8.8Hz，1H)，7.78(dd，J＝8.8，2.0Hz，1H)，7.47(dd，J＝14.0，8.0Hz，1H)，7.05-7.13(m，3H)，7.16(t，J＝8.0Hz，1H)，5.26(s，2H)，4.53(t，J＝5.6Hz，2H)，4.32(s，1H)，3.67(dd，J＝11.6，6.0Hz，2H).
ESI-MS?m/z：542.1(M+H)
+，540.1(M-H)
-
Embodiment six:
Compound 6.N-(2-(4-(1-(3-fluorophenyl)-1H-indazole-5-anilino) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl) acrylic amide is synthetic
The preparation method is with compound 1, and different is that II-3a is replaced with II-3c, obtains light yellow solid, yield 56%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.09(s，1H)，9.07(d，J＝1.6Hz，1H)，8.62(s，1H)，8.53(s，1H)，8.23-8.29(m，3H)，8.17(s，1H)，7.84(d，J＝8.8Hz，1H)，7.74(d，J＝2Hz，2H)，7.35-7.38(m，1H)，7.05-7.13(m，3H)，6.06-6.24(m，2H)，5.71(s，2H)，5.66(d，J＝8.8Hz，1H)，4.53(t，J＝5.6Hz，2H)，3.67(dd，J＝11.6，6.0Hz，2H).
ESI-MS?m/z：534.5(M+H)
+，532.5(M-H)
-
Embodiment seven:
Compound 7. (E)-N-(2-(4-(1-(3-fluorophenyl)-1H-indazole-5-anilino) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl)-but-2-enamides synthetic
The preparation method is with compound 1, and different is that II-3a is replaced with II-3c, and vinylformic acid is replaced with Ba Dousuan, obtains light yellow solid, yield 54%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.11(s，1H)，9.09(d，J＝1.6Hz，1H)，8.64(s，1H)，8.54(s，1H)，8.24-8.30(m，2H)，8.13-8.17(m，2H)，7.84(d，J＝9.2Hz，1H)，7.74(s，2H)，7.35-7.40(m，1H)，7.05-7.13(m，3H)，6.60-6.66(m，1H)，5.87(d，J＝8.8Hz，1H)，5.71(s，2H)，4.53(t，J＝5.6Hz，2H)，3.67(dd，J＝11.6，6.0Hz，2H)，1.77(dd，J＝6.8，1.6Hz，3H).
ESI-MS?m/z：548.5(M+H)
+，546.5(M-H)
-
Embodiment eight:
Compound 8. (E)-N-(2-(4-(1-(3-fluorophenyl)-1H-indazole-5-anilino) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl)-4-morphine quinoline butyl-2-alkene acid amides synthetic
The preparation method is with compound 1, and different is that II-3a is replaced with II-3c, vinylformic acid is replaced with (E)-4-morphine quinoline butyl-2-olefin(e) acid, obtains light yellow solid, yield 42%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.09(s，1H)，9.07(d，J＝1.6Hz，1H)，8.62(s，1H)，8.53(s，1H)，8.23-8.29(m，3H)，8.17(s，1H)，7.84(d，J＝8.8Hz，1H)，7.74(d，J＝2Hz，2H)，7.35-7.38(m，1H)，7.05-7.13(m，3H)，6.52-6.59(dt，J＝13.2，6Hz，1H)，6.01(d，J＝15.6Hz，1H)，5.71(s，2H)，4.57(t，J＝6.4Hz，2H)，3.65(d，J＝6.0Hz，2H)，3.53(t，J＝4.8Hz，4H)，3.06(d，J＝6.4Hz，2H)，2.35(s，4H).
ESI-MS?m/z：633.7(M+H)
+，631.7(M-H)
-
Embodiment nine:
Compound 9. (E)-N-(2-(4-(1-(3-fluorophenyl)-1H-indazole-5-anilino) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl)-4-(dimethylamino)-butyl-2-alkene acid amides synthetic
The preparation method is with compound 1, and different is that II-3a is replaced with II-3c, vinylformic acid is replaced with (E)-4-(dimethylamino)-butyl-2-olefin(e) acid, obtains light yellow solid, yield 34%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.09(s，1H)，9.07(s，1H)，8.61(s，1H)，8.53(s，1H)，8.23-8.29(m，3H)，8.17(s，1H)，7.84(d，J＝7.6Hz，1H)，7.74(s，2H)，7.35-7.40(m，1H)，7.05-7.13(m，3H)，6.60-6.66(m，1H)，6.00(d，J＝15.6Hz，1H)，5.71(s，2H)，4.53(t，J＝5.6Hz，2H)，3.67(dd，J＝11.6，6.0Hz，2H)，2.95(d，J＝6.4Hz，2H)，2.10(s，6H).
ESI-MS?m/z：592.1(M+H)
+，590.1(M-H)
-
Embodiment ten:
Compound 10.N-(2-(4-(1-(3-fluorophenyl)-1H-indazole-5-anilino) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl)-2-propine acid amides synthetic
The preparation method is with compound 1, and different is that II-3a is replaced with II-3c, and vinylformic acid is replaced with propynoic acid, obtains light yellow solid, yield 45%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.11(s，1H)，9.08(d，J＝1.6Hz，1H)，8.62(s，1H)，8.53(s，1H)，8.23-8.29(m，3H)，8.17(s，1H)，7.84(d，J＝8.8Hz，1H)，7.74(d，J＝2Hz，2H)，7.35-7.38(m，1H)，7.05-7.13(m，3H)，5.71(s，2H)，4.63(t，J＝5.6Hz，2H)，4.61(s，1H)，3.76(dd，J＝11.6，6.0Hz，2H).
ESI-MS?m/z：532.1(M+H)
+，530.1(M-H)
-
Embodiment 11:
Synthesizing of compound 11.N-(2-(4-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl)-1H-1,2,3 ,-triazol-1-yl) ethyl) acrylic amide
The preparation method is with compound 1, and different is that II-3a is replaced with II-3b, obtains light yellow solid, yield 56%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.14(s，1H)，9.07(s，1H)，8.66(s，2H)，8.23-8.34(m，3H)，7.87-7.89(m，2H)，7.47(t，J＝8.8Hz，1H)，6.06-6.22(m，2H)，5.60(dd，J＝10.0，2.0Hz，1H)，4.59(t，J＝6.4Hz，2H)，3.67(d，J＝11.2Hz，2H).
ESI-MS?m/z：438.1(M+H)
+，436.1(M-H)
-
Embodiment 12:
Synthesizing of compound 12. (E)-N-(2-(4-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl)-1H-1,2,3 ,-triazol-1-yl) ethyl)-but-2-enamides
The preparation method is with compound 1, and different is that II-3a is replaced with II-3b, and vinylformic acid is replaced with Ba Dousuan, obtains light yellow solid, yield 57%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.13(s，1H)，9.09(s，1H)，8.64(s，1H)，8.13-8.29(m，3H)，7.89(s，2H)，7.47(t，J＝8.8Hz，1H)，6.60-6.65(m，1H)，5.86(d，J＝15.2Hz，1H)，4.56(t，J＝5.6Hz，2H)，3.64(dd，J＝11.6，6.0Hz，2H)，1.77(dd，J＝6.8，1.6Hz，3H).
ESI-MS?m/z：452.1(M+H)
+，450.1(M-H)
-
Embodiment 13:
Synthesizing of compound 13. (E)-N-(2-(4-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl)-1H-1,2,3 ,-triazol-1-yl) ethyl)-4-morphine quinoline butyl-2-alkene acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with II-3b, vinylformic acid is replaced with (E)-4-morphine quinoline butyl-2-olefin(e) acid, obtains light yellow solid, yield 46%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.18(s，1H)，9.11(s，1H)，8.69(s，1H)，8.65(s，1H)，8.23-8.34(m，3H)，7.89(s，2H)，7.47(t，J＝8.8Hz，1H)，6.52-6.59(dt，J＝13.2，6Hz，1H)，6.06(d，J＝15.6Hz，1H)，4.57(t，J＝6.4Hz，2H)，3.67(d，J＝6.0Hz，2H)，3.59(t，J＝4.8Hz，4H)，3.21(d，J＝6.4Hz，2H)，2.45(s，4H).
ESI-MS?m/z：537.1(M+H)
+，535.1(M-H)
-
Embodiment 14:
Synthesizing of compound 14. (E)-N-(2-(4-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl)-1H-1,2,3 ,-triazol-1-yl) ethyl)-4-(dimethylamino)-butyl-2-alkene acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with II-3b, vinylformic acid is replaced with (E)-4-(dimethylamino)-butyl-2-olefin(e) acid, obtains light yellow solid, yield 47%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.15(s，1H)，9.08(s，1H)，8.69(s，1H)，8.66(s，1H)，8.21-8.28(m，3H)，7.89(s，2H)，7.47(t，J＝8.8Hz，1H)，6.55-6.58(m，1H)，6.00(d，J＝15.6Hz，1H)，4.57(t，J＝5.6Hz，2H)，3.66(dd，J＝11.6，6.0Hz，2H)，3.02(d，J＝6.4Hz，2H)，2.15(s，6H).
ESI-MS?m/z：495.1(M+H)
+，493.1(M-H)
-
Embodiment 15:
Synthesizing of compound 15.N-(2-(4-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl)-1H-1,2,3 ,-triazol-1-yl) ethyl) propine acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with II-3b, and vinylformic acid is replaced with propynoic acid, obtains light yellow solid, yield 45%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.14(s，1H)，9.07(s，1H)，8.66(s，2H)，8.23-8.34(m，3H)，7.87-7.89(m，2H)，7.47(t，J＝8.8Hz，1H)，4.59(t，J＝6.4Hz，2H)，4.32(s，1H)，3.67(d，J＝11.2Hz，2H).
ESI-MS?m/z：436.1(M+H)
+，434.1(M-H)
-
Embodiment 16:
Synthesizing of compound 16.N-(2-(4-(4-(2-(3-fluorophenyl)-2H-indazole-5-amido) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl) acrylic amide
The preparation method is with compound 1, and different is that II-3a is replaced with II-3d, obtains light yellow solid, yield 38%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.04(s，1H)，9.08(s，1H)，8.68(d，J＝4.4Hz，1H)，8.23-8.29(m，2H)，8.44(s，1H)，8.32(d，J＝8.4Hz，1H)，8.27(s，1H)，7.83(d，J＝8.0Hz，1H)，7.71(d，J＝8.8Hz，1H)，7.62(d，J＝8.8Hz，1H)，7.38-7.44(m，1H)，7.15-7.17(m，3H)，6.06-6.24(m，2H)，5.67(s，2H)，5.60(d，J＝8.8Hz，1H)，4.53(t，J＝5.6Hz，2H)，3.67(dd，J＝11.6，6.0Hz，2H).
ESI-MS?m/z：534.1(M+H)
+，532.1(M-H)
-
Embodiment 17:
Synthesizing of compound 17.N-(2-(4-(4-(2-(3-fluorophenyl)-2H-indazole-5-amido) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl) but-2-enamides
The preparation method is with compound 1, and different is that II-3a is replaced with II-3d, and vinylformic acid is replaced with Ba Dousuan, obtains light yellow solid, yield 29%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.03(s，1H)，9.11(s，1H)，8.62(s，1H)，8.52(s，1H)，8.30(s，1H)，8.21(s，1H)，8.15(t，J＝6.4Hz，1H)，7.65(dd，J＝22.4，8.8Hz，2H)，7.41(dd，J＝14.4，7.6Hz，1H)，7.16(d，J＝8.8Hz，3H)，6.60-6.66(m，1H)，5.87(d，J＝15.2Hz，1H)，5.68(s，2H)，4.56(t，J＝5.6Hz，2H)，3.64(dd，J＝11.6，6.0Hz，2H)，1.77(dd，J＝6.8，1.6Hz，3H).
ESI-MS?m/z：548.1(M+H)
+，546.1(M-H)
-
Embodiment 18:
Synthesizing of compound 18.N-(2-(4-(4-(2-(3-fluorophenyl)-2H-indazole-5-amido) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl)-4-morphine quinoline butyl-2-alkene acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with II-3d, vinylformic acid is replaced with (E)-4-morphine quinoline butyl-2-olefin(e) acid, obtains light yellow solid, yield 34%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.21(s，1H)，9.30(s，1H)，8.88(d，J＝4.4Hz，1H)，8.23-8.29(m，2H)，8.44(s，1H)，8.32(d，J＝8.4Hz，1H)，8.27(s，1H)，7.83(d，J＝8.0Hz，1H)，7.71(d，J＝8.8Hz，1H)，7.62(d，J＝8.8Hz，1H)，7.38-7.44(m，1H)，7.15-7.17(m，3H)，6.52-6.59(dt，J＝13.2，6Hz，1H)，6.06(d，J＝15.6Hz，1H)，5.68(s，2H)，4.56(t，J＝6.0Hz，2H)，3.65(d，J＝6.0Hz，2H)，3.53(t，J＝4.8Hz，4H)，3.04(d，J＝6.4Hz，2H)，2.32(s，4H).
ESI-MS?m/z：633.2(M+H)
+，631.2(M-H)
-
Embodiment 19:
Synthesizing of compound 19.N-(2-(4-(4-(2-(3-fluorophenyl)-2H-indazole-5-amido) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl)-4-(dimethylamino)-butyl-2-alkene acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with II-3d, vinylformic acid is replaced with (E)-4-(dimethylamino)-butyl-2-olefin(e) acid, obtains light yellow solid, yield 58%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.06(s，1H)，9.12(s，1H)，8.68(s，1H)，8.55(s，1H)，8.52(s，1H)，8.22-8.37(m，3H)，7.84(d，J＝8.8Hz，1H)，7.63(s，2H)，7.41(dd，J＝13.6，7.6Hz，1H)，7.16(d，J＝8.8Hz，3H)，6.55-6.62(m，1H)，6.06(d，J＝15.6Hz，1H)，5.68(s，2H)，4.57(t，J＝4.8Hz，2H)，3.67(dd，J＝11.6，6.0Hz，2H)，2.87(d，J＝6.4Hz，2H)，2.26(s，6H).
ESI-MS?m/z：591.2(M+H)
+，589.2(M-H)
-
Embodiment 20:
Synthesizing of compound 20.N-(2-(4-(4-(2-(3-fluorophenyl)-2H-indazole-5-amido) quinazoline-6-yl)-1H-1,2,3-triazol-1-yl) ethyl) propine acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with II-3d, and vinylformic acid is replaced with propynoic acid, obtains light yellow solid, yield 55%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.00(s，1H)，9.08(s，1H)，8.68(d，J＝4.4Hz，1H)，8.23-8.29(m，2H)，8.44(s，1H)，8.32(d，J＝8.4Hz，1H)，8.27(s，1H)，7.83(d，J＝8.0Hz，1H)，7.71(d，J＝8.8Hz，1H)，7.62(d，J＝8.8Hz，1H)，7.38-7.44(m，1H)，7.15-7.17(m，3H)，5.67(s，2H)，4.36(t，J＝5.6Hz，2H)，4.30(s，1H)，3.55(dd，J＝11.6，6.0Hz，2H).
ESI-MS?m/z：532.1(M+H)
+，530.1(M-H)
-
Embodiment 21:
Synthesizing of compound 21.N-((1-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido) quinazoline-6-yl)-1H-1,2,3-triazole-4-yl) methyl) acrylic amide
The preparation method is with compound 1, and different is that II-3a is replaced with I-6c, obtains light yellow solid, yield 35%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.13(s，1H)，9.07(d，J＝2.0Hz，1H)，8.76(t，J＝2.0Hz，1H)，8.73(s，1H)，8.60(s，1H)，8.38(d，J＝8.8Hz，1H)，8.23(s，1H)，8.18(s，1H)，7.96(d，J＝8.8Hz，1H)，7.76(dd，J＝8.8，2.4Hz，2H)，7.54-7.43(m，1H)，7.075-7.05(m，3H)，6.12-6.35(m，2H)，5.71(s，2H)，5.66(d，J＝8.8Hz，1H)，4.53(d，J＝5.6Hz，2H).
ESI-MS?m/z：520.5(M+H)
+，518.5(M-H)
-
Embodiment 22:
Synthesizing of compound 22. (E)-N-((1-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido) quinazoline-6-yl)-1H-1,2,3-triazole-4-yl) methyl)-but-2-enamides
The preparation method is with compound 1, and different is that II-3a is replaced with I-6c, and vinylformic acid is replaced with Ba Dousuan, obtains light yellow solid, yield 46%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.15(s，1H)，9.09(d，J＝2.0Hz，1H)，8.72(s，1H)，8.59(s，1H)，8.55(t，J＝2.0Hz，1H)，8.41(d，J＝8.8Hz，1H)，8.23(s，1H)，8.18(s，1H)，7.96(d，J＝8.8Hz，1H)，7.76(dd，J＝8.8，2.4Hz，2H)，7.54-7.43(m，1H)，7.07-7.05(m，3H)，6.63-6.72(m，1H)，5.96(dd，J＝15.2，2.0Hz，1H)，5.71(s，2H)，4.51(d，J＝6.0Hz，2H)，1.77(dd，J＝6.8，1.2Hz，3H).
ESI-MS?m/z：534.2(M+H)
+，532.2(M-H)
-
Embodiment 23:
Synthesizing of compound 23. (E)-N-((1-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido) quinazoline-6-yl)-1H-1,2,3-triazole-4-yl) methyl)-4-morphine quinoline butyl-2-alkene acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with I-6c, vinylformic acid is replaced with (E)-4-morphine quinoline butyl-2-olefin(e) acid, obtains light yellow solid, yield 43%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.13(s，1H)，9.08(d，J＝2.0Hz，1H)，8.72(s，1H)，8.70(t，J＝2.0Hz，1H)，8.59(s，1H)，8.40(d，J＝8.8Hz，1H)，8.23(s，1H)，8.18(s，1H)，7.96(d，J＝8.8Hz，1H)，7.72(dd，J＝8.8，2.4Hz，2H)，7.34-7.38(m，1H)，7.13-7.05(m，3H)，6.58-6.65(dt，J＝13.2，6Hz，1H)，6.10(d，J＝15.2Hz，1H)，5.72(s，2H)，4.52(d，J＝6.0Hz，2H)，3.57(t，J＝4.8Hz，4H)，3.06(d，J＝5.6Hz，2H)，2.35(s，4H).
ESI-MS?m/z：619.2(M+H)
+，617.2(M-H)
-
Embodiment 24:
Synthesizing of compound 24. (E)-N-((1-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido) quinazoline-6-yl)-1H-1,2,3-triazole-4-yl) methyl)-4-(dimethylamino)-butyl-2-alkene acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with I-6c, vinylformic acid is replaced with (E)-4-(dimethylamino)-butyl-2-olefin(e) acid, obtains light yellow solid, yield 45%.
1H?NMR(400MHz，DMSO-d
6)δppm 10.13(s，1H)，9.09(s，1H)，8.74(s，1H)，8.68(t，J＝2.0Hz，1H)，8.57(s，1H)，8.40(d，J＝8.8Hz，1H)，8.23(s，1H)，8.18(s，1H)，7.94(d，J＝8.8Hz，1H)，7.72(dd，J＝8.8，2.4Hz，2H)，7.34-7.40(m，1H)，7.13-7.05(m，3H)，6.53-6.60(m，1H)，6.07(d，J＝15.6Hz，1H)，5.71(s，2H)，4.52(d，J＝4.8Hz，2H)，2.95(d，J＝6.4Hz，2H)，2.11(s，6H).
ESI-MS?m/z：577.2(M+H)
+，575.2(M-H)
-
Embodiment 25:
Synthesizing of compound 25.N-((1-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido) quinazoline-6-yl)-1H-1,2,3-triazole-4-yl) methyl)-2-propine acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with I-6c, and vinylformic acid is replaced with propynoic acid, obtains light yellow solid, yield 48%.
1H?NMR(400MHz，DMSO-d
6)δppm 10.13(s，1H)，9.07(d，J＝2.0Hz，1H)，8.76(t，J＝2.0Hz，1H)，8.73(s，1H)，8.60(s，1H)，8.38(d，J＝8.8Hz，1H)，8.23(s，1H)，8.18(s，1H)，7.96(d，J＝8.8Hz，1H)，7.76(dd，J＝8.8，2.4Hz，2H)，7.54-7.43(m，1H)，7.075-7.05(m，3H)，5.71(s，2H)，4.53(d，J＝5.6Hz，2H)，4.30(s，1H).
ESI-MS?m/z：518.1(M+H)
+，516.1(M-H)
-
Embodiment 26:
Synthesizing of compound 26.N-((1-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl)-1H-1,2,3-triazole-4-yl) methyl) acrylic amide
The preparation method is with compound 1, and different is that II-3a is replaced with I-6b, obtains light yellow solid, yield 48%.
1H?NMR(400MHz，DMSO-d
6)δppm 10.14(s，1H)，9.07(s，1H)，8.73(s，1H)，8.70(s，1H)，8.38-8.44(m，1H)，8.19(d，J＝6.4Hz，1H)，8.00(d，J＝8.8Hz，1H)，7.83-7.86(m，1H)，7.49(t，J＝8.8Hz，1H)，6.12-6.32(m，2H)，5.63(dd，J＝10.0，2.4Hz，1H)，4.53(d，J＝5.6Hz，2H).
ESI-MS?m/z：423.1(M+H)
+，421.1(M-H)
-
Embodiment 27:
Synthesizing of compound 27. (E)-N-((1-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl)-1H-1,2,3-triazole-4-yl) methyl)-but-2-enamides
The preparation method is with compound 1, and different is that II-3a is replaced with I-6b, and vinylformic acid is replaced with Ba Dousuan, obtains light yellow solid, yield 54%.
1H?NMR(400MHz，DMSO-d
6)δppm 10.15(s，1H)，9.06(d，J＝2.0Hz，1H)，8.72(s，1H)，8.70(s，1H)，8.56(t，J＝5.6Hz，1H)，8.40-8.44(m，1H)，8.19(dd，J＝6.8，2.4Hz，1H)，7.99(d，J＝8.8Hz，1H)，7.82-7.86(m，1H)，7.48(t，J＝8.8Hz，1H)，6.64-6.73(m，1H)，5.95(dd，J＝15.2，1.2Hz，1H)，4.51(d，J＝5.6Hz，2H)，1.80(d，J＝6.8Hz，3H).
ESI-MS?m/z：438.1(M+H)
+，436.1(M-H)
-
Embodiment 28:
Synthesizing of compound 28. (E)-N-((1-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl)-1H-1,2,3-triazole-4-yl) methyl)-4-morphine quinoline butyl-2-alkene acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with I-6b, vinylformic acid is replaced with (E)-4-morphine quinoline butyl-2-olefin(e) acid, obtains light yellow solid, yield 56%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.14(s，1H)，9.07(s，1H)，8.73(s，1H)，8.70(s，2H)，8.38-8.44(m，1H)，8.19(d，J＝6.4Hz，1H)，8.00(d，J＝8.8Hz，1H)，7.83-7.86(m，1H)，7.49(t，J＝8.8Hz，1H)，6.58-6.65(dt，J＝13.2，6Hz，1H)，6.12(d，J＝8.8Hz，1H)，4.51(d，J＝5.6Hz，2H)，3.57(t，J＝4.8Hz，4H)，3.06(d，J＝5.6Hz，2H)，2.35(s，4H).
ESI-MS?m/z：523.1(M+H)
+，521.1(M-H)
-
Embodiment 29:
Synthesizing of compound 29. (E)-N-((1-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl)-1H-1,2,3-triazole-4-yl) methyl)-4-(dimethylamino)-butyl-2-alkene acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with I-6b, vinylformic acid is replaced with (E)-4-(dimethylamino)-butyl-2-olefin(e) acid, obtains light yellow solid, yield 58%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.14(s，1H)，9.07(s，1H)，8.73(s，1H)，8.70(s，2H)，8.38-8.44(m，1H)，8.19(d，J＝6.4Hz，1H)，8.00(d，J＝8.8Hz，1H)，7.83-7.86(m，1H)，7.49(t，J＝8.8Hz，1H)，6.58-6.65(dt，J＝15.2，6.0Hz，1H)，6.11(d，J＝15.6Hz，1H)，4.51(d，J＝5.6Hz，2H)，2.99(d，J＝5.6Hz，2H)，2.14(s，6H).
ESI-MS?m/z：481.1(M+H)
+，479.1(M-H)
-
Embodiment 30:
Synthesizing of compound 30.N-((1-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl)-1H-1,2,3-triazole-4-yl) methyl) propine acid amides
The preparation method is with compound 1, and different is that II-3a is replaced with I-6b, and vinylformic acid is replaced with propynoic acid, obtains light yellow solid, yield 45%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.14(s，1H)，9.07(s，1H)，8.73(s，1H)，8.70(s，2H)，8.38-8.44(m，1H)，8.19(d，J＝6.4Hz，1H)，8.00(d，J＝8.8Hz，1H)，7.83-7.86(m，1H)，7.49(t，J＝8.8Hz，1H)，4.53(d，J＝5.6Hz，2H)，4.30(s，1H).
ESI-MS?m/z：422.1(M+H)
+，420.1(M-H)
-
The embodiment hentriaconta-:
Compound 31.N-(3-chloro-4-(3-fluorine benzyloxy) phenyl)-6-(4-(acrylic amide-N-methyl))-1H-1,2,3-triazol-1-yl)-4-amido quinazoline synthetic
The preparation method is with compound 1, and different is that II-3a is replaced with I-6a, obtains light yellow solid, yield 34%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.2(s，1H)，9.06(s，1H)，8.72(s，1H)，8.65(s，1H)，8.37(dd，J＝8.8，2.0Hz，1H)，8.03(d，J＝2.4Hz，1H)，7.99(d，J＝9.2Hz，1H)，7.76(dd，J＝8.8，2.4Hz，1H)，7.54-7.43(m，1H)，7.35-7.29(m，3H)，7.19(t，J＝8.0Hz，1H)，6.29(dd，J＝17.2，10.0Hz，1H)，6.15(dd，J＝17.2，2.4Hz，1H)，5.64(dd，J＝10.4，2.4Hz，1H)，5.27(s，2H)，4.53(d，J＝6.4Hz，1H)
ESI-MS?m/z：530.1(M+H)
+，528.1(M-H)
-
Embodiment 32:
Synthesizing of compound 32.N-(5-(4-(3-chloro-4-fluoroanilino) quinazoline-6-yl)-1,3,4-oxadiazole-2-yl) acrylic amide
The preparation method is with compound 1, and different is that II-3a is replaced with III-5b, obtains light yellow solid, yield 44%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.11(s，1H)，9.07(s，1H)，8.53(s，1H)，8.32-8.40(m，1H)，8.25(d，J＝6.4Hz，1H)，8.00(d，J＝8.8Hz，1H)，7.85-7.87(m，1H)，7.53(t，J＝8.8Hz，1H)，6.15-6.30(m，2H)，5.80(dd，J＝10.0，2.4Hz，1H)，4.66(d，J＝5.6Hz，2H).
ESI-MS?m/z：411.8(M+H)
+，409.8(M-H)
-
Embodiment 33:
Synthesizing of compound 33. (E)-4-(dimethylamino)-N-(5-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido) quinazoline-6-yl)-1,3,4-oxadiazole-2-yl) but-2-enamides
The preparation method is with compound 1, and different is that II-3a is replaced with 111-5c, vinylformic acid is replaced to (E)-4-(dimethylamino)-butyl-2-olefin(e) acid, obtains light yellow solid, yield 42%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.14(s，1H)，9.21(s，1H)，8.74(s，1H)，8.66(t，J＝2.0Hz，1H)，8.45(d，J＝8.8Hz，1H)，8.33(s，1H)，8.20(s，1H)，7.94(d，J＝8.8Hz，1H)，7.82(dd，J＝8.8，2.4Hz，2H)，7.30-7.35(m，1H)，7.13-7.05(m，3H)，6.53-6.60(m，1H)，6.03(d，J＝15.6Hz，1H)，5.68(s，2H)，4.32(d，J＝4.8Hz，2H)，2.95(d，J＝6.4Hz，2H)，2.10(s，6H).
ESI-MS?m/z：564.6(M+H)
+，562.6(M-H)
-
Embodiment 34:
Compound 34. (E)-N-(synthesizing of 4-(4-(3-chloro-4-fluoroanilino) quinazoline-6-base) oxazole-2-yl)-4-(dimethylamino) but-2-enamides
The preparation method is with compound 1, and different is that II-3a is replaced with IV-4b, vinylformic acid is replaced to (E)-4-(dimethylamino)-butyl-2-olefin(e) acid, obtains light yellow solid, yield 53%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.14(s，1H)，9.07(s，1H)，8.75(s，1H)，8.69(s，1H)，8.38-8.44(m，1H)，8.20(d，J＝6.4Hz，1H)，8.00(d，J＝8.8Hz，1H)，7.85-7.88(m，1H)，7.53(t，J＝8.8Hz，1H)，6.56-6.60(dt，J＝15.2，6.0Hz，1H)，6.13(d，J＝15.6Hz，1H)，2.99(d，J＝5.6Hz，2H)，2.14(s，6H).
ESI-MS?m/z：467.9(M+H)
+，465.9(M-H)
-
Embodiment 35:
Compound 35.N-(synthesizing of 4-(4-(1-(3-fluoroanilino)-1H-indazole-5-amido) quinazoline-6-base) oxazole-2-yl) acrylic amide
The preparation method is with compound 1, and different is that II-3a is replaced with IV-4c, obtains light yellow solid, yield 48%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.13(s，1H)，9.06(d，J＝2.0Hz，1H)，8.78(t，J＝2.0Hz，1H)，8.70(s，1H)，8.66(s，1H)，8.34(d，J＝8.8Hz，1H)，8.20(s，1H)，8.16(s，1H)，7.99(d，J＝8.8Hz，1H)，7.86(dd，J＝8.8，2.4Hz，2H)，7.54-7.43(m，1H)，7.07-7.05(m，3H)，6.17-6.35(m，2H)，5.71(s，2H)，5.66(d，J＝8.8Hz，1H).
ESI-MS?m/z：506.5(M+H)
+，504.5(M-H)
-
Embodiment 36:
Synthesizing of compound 36.N-(4-(4-(3-chloro-4-fluoroanilino) quinazoline-6-yl) thiazol-2-yl) acrylic amide
The preparation method is with compound 1, and different is that II-3a is replaced with IV-4f, obtains light yellow solid, yield 42%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.13(s，1H)，9.06(s，1H)，8.77(s，1H)，8.75(s，2H)，8.38-8.44(m，1H)，8.25(d，J＝6.4Hz，1H)，8.00(d，J＝8.8Hz，1H)，7.83-7.86(m，1H)，7.55(t，J＝8.8Hz，1H)，6.08-6.22(m，2H)，5.63(dd，J＝10.0，2.4Hz，1H).
ESI-MS?m/z：426.8(M+H)
+，424.9(M-H)
-
Embodiment 37:
Synthesizing of compound 37.N-(4-(4-(1-(3-fluoroanilino)-1H-indazole-5-amido) quinazoline-6-yl) thiazol-2-yl) acrylic amide
The preparation method is with compound 1, and different is that II-3a is replaced with IV-4g, obtains light yellow solid, yield 50%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.16(s，1H)，9.07(d，J＝2.0Hz，1H)，8.78(t，J＝2.0Hz，1H)，8.70(s，1H)，8.66(s，1H)，8.35(d，J＝8.8Hz，1H)，8.28(s，1H)，8.16(s，1H)，7.99(d，J＝8.8Hz，1H)，7.86(dd，J＝8.8，2.0Hz，2H)，7.54-7.43(m，1H)，7.07-7.05(m，3H)，6.17-6.35(m，2H)，5.71(s，2H)，5.66(d，J＝8.8Hz，1H).
ESI-MS?m/z：522.6(M+H)
+，520.6(M-H)
-
Embodiment 38:
Synthesizing of compound 38. (E)-N-((5-(4-(3-chloro-4-fluoroanilino) quinazoline-6-yl)-1H-imidazoles-2-yl) methyl)-4-(dimethylamino) but-2-enamides
The preparation method is with compound 1, and different is that II-3a is replaced with V-2b, vinylformic acid is replaced to (E)-4-(dimethylamino)-butyl-2-olefin(e) acid, obtains light yellow solid, yield 29%.
1H?NMR(400MHz，DMSO-d
6)δppm?11.90(bs，1H)，10.13(s，1H)，9.06(s，1H)，8.83(s，2H)，8.75(s，2H)，8.40-8.43(m，1H)，8.19(d，J＝6.4Hz，1H)，8.00(d，J＝8.8Hz，1H)，7.80-7.85(m，1H)，7.55(t，J＝8.8Hz，1H)，6.58-6.65(dt，J＝15.2，6.4Hz，1H)，6.14(d，J＝15.6Hz，1H)，4.53(d，J＝6.4Hz，2H)，2.99(d，J＝6.4Hz，2H)，2.14(s，6H).
ESI-MS?m/z：481.0(M+H)
+，479.0(M-H)
-
Embodiment 39:
Synthesizing of compound 39. (E)-4-(dimethylamino)-N-((5-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido) quinazoline-6-yl)-1H-imidazoles-2-yl) methyl) but-2-enamides
The preparation method is with compound 1, and different is that II-3a is replaced with V-2c, vinylformic acid is replaced to (E)-4-(dimethylamino)-butyl-2-olefin(e) acid, obtains light yellow solid, yield 29%.
1H?NMR(400MHz，DMSO-d
6)δppm?11.90(bs，1H)，10.14(s，1H)，9.07(s，1H)，8.70(s，1H)，8.68(t，J＝2.4Hz，1H)，8.53(s，1H)，8.40(d，J＝8.8Hz，1H)，8.26(s，1H)，8.10(s，1H)，7.94(d，J＝8.8Hz，1H)，7.70(dd，J＝8.8，2.4Hz，2H)，7.34-7.40(m，1H)，7.15-7.08(m，3H)，6.54-6.60(m，1H)，6.04(d，J＝15.6Hz，1H)，5.71(s，2H)，4.52(d，J＝4.8Hz，2H)，2.95(d，J＝6.4Hz，2H)，2.11(s，6H).
ESI-MS?m/z：576.6(M+H)
+，574.6(M-H)
-
Embodiment 40:
Synthesizing of compound 40.N-(5-(4-(3-chloro-4-fluoroanilino) quinazoline-6-yl) furans-2-yl) acrylic amide
The preparation method is with compound 1, and different is that II-3a is replaced with VI-4b, obtains light yellow solid, yield 46%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.14(s，1H)，9.07(s，1H)，8.43-8.46(m，1H)，8.37(d，J＝6.8Hz，1H)，8.00(d，J＝8.8Hz，1H)，7.85-7.87(m，1H)，7.53(t，J＝8.8Hz，1H)，7.32(d，J＝8.8Hz，1H)，7.25(d，J＝8.8Hz，1H)，6.15-6.30(m，2H)，5.80(dd，J＝10.0，2.4Hz，1H)，4.66(d，J＝5.6Hz，2H).
ESI-MS?m/z：423.8(M+H)
+，421.8(M-H)
-
Embodiment 41:
Synthesizing of compound 41.N-(5-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido) quinazoline-6-yl) furans-2-yl) acrylic amide
The preparation method is with compound 1, and different is that II-3a is replaced with VI-4c, obtains light yellow solid, yield 56%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.13(s，1H)，9.07(d，J＝2.0Hz，1H)，8.76(t，J＝2.0Hz，1H)，8.73(s，1H)，8.60(s，1H)，8.38(d，J＝8.8Hz，1H)，8.18(s，1H)，7.96(d，J＝8.8Hz，1H)，7.76(dd，J＝8.8，2.4Hz，2H)，7.54-7.43(m，1H)，7.30(d，J＝8.8Hz，1H)，7.20(d，J＝8.8Hz，1H)，7.07-7.05(m，3H)，6.12-6.35(m，2H)，5.71(s，2H)，5.62(d，J＝8.8Hz，1H)，4.44(d，J＝5.6Hz，2H).
ESI-MS?m/z：519.5(M+H)
+，517.5(M-H)
-
Embodiment 42:
Synthesizing of compound 42. (E)-N-(5-(4-(3-chloro-4-fluoroanilino) quinazoline-6-yl) thiophene-2-yl)-4-(dimethylamino) but-2-enamides
The preparation method is with compound 1, and different is that II-3a is replaced with VI-4f, obtains light yellow solid, yield 54%.
1H?NMR(400MHz，DMSO-d
6)δppm?10.12(s，1H)，9.05(s，1H)，8.53-8.56(m，1H)，8.38(d，J＝6.8Hz，1H)，8.00(d，J＝8.8Hz，1H)，7.85-7.87(m，1H)，7.72(d，J＝8.8Hz，1H)，7.65(d，J＝8.8Hz，1H)，7.58(t，J＝8.8Hz，1H)，6.04(d，J＝15.6Hz，1H)，5.88(dd，J＝10.0，2.0Hz，1H)，4.66(d，J＝5.6Hz，2H)，2.95(d，J＝6.4Hz，2H)，2.11(s，6H).
ESI-MS?m/z：497.0(M+H)
+，495.0(M-H)
-
Embodiment 43:
Synthesizing of compound 43. (E) N-(5-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido) quinazoline-6-yl) thiophene-2-yl)-4-(dimethylamino) but-2-enamides
The preparation method is with compound 1, and different is that II-3a is replaced with VI-4g, obtains light yellow solid, yield 37%.
1H?NMR(400MHz，DMSO-d
6)δppm?
1H?NMR(400MHz，DMSO-d
6)δppm?10.14(s，1H)，9.21(s，1H)，8.74(s，1H)，8.66(t，J＝2.0Hz，1H)，8.45(d，J＝8.8Hz，1H)，8.33(s，1H)，8.20(s，1H)，7.94(d，J＝8.8Hz，1H)，7.82(dd，J＝8.8，2.4Hz，2H)，7.68(d，J＝8.8Hz，1H)，7.61(d，J＝8.8Hz，1H)，7.30-7.35(m，1H)，7.13-7.05(m，3H)，6.53-6.60(m，1H)，6.03(d，J＝15.6Hz，1H)，5.68(s，2H)，4.32(d，J＝4.8Hz，2H)，2.95(d，J＝6.4Hz，2H)，2.10(s，6H).
ESI-MS?m/z：592.6(M+H)
+，590.6(M-H)
-
The test of embodiment 44 enzyme inhibition activities
External enzyme inhibition activity is used ELISA
Target compound is measured employing Z '-LYTE to EGFR and HER2 enzyme inhibition activity
TMKinases testing cassete (invitrogen
TM, Z '-LYTE
TMKinase assay kit-TYR6peptide, reference: Nature, 373, pp.536-9 (1995)) test.
According to Z '-LYTE
TMKinases testing cassete working instructions carry out the reagent configuration; Earlier be added on 384 orifice plates to enzyme and medicine according to certain proportioning respectively, mixing is placed 30min; Add ATP then, mixing is placed 2h; Add 5 μ L Development Regent, mixing under room temperature, is placed 15min, 30min, and 1h detects with ELIASA; Add the Stop regent of 5 μ L behind the 1h, detect with ELIASA behind the mixing.Calculate corresponding phosphorylation ratio,, obtain dose response curve, therefrom try to achieve the half-inhibition concentration (IC of medicine according to drug concentrations and corresponding kinase inhibition rate mapping
50).The result is following:
Half-inhibition concentration (the IC of table 1 couple EGFR and HER2 enzyme
50)
Above content is to combine concrete preferred implementation to the further explain that the present invention did, and can not assert that practical implementation of the present invention is confined to these explanations.For the those of ordinary skill of technical field under the present invention, under the prerequisite that does not break away from the present invention's design, can also make some simple deduction or replace, all should be regarded as belonging to protection scope of the present invention.
Claims (10)
1. tyrosine kinase irreversible inhibitor is characterized in that general formula of molecular structure I is following:
General formula I
Wherein, Y restrains acceptor class and active alkyls compound for stepping,
X is for containing one or more heteroatomic ring compounds,
Ar is phenyl and substituted phenyl, and contains the also aryl and the heteroaryl compound of lopps,
R is H, C1-C6 alkyl and unsaturated alkyl,
W is C1-C6 alkyl and unsaturated alkyl or do not have,
R
6Be H, C1-C6 alkyl and unsaturated alkyl, C6-C10 substituted aralkyl, F, Cl, Br, I, CF
3, CHF
2, CH
2F, OR
7, NR
7R
8, CN, CO
2R
7, CONR
7R
8, SO
2R
7, SO
2NR
7R
8, NO
2, NCONR
7R
8, NCO
2R
7, OCONR
7R
8, CSNR
7R
8, NCSNR
7R
8,
R
7, R
8Can separately or be respectively: the saturated and unsaturated alkyl of hydrogen, C1-6 and the substituted alkyl of heteroatoms.
2. a kind of tyrosine kinase irreversible inhibitor according to claim 1 is characterized in that: II is following for the X general structure:
General formula I I
Wherein, V, U, T, Q, Z can be simultaneously or are CH independently, O, S, N, NH group form particularly aryl-heterocyclic substituted radical of cyclic substituents,
Y is an acrylic, the propine acidic group, and vinyl sulfonic acid base and phosphate and corresponding substitutional crylic acid base, propynoic acid group, acrylic, propine acidic group come as stepping the gram acceptor.
3. a kind of tyrosine kinase irreversible inhibitor according to claim 2 is characterized in that X is following group or substituted following group:
Wherein, R
2Saturated and unsaturated alkyl and the substituted alkyl of heteroatoms for hydrogen, C1-6;
Y is preferably following group:
Wherein, R
3, R
4, R
5Can be H independently perhaps simultaneously, F, Cl, C1-C6 alkyl or unsaturated alkyl contain O, N, S, heteroatomic C1-C6 alkyl such as P, cyclic alkyl or unsaturated chain and cyclic alkyl, R
3, R
4, R
5Two substituting groups also can Cheng Huan;
W is C1-C6 alkyl and unsaturated alkyl;
R is H, C1-C6 alkyl and unsaturated alkyl;
Ar is following group:
4. a kind of tyrosine kinase irreversible inhibitor according to claim 2 is characterized in that: X is preferably following group:
Wherein, R
2Saturated and unsaturated alkyl and the substituted alkyl of heteroatoms for hydrogen, C1-6;
Y is following group:
Wherein, R
3Be preferably H, F, Cl, C1-C6 alkyl or unsaturated alkyl,
R
9And R
10Can be simultaneously or independent be H, alkyl and substituted alkyl; R
9And R
10Also can form ring-type and contain heteroatomic ring texture.
Ar is preferably following group:
5. a kind of tyrosine kinase irreversible inhibitor according to claim 2 is characterized in that: Y is following group:
Wherein, R
3Be preferably H, the C1-C6 alkyl;
R
9And R
10Can be simultaneously or independent be H, alkyl and substituted alkyl, R
9And R
10Also can form ring-type and contain heteroatomic ring texture.
6. a kind of tyrosine kinase irreversible inhibitor according to claim 1 is characterized in that being selected from one of following compound:
General formula I
Annotate: "-" expression does not have.
7. the pharmacy acceptable salt of each described tyrosine kinase irreversible inhibitor of claim 1-6.
8. the pharmacy acceptable salt of tyrosine kinase irreversible inhibitor according to claim 7, the pharmacy acceptable salt that it is characterized in that described tyrosine kinase irreversible inhibitor is the salt of said tyrosine kinase irreversible inhibitor and mineral acid or organic acid list or diacid addition.
9. the preparation method of the described tyrosine kinase irreversible inhibitor of claim 1 is characterized in that adopting following route:
10. the application of each described tyrosine kinase irreversible inhibitor of claim 1-6 in the preparation antitumor drug.
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