CN102872018B - Tyrosine kinase irreversible inhibitor and preparation method and applications thereof - Google Patents

Tyrosine kinase irreversible inhibitor and preparation method and applications thereof Download PDF

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Publication number
CN102872018B
CN102872018B CN201210408582.8A CN201210408582A CN102872018B CN 102872018 B CN102872018 B CN 102872018B CN 201210408582 A CN201210408582 A CN 201210408582A CN 102872018 B CN102872018 B CN 102872018B
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compound
tyrosine kinase
base
quinazoline
irreversible inhibitor
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CN102872018A (en
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张健存
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Guangzhou Hengnuokang Pharmaceutical Technology Co., Ltd.
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Guangzhou Hengnuokang Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Abstract

The invention provides a tyrosine kinase irreversible inhibitor shown in a formula I or pharmaceutically acceptable salt thereof, a preparation method for the tyrosine kinase irreversible inhibitor and applications of the tyrosine kinase irreversible inhibitor. The invention belongs to the field of pharmaceutical chemistry. The tyrosine kinase irreversible inhibitor or the pharmaceutically acceptable salt thereof is very high in activity of inhibiting growth of cancer cells, and is especially remarkable in effect of inhibiting the growth of cancer cells with high expression of an epidermal growth factor receptor (EGFR) and type-2 human epidermal growth factor receptor (HER2).

Description

Tyrosine kinase irreversible inhibitor and its production and use
Technical field
The invention belongs to medicinal chemistry art, specifically, particularly relate to a tyrosine kinase irreversible inhibitor or its pharmaceutically acceptable salt and its production and use.
Background technology
Under normal circumstances, cell needs to obtain growth signals from resting state to vegetative state.These growth signals proceed to cell by the receptors bind on specific signaling molecule and cell membrane.EGF is wherein one of most important growth signals molecule.EGF receptor is distributed widely in the multi-functional transmembrane glycoprotein on each histiocyte of human body, belong to one of ErbB family member, this family has four members, be respectively EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), HER4 (erbB-4).They are Single polypeptide chain, and relative molecular mass about 1.7 × 1O5 ~ 1.85 × 1O5, respectively by the coded by said gene be positioned on coloured differently body.Often there are EGFR and HER2 two kinds of receptor process LAN phenomenons, the generation of this process LAN phenomenon and tumor, evolution close relation in multiple human tumor cell.
Finding in clinical tumor research, all can there is the process LAN phenomenon of one or more ErbB receptors in the malignant tumor of known 70%.In the kinds of tumor cells such as breast carcinoma, bladder cancer, pulmonary carcinoma, carcinoma of prostate, find that the expression of EGFR exceedes 100 times of normal cell level; Amplification or the process LAN phenomenon of HER2 is found in the kinds of tumor cells such as breast carcinoma, ovarian cancer, cervical cancer, carcinoma of prostate, nonsmall-cell lung cancer, nasopharyngeal carcinoma.The phenomenon of this process LAN indicates tumor patient prognosis mala usually, shows as that life cycle is short, tumor easily recurs, easily far-end transfer etc. occurs, and to chemotherapy or hormone therapy insensitive.
The Growth of Cells signal tyrosine kinase mediated due to ErbB plays very important effect in the generation, development of tumor, blocks the object that ErbB Cellular signalling network can reach Tumor suppression.With micromolecule ErbB receptor tyrosine kinase inhibitors (Tyrosine kinase inhibitors, TKIs), with the ATP-binding domain of ATP competitive binding in ErbB receptor tyrosine kinase, suppress kinase whose catalytic activity, thus the conduction blocking cell proliferation signals blocks one of ErbB receptor signaling pathways, the most effective approach of Tumor suppression growth.The tyrosine kinase micromolecular inhibitor of current exploitation listing comprises gefitinib (Iressa), erlotinid hydrochloride (Erlotinib), hydrochloric acid Conmana (Kai Meina) Lapatinib etc., wherein gefitinib, erlotinid hydrochloride, hydrochloric acid Conmana is EGFR reversible inhibitor, and Lapatinib is the dual reversible inhibitor of EGFR/HER2.
But external clinical study results finds, only about 10% tumour patient has objective reaction to said medicine, and all the other are all reactionless or have resistance.Treat start time about 10% tumour patient that responds in, great majority are also final produces resistance to it, and prolongation patient's life-span is not improved.Trace it to its cause, be the rapid generation of drug resistance.EGFR T790M sudden change is the major reason causing drug resistance, the change of the amino acid residue skeleton that sudden change causes makes reversible EGFR inhibitor as the ATP-binding domain of gefitinib, erlotinid hydrochloride disengaging ErbB receptor tyrosine kinase, thus loss of activity.
In order to overcome drug resistance and the large shortcoming of early stage reversible inhibitor dosage, scholars start the research focusing on irreversible inhibitor.Sulfydryl on Cys773 and the Cys805 amino acid residue at edge, EGFR and HER2 kinases ATP-binding domain is utilized to have the feature of stronger nucleophilicity, a Michael addition receptor is introduced in drug molecule, enable drug molecule and kinases form covalent bond to be combined, reach the object of irreversible suppression.
Large quantifier elimination shows, the double inhibitor of development targeting EGFR and HER2 tyrosine kinase has following advantage: 1. suppress EGFR and HER2 two kinds of tyrosine kinase simultaneously, is easier to overcome other members of EGFR family when using single tyrosine kinase inhibitor and raises the Growth of Cells signal redundancy caused thus the Drug resistance produced; 2., because EGFR and HER2 heterodimer activity is the highest, the double inhibitor of EGFR and HER2 tyrosine kinase is effective to most cancer patients.3., compared with single inhibitor, double inhibitor has synergistic effect to inhibiting tumour cells effect.In vitro and in vivo test also shows, is greater than the suppression to single receptor to the anticancer effect of EGFR and HER2 tyrosine kinase double inhibition.In addition with use compared with two medicines acting on single target spot respectively simultaneously, the medicine patient acting on two target spots uses more convenient, can also avoid the interaction of medicine and medicine.
In sum, the dual irreversible inhibitor developing targeting EGFR and HER2 tyrosine kinase is the selection of rationality.
At present, the irreversible dual tyrosine kinase inhibitor entering clinical research has BIBW2992, HKI-272 and PF299804, and clinical laboratory data shows that this kind of inhibitor has good DEVELOPMENT PROSPECT.
Recently disclosed relevant to EGFR and/or HER2 tyrosine kinase inhibitor have following patent: the tyrosine kinase irreversible inhibitor that CN101824029 announces, its medical composition and its use; WO2009012647 announce quinazoline derivative preparation method and in application pharmaceutically; CN102153544 discloses preparation and the purposes of a class Novel tyrosine kinase inhibitors; The protein tyrosine kinase aryl with selective inhibition of HER-2-2 autophosphorylation properties that CN1187129 announces and heteroaryl quinazoline compounds; The human epidermis growth factor acceptor 2 tyrosinase inhibitor that CN1651418 announces; The quinazoline compounds that CN101003513 announces or its officinal salt and its preparation method and medicinal usage; 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 with anti-tumor activity that CN101367793 announces.
Summary of the invention
First object of the present invention is to provide a kind of tyrosine kinase irreversible inhibitor or its pharmaceutically acceptable salt, and its general formula of molecular structure I is as follows:
Wherein, Y is selected from: step gram youngster's receptor compounds, active alkylation compounds;
Ar is selected from: phenyl, the phenyl of replacement, contains and the aryl of lopps, heteroaryl;
R is selected from: H, C 1-C 6alkyl or unsaturated alkyl;
W is selected from: C 1-C 6alkyl or substituted alkyl or unsaturated alkyl;
A, B, C are optionally separately: CH, N, S or nothing.
In certain embodiments, the group comprising A, B, C described in is selected from one of following:
Wherein, R 6be selected from: H, C 1-C 6alkyl or unsaturated alkyl, C 6-C 10substituted 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 8be optionally separately: hydrogen, C 1-6the alkyl of saturated and unsaturated alkyl and hybrid atom MCM-41.
In certain embodiments, Y is selected from following group:
Wherein, R 3, R 4, R 5be optionally separately: H, F, CN, Cl, C 1-C 6alkyl or unsaturated alkyl, containing the heteroatomic C of O, N, S, P 1-C 6alkyl, cyclic alkyl, unsaturated chain or cyclic alkyl, R 3, R 4, R 5in any two substituent group ring formation.
In certain embodiments,
R 9, R 10be optionally separately: hydrogen, C 1-6saturated and unsaturated alkyl, the alkyl containing O, N, S, P hybrid atom MCM-41; R 9and R 10ring formation;
n＝1-6。
W is preferably CH 2, CH 2cH 2, CH 2cH 2cH 2;
R is preferably H, CH 3, CH 2cH 3;
In certain embodiments, Ar is preferably from following group:
Wherein, R 6definition as above.
In certain embodiments, this tyrosine kinase irreversible inhibitor is preferably from following compound:
Wherein, Y is selected from following group:
R 3, R 4, R 5be optionally separately: H, F, CN, Cl, C 1-C 6alkyl or unsaturated alkyl, containing the heteroatomic C of O, N, S, P 1-C 6alkyl, cyclic alkyl, unsaturated chain or cyclic alkyl, R 3, R 4, R 5in any two substituent group ring formation, become containing heteroatomic 3-8 ring;
Ar is selected from following group:
Wherein, R 6definition as claim 2;
R 7, R 8be optionally separately: hydrogen, C 1-6the alkyl of saturated and unsaturated alkyl and hybrid atom MCM-41.
In certain embodiments, Ar is particularly preferably from following group:
In certain embodiments, this tyrosine kinase irreversible inhibitor is preferably from one of following compound:
Compound 1, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-quinazoline-6-base)-propyl-2-alkynes)-acrylamide;
Compound 2, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-base)-propyl-2-alkynes)-but-2-enamides;
Compound 3, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-base)-propyl-2-alkynes)-4-morpholine butyl-2-alkene amide;
Compound 4, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-base)-propyl-2-alkynes)-4-(dimethylamino)-butyl-2-alkene amide;
Compound 5, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-base)-propyl-2-alkynes)-propine amide;
Compound 6, N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl) acrylamide;
Compound 7, (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl) but-2-enamides;
Compound 8, (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl)-4-morpholine butyl-2-alkene amide;
Compound 9, (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl)-4-(dimethylamino)-butyl-2-alkene amide;
Compound 10, N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl) propine amide;
Compound 11, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-Pyrimidothiophene-6-base)-propyl-2-alkynes)-acrylamide;
Compound 12, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-base)-propyl-2-alkynes)-but-2-enamides;
Compound 13, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-base)-propyl-2-alkynes)-4-morpholine butyl-2-alkene amide;
Compound 14, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-base)-propyl-2-alkynes)-4-(dimethylamino)-butyl-2-alkene amide;
Compound 15, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-base)-propyl-2-alkynes)-propine amide;
Compound 16, N-(3-(4-(the chloro-4-fluoroaniline of 3-)-Pyrimidothiophene-6-base) Propargyl) acrylamide;
Compound 17, (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-)-Pyrimidothiophene-6-base) Propargyl) but-2-enamides;
Compound 18, (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-)-Pyrimidothiophene-6-base) Propargyl)-4-morpholine butyl-2-alkene amide;
Compound 19, (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-)-Pyrimidothiophene-6-base) Propargyl)-4-(dimethylamino)-butyl-2-alkene amide;
Compound 20, N-(3-(4-(the chloro-4-fluoroaniline of 3-)-Pyrimidothiophene-6-base) Propargyl) propine amide.
Second object of the present invention is to provide the preparation method of above-mentioned tyrosine kinase irreversible inhibitor or its pharmaceutically acceptable salt, adopts with line:
Wherein:
3rd object of the present invention is to provide above-mentioned tyrosine kinase irreversible inhibitor or its pharmaceutically acceptable salt preparing the application in antitumor drug.
Compared with prior art, the beneficial effect that the present invention has is: tyrosine kinase irreversible inhibitor provided by the present invention.Sulfydryl on Cys773 and the Cys805 amino acid residue at edge, EGFR and HER2 kinases ATP-binding domain is utilized to have the feature of stronger nucleophilicity, a Michael addition receptor is introduced in drug molecule, enable drug molecule and kinases form covalent bond to be combined, reach the object of irreversible suppression.Thus have the following advantages: 1. suppress EGFR and HER2 two kinds of tyrosine kinase simultaneously, be easier to overcome other members of EGFR family when using single tyrosine kinase irreversible inhibitor and raise the Growth of Cells signal redundancy caused thus the Drug resistance produced; 2., because EGFR and HER2 heterodimer activity is the highest, the double inhibitor of EGFR and HER2 tyrosine kinase is effective to most cancer patients.3., compared with single inhibitor, double inhibitor has synergistic effect to inhibiting tumour cells effect.In vitro and in vivo test also shows, is greater than the suppression to single receptor to the anticancer effect of EGFR and HER2 tyrosine kinase double inhibition.In addition with use compared with two medicines acting on single target spot respectively simultaneously, the medicine patient acting on two target spots uses more convenient, can also avoid the interaction of medicine and medicine.
Detailed description of the invention
The compounds of this invention and salt thereof also can by becoming known for the method preparation of preparative chemistry related compound, and the raw material related in an embodiment all obtains by the similar approach of prior art.
Embodiment 1
The preparation of compound 1, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-quinazoline-6-base)-propyl-2-alkynes)-acrylamide.
Circuit one:
According to above-mentioned circuit, step 1) prepare Compound I-2, i.e. 2-amido-5-iodo-benzoic acid methyl ester, method is as follows:
50.19g (332.42mmol) methyl anthranilate is added in two mouthfuls of flasks of 250mL that Dropping funnel is housed, the 100mL tert-butyl alcohol and 50mL water, add 44.32g (174.52mmol) iodine under stirring in batches, then slowly drip the hydrogen peroxide of 40mL 30%, in oil bath, be heated to 50 DEG C of insulation 2h.TLC monitors reaction.After reaction terminates, reaction system is cooled to room temperature, adds the saturated aqueous solution of sodium bisulfite of 50mL, stirs evenly, then 150mL extraction into ethyl acetate is used three times, merge organic facies, with the water washing of 50mL saturated common salt, anhydrous sodium sulfate drying, revolve steaming and remove about 100mL ethyl acetate, be placed in refrigerator recrystallization, obtain pale yellow crystals 55.23g, yield 60%.
The characterization data of this compound is: 1H NMR (400MHz, CDCl3) δ ppm 8.14 (d, J=2.4Hz, 1H), 7.47 (d, J=8.8Hz, 1H), 6.53 (d, J=8.8Hz, 1H), 5.70 (s, 2H), 3.86 (s, 3H).ESI-MS m/z：276.4(M-H)。
This structural formula of compound is:
Step 2) prepare Compound I-3, i.e. 6-iodine quinazoline-4 (3H) ketone, method is as follows:
In two mouthfuls of flasks of 250mL that reflux condensing tube is housed, add 37.92g (136.91mmol) 2-amido-5-iodo-benzoic acid methyl ester (i.e. I-2), 50mL dry formamide, nitrogen protection, in oil bath, be heated to 180 DEG C, stir 4h.TLC monitors reaction.After reaction terminates, remove oil bath, reaction system is cooled to room temperature, adds 100mL water, and stir, sucking filtration, filter cake 100mL water washing twice, drains, and then uses 50mL washed with diethylether twice, vacuum drying, obtains Off-white solid 32.04g, yield 86%.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 12.40 (s, 1H), 8.38 (d, J=2.0Hz, 1H), 8.13 (s, 1H), 8.10 (dd, J=8.8,2.0Hz, 1H), 7.46 (d, J=8.8Hz, 1H) .ESI-MS m/z:273.0 (M+H)+, 270.9 (M-H)
This structural formula of compound is:
Step 3) prepare Compound I-5a, method is as follows:
1.36g (5mmol) 6-iodine quinazoline-4 (3H) ketone (i.e. I-3) is added in two mouthfuls of flasks of 25mL that reflux condensing tube is housed, 0.92g (6mmol) phosphorus oxychloride, 6mL toluene, nitrogen protection, then 0.9mL triethylamine is slowly added with syringe, finish, with be heated to 75 DEG C in oil bath and react 2h, slightly cold, add the acetonitrile solution of 1.2g 1-(3-luorobenzyl)-1H-indazole-5-ammonia, again be warming up to and be cooled to 75 DEG C of reaction 2h, reaction terminates, naturally room temperature is down to, sucking filtration, filter cake proceeds in 15mL 1M sodium hydroxide solution and stirs 2h, sucking filtration, filter cake vacuum drying, obtain yellowish powder 1.2g, yield 48%.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm, 10.10 (s, 1H), 8.92 (s, 1H), 8.51 (s, 1H), 8.21 (d, J=23Hz, 3H), 7.70-7.50 (s, 3H), 7.36 (dd, J=14Hz, 1H), 7.10 (d, J=8.4Hz, 1H), 7.06-6.83 (m, 3H), 5.70 (s, 2H). [M+H] +=496.4.
This structural formula of compound is:
Step 4) prepare Compound I-6a, method is as follows:
Under nitrogen protection, 0.495g I-5a is added in two mouthfuls of flasks of 25mL, dry THF 3mL, diisopropyl ammonia 0.4mL, degassed 5min, add two (triphenylphosphine) palladium chloride 40mg (5%mol), Hydro-Giene (Water Science). 19mg (10%mol), 0.193g propine amido t-butyl formate is slowly injected under room temperature, finish, stirred at ambient temperature reaction 2h, TLC monitors, reaction terminates, pillar chromatography, product is proceeded in the dichloromethane solution of 10mL30%TFA, stirring at room temperature is reacted, TLC monitors, reaction terminates, revolve and steam to dry, residue saturated sodium bicarbonate solution washs 3 times, sucking filtration, filtration cakes torrefaction, obtain I-6a 0.25g yield 60%.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm, 10.10 (s, 1H), 8.92 (s, 1H), 8.51 (s, 1H), 8.21 (d, J=23Hz, 3H), 7.70-7.50 (s, 3H), 7.36 (dd, J=14Hz, 1H), 7.10 (d, J=8.4Hz, 1H), 7.06-6.83 (m, 3H), 5.70 (s, 2H), 5.0 (s, 2H), 3.36 (s, 2H). [M+H] +=423.5.
This structural formula of compound is:
Step 5) prepare compound 1, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-quinazoline-6-base)-propyl-2-alkynes)-acrylamide, method is as follows:
Under nitrogen protection, in the reaction bulb of 5mL clean dried, add I-6a 42mg, acrylic acid 8mg, HOBt 3mg; dry dichloromethane 3mL, and the triethylamine of catalytic amount, stir 5min under ice-water bath, add 25mg EDCI; stirring reaction 30 minutes, rises to room temperature naturally, continues stirring reaction, TLC; monitoring, reaction terminates, and uses 30mL dchloromethane; washing, saturated common salt is washed, dry; quick post excessively, obtains target product 30mg, yield 62.5%.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 8.82 (s, 1H), 8.75 (s, 1H), 8.21 (d, J=13.2Hz, 3H), 7.85 (s, 1H), 7.70-7.74 (m, 2H), 7.32-7.34 (m, 1H), 7.03-7.11 (m, 4H), 6.13-6.30 (m, 2H), 5.72 (s, 2H), 5.66 (d, J=10.0Hz, 1H), 4.30 (d, J=3.2Hz, 2H) .ESI-MS m/z:477.1 (M+H), 475.1 (M-H).
The structural formula of this compound is:
Embodiment 2
Compound 2, the preparation of (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-base)-propyl-2-alkynes)-but-2-enamides.
Step 1)-4) with embodiment 1, step 5) as follows:
Select 2-butylene acid, with 1-6a, condensation reaction, operational approach, as embodiment 1, obtains target product.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 10.01 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.54-7.64 (m, 3H), 7.33-7.39 (m, 1H), 7.04-7.12 (m, 4H), 6.67-6.72 (m, 1H), 5.95 (d, J=14.8Hz, 1H), 5.70 (s, 2H), 4.27 (d, J=5.2Hz, 2H), 1.81 (d, J=6.0Hz, 3H) .ESI-MS m/z:491.2 (M+H), 489.2 (M-H).
This structural formula of compound is:
Embodiment 3
Compound 3, the preparation of (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-base)-propyl-2-alkynes)-4-morpholine butyl-2-alkene amide.
Step 1)-4) with embodiment 1, step 5) as follows:
Select the acid of 4-morpholine 2-butylene, with 1-6a, condensation reaction, operational approach, as embodiment 1, obtains target product.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 10.01 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.54-7.64 (m, 3H), 7.33-7.39 (m, 1H), 7.04-7.12 (m, 4H), 6.67-6.72 (m, 1H), 6.05-6.15 (m, 1H), 5.70 (s, 2H), 4.27 (d, J=4.0Hz, 2H), 3.53 (t, J=4.8Hz, 4H), 3.04 (d, J=6.4Hz, 2H), 2.32 (s, 4H) .ESI-MS m/z:576.2 (M+H), 574.2 (M-H).
This structural formula of compound is:
Embodiment 4
Compound 4, the preparation of (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-base)-propyl-2-alkynes)-4-(dimethylamino)-butyl-2-alkene amide.
Step 1)-4) with embodiment 1, step 5) as follows:
Select 4-dimethyl-2-butylene acid, with 1-6a, condensation reaction, operational approach, as embodiment 1, obtains target product.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 10.01 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.54-7.64 (m, 3H), 7.33-7.39 (m, 1H), 7.04-7.12 (m, 4H), 6.67-6.72 (m, 1H), 6.05-6.15 (m, 1H), 5.70 (s, 2H), 4.27 (d, J=4.0Hz, 2H), 3.67 (dd, J=11.6, 6.0Hz, 2H), 2.19 (s, 6H) .ESI-MS m/z:534.2 (M+H), 532.2 (M-H)
This structural formula of compound is:
Embodiment 5
The preparation of compound 5, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-base)-propyl-2-alkynes)-propine amide.
Step 1)-4) with embodiment 1, step 5) as follows:
Select acetylenecarboxylic acid, with 1-6a, condensation reaction, operational approach, as embodiment 1, obtains target product.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 8.82 (s, 1H), 8.75 (s, 1H), 8.21 (d, J=13.2Hz, 3H), 7.85 (s, 1H), 7.70-7.74 (m, 2H), 7.32-7.34 (m, 1H), 7.03-7.11 (m, 4H), 5.72 (s, 2H), 4.35 (d, J=5.6Hz, 2H), 4.30 (s, 1H) .ESI-MS m/z:475.1 (M+H), 473.1 (M-H).
This structural formula of compound is:
Embodiment 6
The preparation of compound 6, N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl) acrylamide.
According to the circuit one in embodiment 1, step 1) prepare Compound I-2, i.e. 2-amido-5-iodo-benzoic acid methyl ester, method is as follows:
50.19g (332.42mmol) methyl anthranilate is added in two mouthfuls of flasks of 250mL that Dropping funnel is housed, the 100mL tert-butyl alcohol and 50mL water, add 44.32g (174.52mmol) iodine under stirring in batches, then slowly drip the hydrogen peroxide of 40mL 30%, in oil bath, be heated to 50 DEG C of insulation 2h.TLC monitors reaction.After reaction terminates, reaction system is cooled to room temperature, adds the saturated aqueous solution of sodium bisulfite of 50mL, stirs evenly, then 150mL extraction into ethyl acetate is used three times, merge organic facies, with the water washing of 50mL saturated common salt, anhydrous sodium sulfate drying, revolve steaming and remove about 100mL ethyl acetate, be placed in refrigerator recrystallization, obtain pale yellow crystals 55.23g, yield 60%.
The characterization data of this compound is: 1H NMR (400MHz, CDCl3) δ ppm 8.14 (d, J=2.4Hz, 1H), 7.47 (d, J=8.8Hz, 1H), 6.53 (d, J=8.8Hz, 1H), 5.70 (s, 2H), 3.86 (s, 3H).ESI-MS m/z：276.4(M-H)。
This structural formula of compound is:
Step 2) prepare Compound I-3, i.e. 6-iodine quinazoline-4 (3H) ketone, method is as follows:
In two mouthfuls of flasks of 250mL that reflux condensing tube is housed, add 37.92g (136.91mmol) 2-amido-5-iodo-benzoic acid methyl ester (i.e. I-2), 50mL dry formamide, nitrogen protection, in oil bath, be heated to 180 DEG C, stir 4h.TLC monitors reaction.After reaction terminates, remove oil bath, reaction system is cooled to room temperature, adds 100mL water, and stir, sucking filtration, filter cake 100mL water washing twice, drains, and then uses 50mL washed with diethylether twice, vacuum drying, obtains Off-white solid 32.04g, yield 86%.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 12.40 (s, 1H), 8.38 (d, J=2.0Hz, 1H), 8.13 (s, 1H), 8.10 (dd, J=8.8,2.0Hz, 1H), 7.46 (d, J=8.8Hz, 1H) .ESI-MS m/z:273.0 (M+H)+, 270.9 (M-H)
This structural formula of compound is:
Step 3) prepare Compound I-5b, method is as follows:
Replace 1-(3-luorobenzyl)-1H-indazole-5-ammonia with the chloro-4-fluoroaniline of 3-, detailed step prepares Compound I-5a with in embodiment 1 by I-3, obtained I-5b, yield 72%.
These characterization of compound data are: 1H NMR (400MHz, DMSO-d6) δ ppm, 9.98 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.22 (dd, J=2.8Hz, J=6.8Hz, 1H), 7.84-7.9 (d, J=9.2Hz, J=4Hz, 2H), 7.74 (d, 1H), 7.47 (s, 1H). [M+H] +=400.4.
This structural formula of compound is:
Step 4) prepare Compound I-6b, method is as follows:
With I-5b substitute I-5a, detailed step prepares Compound I-6a with in embodiment 1 by I-5a, obtained I-6b, yield 63.0%.
These characterization of compound data are: 1H NMR (400MHz, DMSO-d6) δ ppm, 9.98 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.22 (dd, J=2.8Hz, J=6.8Hz, 1H), 7.84-7.9 (d, J=9.2Hz, J=4Hz, 2H), 7.74 (d, 1H), 7.47 (s, 1H), 5.1 (s, 2H), 3.35 (s, 2H), [M+H] +=327.7.
This structural formula of compound is:
Step 5) preparation of compound 6, N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl) acrylamide, method is as follows:
Under nitrogen protection, in the reaction bulb of 5mL clean dried, add I-6b 42mg, acrylic acid 8mg, HOBt 3mg; dry dichloromethane 3mL, and the triethylamine of catalytic amount, stir 5min under ice-water bath, add 25mg EDCI; stirring reaction 30 minutes, rises to room temperature naturally, continues stirring reaction; TLC, monitoring, reaction terminates; use 30mL dchloromethane, washing, saturated common salt is washed; drying, quick post excessively, obtains target product.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 10.02 (s, 1H), 8.83 (s, 1H), 8.80 (s, 1H), 8.60 (s, 1H), 7.89 (s, 2H), 7.55-7.62 (m, 3H), 6.13-6.30 (m, 2H), (5.66 d, J=10.0Hz, 1H), 4.30 (d, J=3.2Hz, 2H) .ESI-MS m/z:381.0 (M+H), 379.0 (M-H).
This structural formula of compound is:
Embodiment 7
Compound 7, the preparation of (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl) but-2-enamides.
Step 1)-4) with embodiment 6, step 5) as follows:
Select 2-butylene acid, with 1-6b, condensation reaction, operational approach, as embodiment 6, obtains target product.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 10.02 (s, 1H), 8.83 (s, 1H), 8.80 (s, 1H), 8.60 (s, 1H), 7.89 (s, 2H), 7.55-7.62 (m, 3H), 6.71-6.75 (m, 1H), 5.97 (d, J=14.8Hz, 1H), 4.26 (d, J=5.2Hz, 2H), 1.81 (d, J=6.0Hz, 3H) .ESI-MS m/z:395.0 (M+H), 393.0 (M-H).
This structural formula of compound is:
Embodiment 8
Compound 8, the preparation of (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl)-4-morpholine butyl-2-alkene amide.
Step 1)-4) with embodiment 6, step 5) as follows:
Select 4-morpholine-2-butenoic acid, with 1-6b, condensation reaction, operational approach, as embodiment 6, obtains target product.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 10.00 (s, 1H), 8.71 (s, 1H), 8.70 (s, 1H), 8.21 (s, 1H), 7.84 (s, 2H), 7.55-7.62 (m, 3H), 6.67-6.72 (m, 1H), 6.05-6.15 (m, 1H), 4.27 (d, J=4.0Hz, 2H), 3.58 (t, J=4.8Hz, 4H), 3.07 (d, J=6.4Hz, 2H), 2.36 (s, 4H) .ESI-MS m/z:480.1 (M+H), 478.1 (M-H).
This structural formula of compound is:
Embodiment 9
Compound 9, the preparation of (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl)-4-(dimethylamino)-butyl-2-alkene amide.
Step 1)-4) with embodiment 6, step 5) as follows:
Select 4-dimethyl-butenoic acid, with 1-6b, condensation reaction, operational approach, as embodiment 6, obtains target product.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 10.00 (s, 1H), 8.71 (s, 1H), 8.70 (s, 1H), 8.22 (s, 1H), 7.83 (s, 2H), 7.55-7.62 (m, 3H), 6.67-6.72 (m, 1H), 6.05-6.15 (m, 1H), 4.27 (d, J=5.2Hz, 2H), 3.00 (dd, J=11.6,6.0Hz, 2H), 2.17 (s, 6H) .ESI-MS m/z:438.2 (M+H), 436.1 (M-H).
This structural formula of compound is:
Embodiment 10
The preparation of compound 10, N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl) propine amide.
Step 1)-4) with embodiment 6, step 5) as follows:
Select acetylenecarboxylic acid, with 1-6b, condensation reaction, operational approach, as embodiment 6, obtains target product.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 10.02 (s, 1H), 8.83 (s, 1H), 8.80 (s, 1H), 8.60 (s, 1H), 7.89 (s, 2H), 7.55-7.62 (m, 3H), (4.35 d, J=3.2Hz, 2H), 4.30 (s, 1H) .ESI-MS m/z:379.0 (M+H), 377.0 (M-H).
This structural formula of compound is:
Embodiment 11
The preparation of compound 11, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-Pyrimidothiophene-6-base)-propyl-2 alkynes)-acrylamide.
Circuit two:
According to above-mentioned circuit, step 1) prepare Compound II per-2, i.e. thieno [2,3-D] pyrimidine-4 (3H)-one, method is as follows:
25g (136.91mmol) 2-amino-thenoic acid ethyl ester (i.e. Compound II per-1) is added in two mouthfuls of flasks of 250mL that reflux condensing tube is housed; 100mL dry formamide; nitrogen protection, is heated to 180 DEG C in oil bath, stirring reaction 6h.TLC monitors reaction.After reaction terminates, remove oil bath, reaction system is cooled to room temperature, adds 100mL water, and stir, sucking filtration, filter cake 100mL water washing twice, drains, and then uses 50mL washed with diethylether twice, vacuum drying, obtains Off-white solid 13.4g, yield 60%.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 12.50 (1H, brs), 8.13 (1H, s), 7.60 (1H, d, J=5.8Hz), 7.41 (1H, d, J=6.0Hz), m/z=167 (M+H)+.
This structural formula of compound is:
Step 2) prepare Compound II per-3a, method is as follows:
1.52g (10mmol) thieno [2 is added in two mouthfuls of flasks of 25mL that reflux condensing tube is housed, 3-D] pyrimidine-4 (3H)-one (i.e. Compound II per-2), 1.7g (11mmol) phosphorus oxychloride, the dry toluene of 8mL, nitrogen protection, then 1.5mL triethylamine is slowly added with syringe, finish, with be heated to 75 DEG C in oil bath and react 2h, slightly cold, add the acetonitrile solution of 2g 1-(3-luorobenzyl)-1H-indazole-5-ammonia, again be warming up to and be cooled to 75 DEG C of reaction 2h, reaction terminates, naturally room temperature is down to, sucking filtration, filter cake proceeds in 15mL 1M sodium hydroxide solution and stirs 2h, sucking filtration, filter cake vacuum drying, obtain N-(1-(3-luorobenzyl)-1H-indazole-5-base)-thieno [2, 3-D] pyrimidine 4-ammonia 2.7g, yield 72%.
The characterization data of this compound is: 1H-NMR (DMSO-J6) δ 8.56 (s, IH), 8.15 (s, IH), 7.50 (dd, IH), 7.30-7.38 (m, 2H), 7.20 (d, IH), 7.05 (s, IH), 6.98 (d, IH), 6.80 (dd, IH), 6.77-6.87 (m, 3H), 4.89 (s, 2H) [M+H] +=376.4.
This structural formula of compound is:
Step 3) prepare Compound II per-4a, method is as follows:
Under nitrogen protection, to be equipped with reflux condensing tube 25mL two mouthfuls of flasks in add II-3a 1.8g, N-chlorosuccinimide 1.3g; glacial acetic acid 20 milliliters, is warming up to 95 DEG C of reaction 2h, TLC monitoring; reaction terminates, and revolve and steam removing glacial acetic acid, residue uses saturated sodium bicarbonate successively; water washing; drying, obtains N-(1-(3-luorobenzyl)-1H-indazole-5-base)-6-chlorothiophene also [2,3-D] pyrimidine 4-ammonia; 1.5g, yield 75%.
These characterization of compound data are: 1H NMR (400MHz, DMSO-d6) δ ppm, 9.97 (s, 1H), 8.92 (s, 1H), 8.51 (s, 1H), 8.21 (d, J=8.0Hz, 1H), 7.70 (s, 1H), 7.36 (dd, J=14Hz, 2H), 7.10 (d, J=8.4Hz, 1H), 7.06-6.83 (m, 3H), 5.71 (s, 2H) [M+H] +=410.8.
This structural formula of compound is:
Step 4) prepare Compound II per-5a, method is as follows:
Under nitrogen protection, 0.4g II-4a is added in two mouthfuls of flasks of 25mL, dry THF 3mL, diisopropyl ammonia 0.4mL, degassed 5min, add two (triphenylphosphine) palladium chloride 40mg (5%mol), Hydro-Giene (Water Science). 19mg (10%mol), 0.193g propine amido t-butyl formate is slowly injected under room temperature, finish, stirred at ambient temperature reaction 2h, TLC monitors, reaction terminates, pillar chromatography, product is proceeded in the dichloromethane solution of 10mL30%TFA, stirring at room temperature is reacted, TLC monitors, reaction terminates, revolve and steam to dry, residue saturated sodium bicarbonate solution washs 3 times, sucking filtration, filtration cakes torrefaction, obtain II-5a 0.25g yield 59.2%.
These characterization of compound data are: 1H NMR (400MHz, DMSO-d6) δ ppm, 9.97 (s, 1H), 8.92 (s, 1H), 8.51 (s, 1H), 8.21 (d, J=8.0Hz, 1H), 7.70 (s, 1H), 7.36 (dd, J=14Hz, 2H), 7.10 (d, J=8.4Hz, 1H), 7.06-6.83 (m, 3H), 5.71 (s, 2H), 5.0 (s, 2H), 3.36 (s, 2H). [M+H] +=429.5.
This structural formula of compound is:
Step 5) preparation of compound 11, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-Pyrimidothiophene-6-base)-propyl-2-alkynes)-acrylamide, method is as follows:
By Compound II per-5a and acrylic acid at EDCI, HOBT and triethylamine condensation reaction in DMF, operational approach, as embodiment 1, obtains target product.Obtain.
These characterization of compound data are: 1H-NMR (DMSO-d6) δ 8.66 (s, IH), 8.19 (s, IH), 7.50 (dd, IH), 7.25-7.33 (m, 2H), 7.15 (s, IH), 6.99 (d, IH), 6.80 (dd, IH), 6.75-6.85 (m, 3H), 6.10-6.38 (m, 3H), 4.89 (s, 2H), 3.40 (s, 2H) [M+H] +=483.15.
This structural formula of compound is:
Embodiment 12
Compound 12, the preparation of (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-base)-propyl-2-alkynes)-but-2-enamides.
Step 1)-4) with embodiment 11, step 5) as follows:
Select 2-butylene acid, react in DMF at EDCI, HOBT and triethylamine, with II-5a, condensation reaction, operational approach, as embodiment 1, obtains target product.
These characterization of compound data are: 1H-NMR (DMSO-d6) δ 8.58 (s, IH), 8.20 (s, IH), 7.49 (dd, IH), 7.20-7.35 (m, 2H), 7.12 (s, IH), 6.97 (d, IH), 6.81 (dd, IH), 6.77-6.87 (m, 3H), 6.38 (m, 1H), 6.10 (d, 1H), 4.89 (s, 2H), 3.40 (s, 2H), 1.73 (s, 3H) [M+H] +=496.1.
This structural formula of compound is:
Embodiment 13
Compound 13, the preparation of (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-base)-propyl-2-alkynes)-4-morpholine butyl-2-alkene amide.
Step 1)-4) with embodiment 11, step 5) as follows:
Select 4-morpholine-2-butenoic acid, react at EDCI, HOBT and triethylamine in DMF, with II-5a, condensation reaction, operational approach, as embodiment 1, obtains target product.
These characterization of compound data are: 1H-NMR (DMSO-d6) δ 8.73 (s, IH), 8.35 (s, IH), 7.82 (dd, IH), 7.50-7.62 (m, 2H), 7.20 (s, IH), 6.95 (d, IH), 6.87 (dd, IH), 6.73-6.83 (m, 3H), 6.38 (m, 1H), 6.10 (d, 1H), 4.89 (s, 2H), 3.68 (d, 2H), 3.40 (s, 2H), 3.0 (m, 2H), 2.20 (d, 8H) [M+H] +=567.2.
This structural formula of compound is:
Embodiment 14
Compound 14, the preparation of (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-base)-propyl-2-alkynes)-4-(dimethylamino)-butyl-2-alkene amide.
Step 1)-4) with embodiment 11, step 5) as follows:
Select 4-dimethylamino-2-butylene acid, react in DMF at EDCI, HOBT and triethylamine, with II-5a, condensation reaction, operational approach, as embodiment 1, obtains target product.
These characterization of compound data are: 1H-NMR (DMSO-d6) δ 8.68 (s, IH), 8.23 (s, IH), 7.49 (dd, IH), 7.20-7.35 (m, 2H), 7.12 (s, IH), 6.97 (d, IH), 6.81 (dd, IH), 6.77-6.87 (m, 3H), 6.30 (m, 1H), 6.10 (d, 1H), 4.89 (s, 2H), 3.62 (m, 4H), 3.40 (s, 2H), 3.02 (m, 2H), 2.31 (s, 6H) [M+H] +=526.2.
This structural formula of compound is:
Embodiment 15
The preparation of compound 15, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-base)-propyl-2-alkynes)-propine amide.
Step 1)-4) with embodiment 11, step 5) as follows:
Select propargylic acid, react at EDCI, HOBT and triethylamine in DMF, with II-5a, condensation reaction, operational approach, as embodiment 1, obtains target product.
These characterization of compound data are: 1H-NMR (DMSO-d6) δ 8.56 (s, IH), 8.15 (s, IH), 7.50 (dd, IH), 7.30-7.38 (m, 2H), 7.15 (s, IH), 6.98 (d, IH), 6.80 (dd, IH), 6.77-6.87 (m, 3H), 4.89 (s, 2H), 3.40 (s, 2H), 2.77 (s, 1H) [M+H] +=481.1.
This structural formula of compound is:
Embodiment 16
The preparation of compound 16, N-(3-(4-(the chloro-4-fluoroaniline of 3-)-Pyrimidothiophene-6-base) Propargyl) acrylamide.
According to the circuit two in embodiment 11, step 1) prepare Compound II per-2, i.e. thieno [2,3-D] pyrimidine-4 (3H)-one, method is as follows:
25g (136.91mmol) 2-amino-thenoic acid ethyl ester (i.e. Compound II per-1) is added in two mouthfuls of flasks of 250mL that reflux condensing tube is housed; 100mL dry formamide; nitrogen protection, is heated to 180 DEG C in oil bath, stirring reaction 6h.TLC monitors reaction.After reaction terminates, remove oil bath, reaction system is cooled to room temperature, adds 100mL water, and stir, sucking filtration, filter cake 100mL water washing twice, drains, and then uses 50mL washed with diethylether twice, vacuum drying, obtains Off-white solid 13.4g, yield 60%.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm 12.50 (1H, brs), 8.13 (1H, s), 7.60 (1H, d, J=5.8Hz), 7.41 (1H, d, J=6.0Hz), m/z=167 (M+H)+.
This structural formula of compound is:
Step 2) prepare Compound II per-3b, method is as follows:
With 1-(3-the luorobenzyl)-1H-indazole-5-ammonia in 3-chloro-4-fluoroaniline alternative embodiment 11, detailed step prepares Compound II per-3a with in embodiment 11 by Compound II per-2, obtained II-3b, yield 75%.
The characterization data of this compound is: 1H NMR (400MHz, DMSO-d6) δ ppm, 9.93 (s, 1H), 8.60 (s, 1H), 7.29 (d, J=5.0Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 6.80 (s, 1H), 6.76 (s, 1H). [M+H] +=280.
This structural formula of compound is:
Step 3) prepare Compound II per-4b, method is as follows:
With II-3b substitute I I-3a, detailed step prepares Compound II per-4a with embodiment 11 by Compound II per-3a, obtained II-4b, yield 71%.
These characterization of compound data are: 1H NMR (400MHz, DMSO-d6) δ ppm, 9.93 (s, 1H), 8.60 (s, 1H), 7.29 (d, J=5.0Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 6.80 (s, 1H), 6.76 (s, 1H). [M+H] +=359.8.
This structural formula of compound is:
Step 4) prepare Compound II per-5b, method is as follows:
With II-4b substitute I I-4a, detailed step with in embodiment 11 by compound II-4a for Compound II per-5a, obtained II-5b, yield 63.0%.
These characterization of compound data are: 1H NMR (400MHz, DMSO-d6) δ ppm, 9.93 (s, 1H), 8.60 (s, 1H), 7.29 (d, J=5.0Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 6.80 (s, 1H), 6.76 (s, 1H), 5.0 (s, 2H), 3.36 (s, 2H). [M+H] +=327.8.
This structural formula of compound is:
Step 5) preparation of compound 16, N-(3-(4-(the chloro-4-fluoroaniline of 3-)-Pyrimidothiophene-6-base) Propargyl) acrylamide, method is as follows:
By Compound II per-5b and acrylic acid at EDCI, HOBT and triethylamine condensation reaction in DMF, operational approach, as embodiment 1, obtains target product.
These characterization of compound data are: 1H-NMR (DMSO-d6) δ 8.01 (s, IH), 7.47 (s, IH), 7.23 (d, IH), 7.08 (m, 1H), 6.70 (m, 1H), 6.55-6.45 (m, 3H), 6.35 (d, 1H), 6.2 (m, 1H), 5.88 (m, 1H), 3.46 (s, 1H) [M+H] +=386.1.
This structural formula of compound is:
Embodiment 17
Compound 17, the preparation of (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-)-Pyrimidothiophene-6-base) Propargyl)-4-morpholine butyl-2-alkene amide.
Step 1)-4) with embodiment 16, step 5) as follows:
Select 2-butylene acid, react in DMF at EDCI, HOBT and triethylamine, with II-5b, condensation reaction, operational approach, as embodiment 1, obtains target product.
These characterization of compound data are: 1H-NMR (DMSO-d6) δ 8.15 (s, IH), 7.57 (s, IH), 7.25 (d, IH), 7.09 (m, 1H), 6.73 (m, 1H), 6.55-6.45 (m, 3H), 6.33 (d, 1H), 6.15 (m, 1H), 5.98 (m, 1H), 3.40 (s, 1H), 1.78 (s, 3H) [M+H] +=400.05.
This structural formula of compound is:
Embodiment 18
Compound 18, the preparation of (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-)-Pyrimidothiophene-6-base) Propargyl)-4-morpholine butyl-2-alkene amide.
Step 1)-4) with embodiment 16, step 5) as follows:
Select 4-morpholine-2-butenoic acid, react at EDCI, HOBT and triethylamine in DMF, with II-5b, condensation reaction, operational approach, as embodiment 1, obtains target product.
These characterization of compound data are: 1H-NMR (DMSO-d6) δ 8.11 (s, IH), 7.55 (s, IH), 7.23 (d, IH), 7.11 (m, 1H), 6.72 (m, 1H), 6.55-6.45 (m, 3H), 6.38 (d, 1H), 6.12 (m, 1H), 5.98 (m, 1H), 3.42 (s, 1H), 3.01 (d, 2H), 2.31 (s, 8H) [M+H] +=471.1.
This structural formula of compound is:
Embodiment 19
Compound 19, the preparation of (E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-)-Pyrimidothiophene-6-base) Propargyl)-4-(dimethylamino)-butyl-2-alkene amide.
Step 1)-4) with embodiment 16, step 5) as follows:
Select 4-dimethylamino-2-butylene acid, react in DMF at EDCI, HOBT and triethylamine, with II-5b, condensation reaction, operational approach, as embodiment 1, obtains target product.
These characterization of compound data are: 1H-NMR (DMSO-d6) δ 8.11 (s, IH), 7.55 (s, IH), 7.24 (d, IH), 7.11 (m, 1H), 6.72 (m, 1H), 6.55-6.45 (m, 3H), 6.38 (d, 1H), 6.12 (m, 1H), 5.98 (m, 1H), 3.71 (m, 4H), 3.42 (s, 1H), 3.02 (d, 2H), 2.41 (m, 6H) [M+H] +=429.1.
This structural formula of compound is:
Embodiment 20
The preparation of compound 20, N-(3-(4-(the chloro-4-fluoroaniline of 3-)-Pyrimidothiophene-6-base) Propargyl) propine amide.
Step 1)-4) with embodiment 16, step 5) as follows:
Select 4-dimethylamino-2-butylene acid, react in DMF at EDCI, HOBT and triethylamine, with II-5b, condensation reaction, operational approach, as embodiment 1, obtains target product.
These characterization of compound data are: 1H-NMR (DMSO-d6) δ 8.01 (s, IH), 7.47 (s, IH), 7.21 (d, IH), 7.08 (m, 1H), 6.55-6.45 (m, 3H), 6.21 (m, 1H), 5.89 (m, 1H), 3.44 (s, 1H), 2.72 (s, 1H) [M+H] +=385.04.
This structural formula of compound is:
Embodiment 21
Vitro enzyme inhibit activities euzymelinked immunosorbent assay (ELISA) is adopted to measure enzyme inhibition activity.Concrete grammar is as follows:
Target compound measures EGFR and HER2 enzyme inhibition activity and adopts Z '-LYTE tMkinases testing cassete (invitrogenTM, Z '-LYTE Kinase assay kit-TYR6peptide, list of references: Nature, 373, pp.536-9 (1995)) is tested.
According to Z '-LYTE tMkinases testing cassete operation instructions carry out reagent configuration; First enzyme and medicine are added on 384 orifice plates according to certain proportioning respectively, mixing, place 30min; Then add ATP, mixing, place 2h; Add 5 μ L Development Regent, mixing, under room temperature, place 15min, 30min, 1h microplate reader and detect; Add the Stop regent of 5 μ L after 1h, detect by microplate reader after mixing.Calculate corresponding phosphorylation ratio, the concentration according to medicine is mapped with corresponding kinase inhibition rate, obtains dose-effect curve, therefrom tries to achieve the half-inhibition concentration (IC50) of medicine.Result is as follows:
The half-inhibition concentration (IC50) of table 1 pair EGFR and HER2 enzyme
From the above results, tyrosine kinase irreversible inhibitor provided by the present invention is simultaneously inhibited to EGFR and HER2 two kinds of tyrosine kinase, its half-inhibition concentration is compared with positive control Lapatinib, or be better than positive control, or it is suitable to being less than positive control, particularly compound 5 and compound 11, it is all less than positive control to the half-inhibition concentration of EGFR and HER2 two kinds of tyrosine kinase, has good enzyme inhibition activity.
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.

Claims (5)

1. the tyrosine kinase irreversible inhibitor shown in formula I or its pharmaceutically acceptable salt:
Wherein,
Ar is selected from following group:
Wherein: R6 ' is selected from; F, Cl, Br, I;
R is selected from: H;
W is selected from: C 1-C6 alkyl;
The group of the described A of comprising, B, C is selected from:
Wherein, R6 is selected from: H;
Y is selected from following group:
Wherein, R 4, R 5elect as: H;
R 3, elect as: H, C 1alkyl, the C containing O, N hybrid atom MCM-41 1-C 6alkyl, cyclic alkyl.
2. tyrosine kinase irreversible inhibitor according to claim 1 or its pharmaceutically acceptable salt, is characterized in that, Ar is selected from following group:
3. tyrosine kinase irreversible inhibitor according to claim 1 or its pharmaceutically acceptable salt, is characterized in that, is selected from one of following compound:
N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-quinazoline-6-base)-propyl-2-alkynes)-acrylamide;
(E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-base)-propyl-2-alkynes)-but-2-enamides;
(E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-base)-propyl-2-alkynes)-4-morpholine butyl-2-alkene amide;
(E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-base)-propyl-2-alkynes)-4-(dimethylamino)-butyl-2-alkene amide;
N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl) acrylamide;
(E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl) but-2-enamides;
(E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl)-4-morpholine butyl-2-alkene amide;
(E)-N-(3-(4-(the chloro-4-fluoroaniline of 3-) quinazoline-6-base) Propargyl)-4-(dimethylamino)-butyl-2-alkene amide.
4. the preparation method of tyrosine kinase irreversible inhibitor according to claim 1 or its pharmaceutically acceptable salt, is characterized in that adopting following route to synthesize:
5. the tyrosine kinase irreversible inhibitor described in any one of claim 1-3 or its pharmaceutically acceptable salt are preparing the application in antitumor drug.
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