CN102872018A - 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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CN102872018A
CN102872018A CN2012104085828A CN201210408582A CN102872018A CN 102872018 A CN102872018 A CN 102872018A CN 2012104085828 A CN2012104085828 A CN 2012104085828A CN 201210408582 A CN201210408582 A CN 201210408582A CN 102872018 A CN102872018 A CN 102872018A
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tyrosine kinase
quinazoline
amido
indazole
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CN102872018B (en
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张健存
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Guangzhou Hengnuokang Pharmaceutical Technology Co., Ltd.
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张健存
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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 the pharmaceutical chemistry field, 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 need to obtain growth signals from the resting state to the vegetative state.These growth signals change cell over to by the receptors bind on specific signaling molecule and the cell membrane.EGF is one of most important growth signals molecule wherein.The EGF receptor is the multi-functional transmembrane glycoprotein that is distributed widely 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 is 1.7 * 1O5～1.85 * 1O5 approximately, respectively by the coded by said gene that is positioned on the coloured differently body.Two kinds of receptors of EGFR and HER2 often occur and cross the expression phenomenon in multiple human tumor cell, this mistake is expressed generation, the evolution close relation of phenomenon and tumor.
Find in the clinical tumor research, the excessively expression phenomenon of one or more ErbB receptors all can appear in known 70% malignant tumor.The expression of discovery EGFR is above 100 times of the normal cell level in the kinds of tumor cells such as breast carcinoma, bladder cancer, pulmonary carcinoma, carcinoma of prostate; In the kinds of tumor cells such as breast carcinoma, ovarian cancer, cervical cancer, carcinoma of prostate, nonsmall-cell lung cancer, nasopharyngeal carcinoma, find the amplification of HER2 or cross the expression phenomenon.This phenomenon of cross expressing indicates the tumor patient prognosis mala usually, shows as that life cycle is short, tumor easily recurs, far-end transfer etc. easily occurs, and insensitive to chemotherapy or hormone therapy.
Because the tyrosine kinase mediated Growth of Cells signal of ErbB plays very important effect in the generation of tumor, development, blocking-up ErbB Cellular signalling network can reach the purpose that suppresses tumor.With micromolecule ErbB receptor tyrosine kinase inhibitors (Tyrosine kinase inhibitors, TKIs), with the ATP-binding domain of ATP competitive binding in the ErbB receptor tyrosine kinase, suppress kinase whose catalytic activity, thereby the conduction of blocking-up cell proliferation signal is blocking-up ErbB receptor signal path, suppresses one of the most effective approach of tumor growth.The tyrosine kinase micromolecular inhibitor of at present exploitation listing comprises gefitinib (Iressa), erlotinid hydrochloride (Erlotinib), hydrochloric acid Conmana (Kai Meina) Lapatinib etc., gefitinib wherein, erlotinid hydrochloride, the hydrochloric acid Conmana is the EGFR reversible inhibitor, and Lapatinib is the dual reversible inhibitor of EGFR/HER2.
But external clinical research found 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 responds when the treatment beginning, great majority also finally produce resistance to it, there is no obvious improvement 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 is so that reversible EGFR inhibitor such as gefitinib, erlotinid hydrochloride 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 large shortcoming of reversible inhibitor dosage, scholars begin to focus on the research of irreversible inhibitor.Utilize that sulfydryl has the characteristics of stronger nucleophilicity on the Cys773 at EGFR and HER2 kinases ATP-binding domain edge and the Cys805 amino acid residue, in drug molecule, introduce a Michael addition receptor, make drug molecule form covalent bonds with kinases, reach the purpose of irreversible inhibition.
A large amount of studies show that, the double inhibitor of development targeting EGFR and HER2 tyrosine kinase has following advantage: 1. suppress simultaneously two kinds of tyrosine kinase of EGFR and HER2, thereby be easier to overcome the Drug resistance of the Growth of Cells signal redundancy generation that other members' rises of EGFR family cause when using single tyrosine kinase inhibitor; 2. because EGFR and HER2 heterodimer activity are the highest, the double inhibitor of EGFR and HER2 tyrosine kinase is effective to most cancer patients.3. compare with single inhibitor, double inhibitor has synergistic effect to the inhibiting tumour cells effect.External and in vivo test also shows, to the anticancer effect of EGFR and HER2 tyrosine kinase double inhibition greater than the inhibition to single receptor.Compare with using simultaneously two medicines that act on respectively single target spot 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 tyrosine kinase is rational selection.
At present, the irreversible dual tyrosine kinase inhibitor that enters clinical research has BIBW2992, HKI-272 and PF299804, and the clinical experiment data show that this class inhibitor 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 WO2009012647 announces and in pharmaceutically application; CN102153544 has announced preparation and the purposes of a class Novel tyrosine kinase inhibitors; Protein tyrosine kinase aryl and heteroaryl quinazoline compounds with selective inhibition of HER-2-2 autophosphorylation properties that CN1187129 announces; The human epidermis growth factor acceptor 2 tyrosinase inhibitor that CN1651418 announces; Quinazoline compounds or its officinal salt and its preparation method and medicinal usage 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 with anti-tumor activity that CN101367793 announces.
Summary of the invention
First purpose of the present invention provides a kind of tyrosine kinase irreversible inhibitor or its pharmaceutically acceptable salt, and I is as follows for its general formula of molecular structure:
Wherein, Y is selected from: step gram youngster receptor compounds, active alkylation compounds;
Ar is selected from: phenyl, and the phenyl of replacement contains the also 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 optional separately to be: CH, N, S or nothing.
In certain embodiments, the group of the described A of comprising, B, C 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 8Choose wantonly separately and be: hydrogen, C 1-6Saturated and unsaturated alkyl and the alkyl that replaces of hetero atom.
In certain embodiments, Y is selected from following group:
Figure BDA00002295855600041
Wherein, R 3, R 4, R 5Choose wantonly separately and be: H, F, CN, Cl, C 1-C 6Alkyl or unsaturated alkyl contain O, N, the heteroatomic C of 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,
Figure BDA00002295855600042
R 9, R 10Choose wantonly separately and be: hydrogen, C 1-6Saturated and unsaturated alkyl, contain the alkyl that O, N, S, P hetero atom replace; 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:
Figure BDA00002295855600043
Wherein, R 6As defined above.
In certain embodiments, this tyrosine kinase irreversible inhibitor is preferably from following chemical compound:
Wherein, Y is selected from following group:
R 3, R 4, R 5Choose wantonly separately and be: H, F, CN, Cl, C 1-C 6Alkyl or unsaturated alkyl contain O, N, the heteroatomic C of 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 and contain heteroatomic 3-8 unit ring;
Ar is selected from following group:
Figure BDA00002295855600053
Wherein, R 6Definition such as claim 2;
R 7, R 8Choose wantonly separately and be: hydrogen, C 1-6Saturated and unsaturated alkyl and the alkyl that replaces of hetero atom.
In certain embodiments, Ar is particularly preferably from following group:
In certain embodiments, this tyrosine kinase irreversible inhibitor is preferably from one of following chemical compound:
Chemical compound 1, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-quinazoline-6-yl)-third-2-alkynes)-acrylamide;
Chemical compound 2, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-2-alkynes)-but-2-enamides;
Chemical compound 3, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-2-alkynes)-4-morpholine butyl-2-alkene amide;
Chemical compound 4, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-2-alkynes)-4-(dimethylamino)-butyl-2-alkene amide;
Chemical compound 5, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-2-alkynes)-propine amide;
Chemical compound 6, N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl) acrylamide;
Chemical compound 7, (E)-N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl) but-2-enamides;
Chemical compound 8, (E)-N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl)-4-morpholine butyl-2-alkene amide;
Chemical compound 9, (E)-N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl)-4-(dimethylamino)-butyl-2-alkene amide;
Chemical compound 10, N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl) propine amide;
Chemical compound 11, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-acrylamide;
Chemical compound 12, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-but-2-enamides;
Chemical compound 13, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-4-morpholine butyl-2-alkene amide;
Chemical compound 14, (E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-4-(dimethylamino)-butyl-2-alkene amide;
Chemical compound 15, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-propine amide;
Chemical compound 16, N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl) acrylamide;
Chemical compound 17, (E)-N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl) but-2-enamides;
Chemical compound 18, (E)-N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl)-4-morpholine butyl-2-alkene amide;
Chemical compound 19, (E)-N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl)-4-(dimethylamino)-butyl-2-alkene amide;
Chemical compound 20, N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl) propine amide.
Second purpose of the present invention provides the preparation method of above-mentioned tyrosine kinase irreversible inhibitor or its pharmaceutically acceptable salt, adopts following circuit:
Figure BDA00002295855600071
Wherein:
Figure BDA00002295855600072
The 3rd purpose of the present invention is to provide above-mentioned tyrosine kinase irreversible inhibitor or the application of its pharmaceutically acceptable salt 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 that sulfydryl has the characteristics of stronger nucleophilicity on the Cys773 at EGFR and HER2 kinases ATP-binding domain edge and the Cys805 amino acid residue, in drug molecule, introduce a Michael addition receptor, make drug molecule form covalent bonds with kinases, reach the purpose of irreversible inhibition.Thereby have the following advantages: 1. suppress simultaneously two kinds of tyrosine kinase of EGFR and HER2, thereby be easier to overcome the Drug resistance of the Growth of Cells signal redundancy generation that other members' rises of EGFR family cause when using single tyrosine kinase irreversible inhibitor; 2. because EGFR and HER2 heterodimer activity are the highest, the double inhibitor of EGFR and HER2 tyrosine kinase is effective to most cancer patients.3. compare with single inhibitor, double inhibitor has synergistic effect to the inhibiting tumour cells effect.External and in vivo test also shows, to the anticancer effect of EGFR and HER2 tyrosine kinase double inhibition greater than the inhibition to single receptor.Compare with using simultaneously two medicines that act on respectively single target spot in addition, the medicine patient who acts on two target spots uses more convenient, can also avoid the interaction of medicine and medicine.
The specific embodiment
The compounds of this invention and salt thereof also can be by becoming known for preparing the method preparation of chemical related compound, and the raw material that relates in an embodiment all can obtain by the similar approach of prior art.
Embodiment 1
Chemical compound 1, the preparation of N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-quinazoline-6-yl)-third-2-alkynes)-acrylamide.
Circuit one:
Figure BDA00002295855600091
According to above-mentioned circuit, step 1) preparation compound I-2, i.e. 2-amido-5-iodo-benzoic acid methyl ester, method is as follows:
In two mouthfuls of flasks of the 250mL that Dropping funnel is housed, add 50.19g (332.42mmol) methyl anthranilate, the 100mL tert-butyl alcohol and 50mL water, stir lower 44.32g (174.52mmol) iodine that in batches adds, then slowly drip the hydrogen peroxide of 40mL 30%, in oil bath, be heated to 50 ℃ of insulation 2h.TLC monitors reaction.After reaction finishes, reaction system is cooled to room temperature, adds the saturated aqueous solution of sodium bisulfite of 50mL, stirs evenly, then use the 150mL ethyl acetate extraction three times, merge organic facies, with the water washing of 50mL saturated common salt, anhydrous sodium sulfate drying, revolve to steam and remove approximately 100mL ethyl acetate, place the refrigerator recrystallization, obtain pale yellow crystals 55.23g, yield 60%.
The characterization data of this chemical 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:
Figure BDA00002295855600092
Step 2) preparation compound I-3, i.e. 6-iodine quinazoline-4 (3H) ketone, method is as follows:
In two mouthfuls of flasks of the 250mL that reflux condensing tube is housed, add 37.92g (136.91mmol) 2-amido-5-iodo-benzoic acid methyl ester (being I-2), the anhydrous Methanamide of 50mL, nitrogen protection is heated to 180 ℃ in oil bath, stir 4h.TLC monitors reaction.Reaction is removed oil bath after finishing, and reaction system is cooled to room temperature, adds 100mL water, stir, and sucking filtration, filter cake is drained with 100mL water washing twice, then uses 50mL ether washed twice, and vacuum drying gets Off-white solid 32.04g, yield 86%.
The characterization data of this chemical 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:
Figure BDA00002295855600101
Step 3) preparation compound I-5a, method is as follows:
In two mouthfuls of flasks of the 25mL that reflux condensing tube is housed, add 1.36g (5mmol) 6-iodine quinazoline-4 (3H) ketone (being I-3); 0.92g (6mmol) phosphorus oxychloride; 6mL toluene; then nitrogen protection slowly adds the 0.9mL triethylamine with syringe, finishes; with be heated in the oil bath 75 ℃ the reaction 2h; slightly cold, the acetonitrile solution of adding 1.2g 1-(3-luorobenzyl)-1H-indazole-5-ammonia again is warming up to and is cooled to 75 ℃ of reaction 2h; reaction finishes; naturally be down to room temperature, sucking filtration, filter cake change in the 15mL 1M sodium hydroxide solution and stir 2h; sucking filtration; the filter cake vacuum drying gets yellowish powder 1.2g, yield 48%.
The characterization data of this chemical 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) preparation compound I-6a, method is as follows:
Under nitrogen protection, in two mouthfuls of flasks of 25mL, add 0.495g I-5a, dry THF 3mL; diisopropyl ammonia 0.4mL, degassed 5min adds two (triphenylphosphine) palladium chloride 40mg (5%mol); Hydro-Giene (Water Science). 19mg (10%mol); slowly inject 0.193g propine amido t-butyl formate under the room temperature, finish stirring reaction 2h under the room temperature; the TLC monitoring; reaction finishes, and the pillar chromatography changes product in the dichloromethane solution of 10mL30%TFA; the stirring at room reaction; the TLC monitoring, reaction finishes, and revolves to steam to doing; residue washs 3 times with saturated sodium bicarbonate solution; sucking filtration, filtration cakes torrefaction gets I-6a 0.25g yield 60%.
The characterization data of this chemical 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:
Figure BDA00002295855600111
Step 5) preparation chemical compound 1, N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-quinazoline-6-yl)-third-2-alkynes)-acrylamide, method is as follows:
Under the 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 the ice-water bath, add 25mg EDCI; stirring reaction 30 minutes rises to room temperature naturally, continues stirring reaction, TLC; monitoring, reaction finishes, with the dilution of 30mL dichloromethane; washing, saturated common salt washing, drying; cross fast post, get target product 30mg, yield 62.5%.
The characterization data of this chemical 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 chemical compound is:
Figure BDA00002295855600121
Embodiment 2
Chemical compound 2, (E)-preparation of N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-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 such as embodiment 1 obtain target product.
The characterization data of this chemical 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:
Figure BDA00002295855600122
Embodiment 3
Chemical compound 3, (E)-preparation of N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-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 such as embodiment 1 obtain target product.
The characterization data of this chemical 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:
Figure BDA00002295855600131
Embodiment 4
Chemical compound 4, (E)-preparation of N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-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 such as embodiment 1 obtain target product.
The characterization data of this chemical 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:
Figure BDA00002295855600141
Embodiment 5
Chemical compound 5, the preparation of N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-2-alkynes)-propine amide.
Step 1)-4) with embodiment 1, step 5) as follows:
Select acetylenecarboxylic acid, with 1-6a, condensation reaction, operational approach such as embodiment 1 obtain target product.
The characterization data of this chemical 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:
Figure BDA00002295855600142
Embodiment 6
Chemical compound 6, the preparation of N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl) acrylamide.
According to the circuit one among the embodiment 1, step 1) preparation compound I-2, i.e. 2-amido-5-iodo-benzoic acid methyl ester, method is as follows:
In two mouthfuls of flasks of the 250mL that Dropping funnel is housed, add 50.19g (332.42mmol) methyl anthranilate, the 100mL tert-butyl alcohol and 50mL water, stir lower 44.32g (174.52mmol) iodine that in batches adds, then slowly drip the hydrogen peroxide of 40mL 30%, in oil bath, be heated to 50 ℃ of insulation 2h.TLC monitors reaction.After reaction finishes, reaction system is cooled to room temperature, adds the saturated aqueous solution of sodium bisulfite of 50mL, stirs evenly, then use the 150mL ethyl acetate extraction three times, merge organic facies, with the water washing of 50mL saturated common salt, anhydrous sodium sulfate drying, revolve to steam and remove approximately 100mL ethyl acetate, place the refrigerator recrystallization, obtain pale yellow crystals 55.23g, yield 60%.
The characterization data of this chemical 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:
Figure BDA00002295855600151
Step 2) preparation compound I-3, i.e. 6-iodine quinazoline-4 (3H) ketone, method is as follows:
In two mouthfuls of flasks of the 250mL that reflux condensing tube is housed, add 37.92g (136.91mmol) 2-amido-5-iodo-benzoic acid methyl ester (being I-2), the anhydrous Methanamide of 50mL, nitrogen protection is heated to 180 ℃ in oil bath, stir 4h.TLC monitors reaction.Reaction is removed oil bath after finishing, and reaction system is cooled to room temperature, adds 100mL water, stir, and sucking filtration, filter cake is drained with 100mL water washing twice, then uses 50mL ether washed twice, and vacuum drying gets Off-white solid 32.04g, yield 86%.
The characterization data of this chemical 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) preparation compound I-5b, method is as follows:
Replace 1-(3-luorobenzyl)-1H-indazole-5-ammonia with 3-chloro-4-fluoroaniline, detailed step makes I-5b with preparing compound I-5a by I-3 among the embodiment 1, 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) preparation compound I-6b, method is as follows:
With I-5b substitute I-5a, detailed step makes I-6b with preparing compound I-6a by I-5a among the embodiment 1, 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:
Figure BDA00002295855600162
Step 5) chemical compound 6, the preparation of N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl) acrylamide, and method is as follows:
Under the 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 the ice-water bath, add 25mg EDCI; stirring reaction 30 minutes rises to room temperature naturally, continues stirring reaction; TLC, monitoring, reaction finishes; with the dilution of 30mL dichloromethane, washing, saturated common salt washing; drying, the quick post of crossing obtains target product.
The characterization data of this chemical 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
Chemical compound 7, (E)-preparation of N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) 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 such as embodiment 6 obtain target product.
The characterization data of this chemical 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:
Figure BDA00002295855600172
Embodiment 8
Chemical compound 8, (E)-preparation of N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) 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 such as embodiment 6 obtain target product.
The characterization data of this chemical 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:
Figure BDA00002295855600181
Embodiment 9
Chemical compound 9, (E)-preparation of N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) 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 such as embodiment 6 obtain target product.
The characterization data of this chemical 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:
Figure BDA00002295855600182
Embodiment 10
Chemical compound 10, the preparation of N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl) propine amide.
Step 1)-4) with embodiment 6, step 5) as follows:
Select acetylenecarboxylic acid, with 1-6b, condensation reaction, operational approach such as embodiment 6 obtain target product.
The characterization data of this chemical 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:
Figure BDA00002295855600191
Embodiment 11
Chemical compound 11, the preparation of N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-Pyrimidothiophene-6-yl) the-the third-2 alkynes)-acrylamide.
Circuit two:
According to above-mentioned circuit, step 1) preparation compound I I-2, i.e. thieno [2,3-D] pyrimidine-4 (3H)-ketone, method is as follows:
In two mouthfuls of flasks of the 250mL that reflux condensing tube is housed, add 25g (136.91mmol) 2-amino-thenoic acid ethyl ester (being compound I I-1), the anhydrous Methanamide of 100mL, nitrogen protection is heated to 180 ℃, stirring reaction 6h in oil bath.TLC monitors reaction.Reaction is removed oil bath after finishing, and reaction system is cooled to room temperature, adds 100mL water, stir, and sucking filtration, filter cake is drained with 100mL water washing twice, then uses 50mL ether washed twice, and vacuum drying gets Off-white solid 13.4g, yield 60%.
The characterization data of this chemical 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:
Figure BDA00002295855600201
Step 2) preparation compound I I-3a, method is as follows:
In two mouthfuls of flasks of the 25mL that reflux condensing tube is housed, add 1.52g (10mmol) thieno [2; 3-D] pyrimidine-4 (3H)-ketone (being compound I I-2); 1.7g (11mmol) phosphorus oxychloride; the dried toluene of 8mL; nitrogen protection; then slowly add the 1.5mL triethylamine with syringe, finish, be heated in the oil bath 75 ℃ the reaction 2h; slightly cold; the acetonitrile solution that adds 2g 1-(3-luorobenzyl)-1H-indazole-5-ammonia again is warming up to and is cooled to 75 ℃ of reaction 2h, and reaction finishes; naturally be down to room temperature; sucking filtration, filter cake change in the 15mL 1M sodium hydroxide solution and stir 2h, sucking filtration; the filter cake vacuum drying; get N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-thieno [2,3-D] pyrimidine 4-ammonia 2.7g, yield 72%.
The characterization data of this chemical compound is: 1H-NMR (DMSO-J6) δ 8.56 (s, IH), and, 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:
Figure BDA00002295855600211
Step 3) preparation compound I I-4a, method is as follows:
Under the nitrogen protection, in two mouthfuls of flasks of the 25mL that reflux condensing tube is housed, add II-3a 1.8g, N-chlorosuccinimide 1.3g; 20 milliliters of glacial acetic acids are warming up to 95 ℃ of reaction 2h, the TLC monitoring; reaction finishes, and revolves to steam to remove glacial acetic acid, and residue is used saturated sodium bicarbonate successively; water washing; drying gets also [2,3-D] pyrimidine 4-ammonia of N-(1-(3-luorobenzyl)-1H-indazole-5-yl)-6-chlorothiophene; 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) preparation compound I I-5a, method is as follows:
Under nitrogen protection, in two mouthfuls of flasks of 25mL, add 0.4g II-4a, dry THF 3mL; diisopropyl ammonia 0.4mL, degassed 5min adds two (triphenylphosphine) palladium chloride 40mg (5%mol); Hydro-Giene (Water Science). 19mg (10%mol); slowly inject 0.193g propine amido t-butyl formate under the room temperature, finish stirring reaction 2h under the room temperature; the TLC monitoring; reaction finishes, and the pillar chromatography changes product in the dichloromethane solution of 10mL30%TFA; the stirring at room reaction; the TLC monitoring, reaction finishes, and revolves to steam to doing; residue washs 3 times with saturated sodium bicarbonate solution; sucking filtration, filtration cakes torrefaction gets 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:
Figure BDA00002295855600221
Step 5) chemical compound 11, the preparation of N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-acrylamide, and method is as follows:
By compound I I-5a and acrylic acid at EDCI, HOBT and triethylamine condensation reaction in DMF, operational approach such as embodiment 1 obtain 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
Chemical compound 12, (E)-preparation of N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-but-2-enamides.
Step 1)-4) with embodiment 11, step 5) as follows:
Select 2-butylene acid, at EDCI, HOBT and triethylamine react in DMF, with II-5a, and condensation reaction, operational approach such as embodiment 1 obtain 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:
Figure BDA00002295855600231
Embodiment 13
Chemical compound 13, (E)-preparation of N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-4-morpholine butyl-2-alkene amide.
Step 1)-4) with embodiment 11, step 5) as follows:
Select 4-morpholine-2-butenoic acid, at EDCI, HOBT and triethylamine react in DMF, with II-5a, and condensation reaction, operational approach such as embodiment 1 obtain target product.
These characterization of compound data are: 1H-NMR (DMSO-d6) δ 8.73 (s, IH), and, 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:
Figure BDA00002295855600232
Embodiment 14
Chemical compound 14, (E)-preparation of N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-4-(dimethylamino)-butyl-2-alkene amide.
Step 1)-4) with embodiment 11, step 5) as follows:
Select 4-dimethylamino-2-butylene acid, at EDCI, HOBT and triethylamine react in DMF, with II-5a, and condensation reaction, operational approach such as embodiment 1 obtain 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:
Figure BDA00002295855600241
Embodiment 15
Chemical compound 15, the preparation of N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-propine amide.
Step 1)-4) with embodiment 11, step 5) as follows:
Select propargylic acid, at EDCI, HOBT and triethylamine react in DMF, with II-5a, and condensation reaction, operational approach such as embodiment 1 obtain 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:
Figure BDA00002295855600242
Embodiment 16
Chemical compound 16, the preparation of N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl) acrylamide.
According to the circuit two among the embodiment 11, step 1) preparation compound I I-2, i.e. thieno [2,3-D] pyrimidine-4 (3H)-ketone, method is as follows:
In two mouthfuls of flasks of the 250mL that reflux condensing tube is housed, add 25g (136.91mmol) 2-amino-thenoic acid ethyl ester (being compound I I-1), the anhydrous Methanamide of 100mL, nitrogen protection is heated to 180 ℃, stirring reaction 6h in oil bath.TLC monitors reaction.Reaction is removed oil bath after finishing, and reaction system is cooled to room temperature, adds 100mL water, stir, and sucking filtration, filter cake is drained with 100mL water washing twice, then uses 50mL ether washed twice, and vacuum drying gets Off-white solid 13.4g, yield 60%.
The characterization data of this chemical 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) preparation compound I I-3b, method is as follows:
With the 1-(3-luorobenzyl) in the 3-chloro-4-fluoroaniline alternative embodiment 11-1H-indazole-5-ammonia, detailed step makes II-3b with preparing compound I I-3a by compound I I-2 among the embodiment 11, yield 75%.
The characterization data of this chemical 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:
Figure BDA00002295855600252
Step 3) preparation compound I I-4b, method is as follows:
With II-3b substitute I I-3a, detailed step prepares compound I I-4a with embodiment 11 by compound I I-3a, makes 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:
Figure BDA00002295855600261
Step 4) preparation compound I I-5b, method is as follows:
With II-4b substitute I I-4a, detailed step with among the embodiment 11 by the standby compound I I-5a of chemical compound II-4a processed, make 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:
Figure BDA00002295855600262
Step 5) chemical compound 16, the preparation of N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl) acrylamide, and method is as follows:
By compound I I-5b and acrylic acid at EDCI, HOBT and triethylamine condensation reaction in DMF, operational approach such as embodiment 1 obtain 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:
Figure BDA00002295855600271
Embodiment 17
Chemical compound 17, (E)-preparation of N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl)-4-morpholine butyl-2-alkene amide.
Step 1)-4) with embodiment 16, step 5) as follows:
Select 2-butylene acid, at EDCI, HOBT and triethylamine react in DMF, with II-5b, and condensation reaction, operational approach such as embodiment 1 obtain 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:
Figure BDA00002295855600272
Embodiment 18
Chemical compound 18, (E)-preparation of N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl)-4-morpholine butyl-2-alkene amide.
Step 1)-4) with embodiment 16, step 5) as follows:
Select 4-morpholine-2-butenoic acid, at EDCI, HOBT and triethylamine react in DMF, with II-5b, and condensation reaction, operational approach such as embodiment 1 obtain 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:
Figure BDA00002295855600281
Embodiment 19
Chemical compound 19, (E)-preparation of N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl)-4-(dimethylamino)-butyl-2-alkene amide.
Step 1)-4) with embodiment 16, step 5) as follows:
Select 4-dimethylamino-2-butylene acid, at EDCI, HOBT and triethylamine react in DMF, with II-5b, and condensation reaction, operational approach such as embodiment 1 obtain 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:
Figure BDA00002295855600282
Embodiment 20
Chemical compound 20, the preparation of N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl) propine amide.
Step 1)-4) with embodiment 16, step 5) as follows:
Select 4-dimethylamino-2-butylene acid, at EDCI, HOBT and triethylamine react in DMF, with II-5b, and condensation reaction, operational approach such as embodiment 1 obtain 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:
Figure BDA00002295855600291
Embodiment 21
Adopt external enzyme inhibition activity to measure enzyme inhibition activity with euzymelinked immunosorbent assay (ELISA).Concrete grammar is as follows:
Target compound is measured employing Z '-LYTE to EGFR and HER2 enzyme inhibition activity 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 the reagent configuration; First enzyme and medicine are added on 384 orifice plates according to certain proportioning respectively, mixing is placed 30min; Then add ATP, mixing is placed 2h; Add 5 μ L Development Regent, mixing under room temperature, is placed 15min, 30min, and 1h detects with microplate reader; Add the Stop regent of 5 μ L behind the 1h, detect with microplate reader behind the mixing.Calculate corresponding phosphorylation ratio, according to the concentration of medicine and corresponding kinase inhibition rate mapping, obtain dose-effect curve, therefrom try to achieve the half-inhibition concentration (IC50) of medicine.The result is as follows:
The half-inhibition concentration (IC50) of table 1 couple EGFR and HER2 enzyme
Figure BDA00002295855600292
Figure BDA00002295855600301
From the above results as can be known, tyrosine kinase irreversible inhibitor provided by the present invention is simultaneously inhibited to EGFR and two kinds of tyrosine kinase of HER2, its half-inhibition concentration is compared with the positive control Lapatinib, or be better than positive control, or suitable to being less than positive control, particularly chemical compound 5 and chemical compound 11, it all less than positive control, has good enzyme inhibition activity to the half-inhibition concentration of EGFR and two kinds of tyrosine kinase of HER2.
The above embodiment has only expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to claim of the present invention.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 (10)

1. the tyrosine kinase irreversible inhibitor shown in the formula I or its pharmaceutically acceptable salt:
Figure FDA00002295855500011
Wherein, Y is selected from: step gram youngster receptor compounds, active alkylation compounds;
Ar is selected from: phenyl, and the phenyl of replacement contains the also 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 optional separately to be: CH, N, S or nothing.
2. tyrosine kinase irreversible inhibitor according to claim 1 or its pharmaceutically acceptable salt is characterized in that, it is one of following that the group of the described A of comprising, B, C is selected from:
Figure FDA00002295855500012
Wherein, R6 is 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 8Choose wantonly separately and be: hydrogen, C 1-6Saturated and unsaturated alkyl and the alkyl that replaces of hetero atom.
3. tyrosine kinase irreversible inhibitor according to claim 1 or its pharmaceutically acceptable salt is characterized in that, Y is selected from following group:
Wherein, R 3, R 4, R 5Choose wantonly separately and be: H, F, CN, Cl, C 1-C 6Alkyl or unsaturated alkyl contain O, N, the heteroatomic C of S, P 1-C 6Alkyl, cyclic alkyl, unsaturated chain or cyclic alkyl, R 3, R 4, R 5In any two substituent group ring formation.
4. tyrosine kinase irreversible inhibitor according to claim 3 or its pharmaceutically acceptable salt is characterized in that, Y is selected from following group:
Figure FDA00002295855500021
R 9, R 10Choose wantonly separately and be: hydrogen, C 1-6Saturated and unsaturated alkyl, contain the alkyl that O, N, S, P hetero atom replace; R 9And R 10Ring formation;
n＝1-6。
5. tyrosine kinase irreversible inhibitor according to claim 1 or its pharmaceutically acceptable salt is characterized in that, Ar is selected from following group:
Figure FDA00002295855500022
Wherein, R 6Definition such as claim 2.
6. tyrosine kinase irreversible inhibitor according to claim 1 or its pharmaceutically acceptable salt is characterized in that, are selected from following chemical compound:
Figure FDA00002295855500023
Wherein, Y is selected from following group:
Figure FDA00002295855500024
R 3, R 4, R 5Choose wantonly separately and be: H, F, CN, Cl, C 1-C 6Alkyl or unsaturated alkyl contain O, N, the heteroatomic C of S, P 1-C 6Alkyl or cyclic alkyl or unsaturated chain or cyclic alkyl, R 3, R 4, R 5In any two substituent group ring formation;
Ar is selected from following group:
Wherein, R 6Definition such as claim 2.
7. tyrosine kinase irreversible inhibitor according to claim 6 or its pharmaceutically acceptable salt is characterized in that, Ar is selected from following group:
Figure FDA00002295855500032
。
8. tyrosine kinase irreversible inhibitor according to claim 1 or its pharmaceutically acceptable salt is characterized in that, are selected from one of following chemical compound:
N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-quinazoline-6-yl)-third-2-alkynes)-acrylamide;
(E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-2-alkynes)-but-2-enamides;
(E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-2-alkynes)-4-morpholine butyl-2-alkene amide;
(E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-2-alkynes)-4-(dimethylamino)-butyl-2-alkene amide;
N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-quinazoline-6-yl)-third-2-alkynes)-propine amide;
N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl) acrylamide;
(E)-N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl) but-2-enamides;
(E)-N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl)-4-morpholine butyl-2-alkene amide;
(E)-N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl)-4-(dimethylamino)-butyl-2-alkene amide;
N-(3-(4-(3-chloro-4-fluoroaniline) quinazoline-6-yl) Propargyl) propine amide;
N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5 amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-acrylamide;
(E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-but-2-enamides;
(E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-4-morpholine butyl-2-alkene amide;
(E)-N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-4-(dimethylamino)-butyl-2-alkene amide;
N-(3-(4-(1-(3-fluorophenyl)-1H-indazole-5-amido)-Pyrimidothiophene-6-yl)-third-2-alkynes)-propine amide;
N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl) acrylamide;
(E)-N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl) but-2-enamides;
(E)-N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl)-4-morpholine butyl-2-alkene amide;
(E)-N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl)-4-(dimethylamino)-butyl-2-alkene amide;
N-(3-(4-(3-chloro-4-fluoroaniline)-Pyrimidothiophene-6-yl) Propargyl) propine amide.
9. the preparation method of tyrosine kinase irreversible inhibitor claimed in claim 6 or its pharmaceutically acceptable salt is characterized in that adopting following route synthetic:
Figure FDA00002295855500041
。
10. each described tyrosine kinase irreversible inhibitor of claim 1-8 or its pharmaceutically acceptable salt application in the preparation antitumor drug.
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WO2014063631A1 (en) * 2012-10-23 2014-05-01 Zhang Jiancun Tyrosine kinase irreversible inhibitor and preparation method and applications thereof
CN106146412A (en) * 2015-03-31 2016-11-23 广州市恒诺康医药科技有限公司 Quinazoline derivant and its preparation method and application
CN108341822A (en) * 2017-01-23 2018-07-31 广州市恒诺康医药科技有限公司 Fxr receptor modulators and its preparation method and application
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WO2014063631A1 (en) * 2012-10-23 2014-05-01 Zhang Jiancun Tyrosine kinase irreversible inhibitor and preparation method and applications thereof
CN106146412A (en) * 2015-03-31 2016-11-23 广州市恒诺康医药科技有限公司 Quinazoline derivant and its preparation method and application
CN106146412B (en) * 2015-03-31 2019-05-24 广州市恒诺康医药科技有限公司 Quinazoline derivant and its preparation method and application
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CN108341822B (en) * 2017-01-23 2021-04-16 广州市恒诺康医药科技有限公司 FXR receptor modulator and preparation method and application thereof
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