CN106068262B

CN106068262B - Quinazoline derivant and preparation method thereof and application in medicine

Info

Publication number: CN106068262B
Application number: CN201580012570.5A
Authority: CN
Inventors: 李瑶; 徐波; 陈雷; 李升�; 刘建余; 钱枚琳
Original assignee: Haisike Pharmaceutical Group Ltd By Share Ltd
Current assignee: Haisco Pharmaceutical Group Co Ltd
Priority date: 2014-04-11
Filing date: 2015-04-13
Publication date: 2019-10-29
Anticipated expiration: 2035-04-13
Also published as: CN106068262A; WO2015154725A1

Abstract

Application the present invention relates to a kind of quinazoline derivant and preparation method thereof and in medicine, specifically the present invention relates to quinazoline derivant or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrugs, it is related to their preparation method, it is related to including the purposes of its pharmaceutical composition and the compound of the present invention pharmaceutical composition in medicine, particularly as the purposes of the bis- target spot inhibitor of EGFR/HER2.

Description

Quinazoline derivant and preparation method thereof and application in medicine

Technical field

Application the present invention relates to a kind of quinazoline derivant and preparation method thereof and in medicine, it is specifically a kind of to have The novel quinazoline derivant of the bis- target spot inhibiting effect of EGFR/HER2 or its stereoisomer, hydrate, solvate, metabolism Product, pharmaceutically acceptable salt, eutectic or prodrug, its pharmaceutical composition and its application in medicine.

Background technique

Receptor tyrosine kinase superfamily in cell surface receptor is by extracellular growth factors to the tune of cell signal Section plays an important role.Receptor tyrosine kinase can catalytic phosphatase group from the tyrosine group that ATP is transferred to substrate.When When not having ligand activation receptor tyrosine kinase, these kinases are in unphosphorylated free state, and kinase domain is in nonactive Structure.When ligand is in conjunction with the extracellular fragment of receptor tyrosine kinase, oligomerization, and autophosphorylation occur for receptor, increase The binding site of signal protein is formd while the catalytic activity of kinases, signal protein is in connection, to activate a plurality of letter Number access.These signal paths connect each other, proliferation, existence, differentiation, function, migration and the apoptosis of regulating cell.When receptor junket Histidine kinase loses regulation, and when abnormal activation, cell can be converted to tumour cell, proliferation, growth ability and drug resistance ability It improves, has stronger at vessel patency, invasiveness and transfer ability (Yarden and Sliwkowski, 2001, Nat Rev Mol Cell Biol, 2,127-137).

Epidermal growth factor (EGF) receptor is a kind of receptor tyrosine enzyme being concerned.EGF receptor family includes 4 Member: EGFR/ErbB1/HER1, ErbB2/HER2/Neu, ErbB3/HER3 and ErbB4/HER4.The letter of normal EGFR activation Number access can adjust the proliferation of cell, at blood vessel, growth, migration and adherency, the cell of Organogenesis Process or adult with Play an important role (Wu, Zhong etc., 2007, J Thorac Oncol, 2,430-439) in intercellular interaction.It is many The molecule time can result in the sustained activation of EGFR kinase activity, constantly trigger a large amount of downstream signal transduction access, including K-ras activation.Therefore EGFR family and tumor formation are closely related.The overexpression of EGFR or mutation are in head and neck cancer, oophoroma, bladder It can be detected in the kinds cancers such as cancer, cervical carcinoma, cancer of the esophagus, gastric cancer, breast cancer, endometrial carcinomas, colon cancer, lung cancer and brain tumor, Usually indicate this undesirable prognosis.In addition, HER2 is considered as a kind of stronger oncoprotein, mutation is also in kinds of tumors As it can be seen that especially breast cancer, lung cancer and colon cancer etc. (Olayioye, Neve etc., 2000, EMBO J, 19,3159-3167).

Currently, having developed a variety of EGFR tyrosine kinase micromolecular inhibitors, such as the Gefitinib and strategic point of the first generation Sieve replaces Buddhist nun, selectively can reversibly inhibit EGFR, to prevent the growth of tumour, especially lacks containing exons 19 (such as del747-750) and exon 21 are mutated tumour (Barker, Gibson etc., 2001, the Bioorg Med of (such as L858R) Chem Lett, 11,1911-1914；Wakeling, Guy etc., 2002, Cancer Res, 62,5749-5754).However, very much Will appear acquired resistance using the patient of Gefitinib and Erlotinib, this acquired resistance have 50%-60% be due to Caused by the T790M mutation that extron 20 occurs.T790M mutation will affect kinase catalytic domain, weaken targeted inhibition agent and target spot Interaction, keep treatment invalid (Pao and Chmielecki, 2010, Nat Rev Cancer, 10,760-774).

The study found that irreversible inhibitor can be with the cysteine residues that play a decisive role in the active site of kinases Covalent bond is formed, a kind of potential strategy for inhibiting T790M mutation is become.And in EGFR family, only EGFR and HER2 There is cysteine in corresponding site.Therefore this irreversible inhibitor has the specificity of height to EGFR and HER2 (Singh, Dobrusin etc., 1997, J Med Chem, 40,1130-1135；Fry, Bridges etc., 1998, Proc Natl Acad Sci USA, 95,12022-12027).Many irreversible double inhibitors (such as Afatinib, linatinib are developed With OK a karaoke club for Buddhist nun etc.), compared to reversible inhibitor, these drugs not only can effectively inhibit EGFR sensitizing mutation at low concentrations (such as del747-750, L858R), and can effectively overcome drug resistance caused by T790M.It is worth noting that, being ground preclinical In studying carefully, irreversible double inhibitors generate quick drug resistance (Ercan, Zejnullahu unlike Gefitinib and Erlotinib Deng 2010, Oncogene, 29,2346-2356；Chmielecki, Foo etc., 2011, Sci Transl Med, 3,90ra59).

In order to meet clinical demand, need to continue to research and develop in the drug resistance and safety that can effectively overcome T790M mutation to generate The bis- target spot inhibitor of EGFR/HER2.

CN10679384 describes the novel amide derivative for inhibiting growth of cancer cells, and structural formula is as follows:

Wherein, A isR₄、R₅、R₆And R₇Respectively stand alone as hydrogen, halogen, N-C_1-6Alkyl or N- hydroxyl Acylamino- or C-C_1-6Anti- the acylamino- (- NHCOC of alkyl_1-6), hydroxycarbonyl group (- COOH), C_1-6Alkoxy carbonyl (- COOC_1-6)、 C_1-6Alkyl, or for by hydroxyl, C_1-6The alkyl that dialkylamine or heterocyclic group replace；R₁Be by the 1-5 X aryl replaced or Heterocyclic group, or the C being substituted with aryl_1-6Alkyl；R₂It is hydrogen, hydroxyl, C_1-6Alkoxy, or by C_1-6Alkoxy or The C that heterocyclic group replaces_1-6Alkoxy；R₃It is hydrogen ,-COOH, C_1-6Alkoxy carbonyl or the unsubstituted acylamino- of N- or The substituted acylamino- of N-；n_aAnd n_bThe respectively integer of 0-6；X is hydrogen, halogen, hydroxyl, cyano, nitro, (halogenated, a dihalo- In generation, is three halogenated) methyl, sulfydryl, C_1-6Alkylthio group, acrylamido, C_1-6Alkyl, C_1-6Alkenyl, C_1-6Alkynyl, C_1-6Alkoxy, Aryloxy group, C_1-6Dialkyl amido, or the C to be replaced by Z_1-6Alkyl or C_1-6Alkoxy, condition are when the quantity of X is two Or more when, X group can be fused together to form ring structure；Y is hydroxyl, C_1-6Alkyl, or the C replaced by Z_1-6Alkane Base, the C_1-6Alkyl contains 1-4 selected from N, O, S, SO and SO₂Group；And Z is C_1-6Alkyl, aryl or heterocyclic group, The aryl group is C_5-12Monocycle or bicyclic aromatic group, the heterocyclic group are to be selected from N, O, S, SO and SO containing 1-4₂ Group C_5-12Monocycle or bicyclic aromatics or nonaromatic, and the aryl and heterocyclic group are unsubstituted, or Person is selected from halogen, hydroxyl, amino, nitro, cyano, C_1-6Alkyl, C_1-6Alkenyl, C_1-6Alkynyl, C_1-6Alkoxy, C_1-6Monoalkyl Amino and C_1-6The substituent group of dialkyl amido replaces.It is not considered as that specifically describing in this patent is a part of the invention.

CN102731485 describes 4- (replacing phenylamino) quinazoline derivant, and structural formula is as follows:

R₁It is selected from R₂Selected from hydrogen or N, N- bis- Methyaminomethyl；R₃Selected from methoxyethyl, tetrahydrofuran -3- base, (S)-tetrahydrofuran -3- base or (R)-tetrahydrofuran -3- base, And each R₄And R₅Independently selected from one or more hydrogen, halogen, C₁-C₁₀Alkyl, C₁-C₁₀Alkoxy and halogenated C₁-C₁₀Alkyl； And if only if R₂For hydrogen, R₃When for methoxyethyl, R₁It is notAnd if only if R₂For N, N- dimethylamino methyl, R₃When for tetrahydrofuran -3- base, R₁It is notIt is not considered as specifically to retouch in this patent Stating is a part of the invention.

WO2011029265 describes quinazoline derivant, and structural formula is as follows:

Wherein, A is selected from carbon atom or nitrogen-atoms；When A is carbon atom, R¹Selected from hydrogen atom or alkoxy, wherein described Alkoxy optionally further replaced one or more substituent groups selected from halogen or alkoxy, R²Selected from cyano；When A is When nitrogen-atoms, R¹Selected from hydrogen atom or alkoxy, wherein the alkoxy is optionally further selected from halogen by one or more Or replaced the substituent group of alkoxy, R²It is unsubstituted；R³With having structure :-D-T-L or-D；D is selected from aryl or heteroaryl, Described in aryl or heteroaryl each independently optionally further by one or more selected from halogen, alkyl or trifluoromethyl Replaced substituent group；T is selected from-(CH₂)r-、-O(CH₂)r-、-NH(CH₂) r- or-S (O) r (CH₂)r-；L is selected from aryl or heteroaryl Base, wherein the aryl or heteroaryl are each independently optionally further replaced one or more halogens or alkyl；R⁴ And R⁵It is each independently selected from hydrogen atom, alkyl, alkoxy, hydroxyl, hydroxyalkyl, halogen, carbonyl, amino, cyano, nitro, carboxylic Acid or carboxylate；B is selected from carbon atom, oxygen atom or S (O) r group；When B is carbon atom, R⁶And R⁷It is each independently selected from hydrogen Atom, alkyl, alkoxy, hydroxyl, hydroxyalkyl, halogen, carbonyl, amino, cyano, nitro, carboxylic acid or carboxylate；When B is that oxygen is former When son or S (O) r group, R⁶And R⁷It is unsubstituted；R⁸Selected from hydrogen atom or alkyl；R⁹Selected from hydrogen atom, alkyl, aryl, carboxyl or Carboxylate；R is 0,1 or 2；And n is 1,2,3,4 or 5.It is not considered as that specifically describing in this patent is a part of the invention.

Summary of the invention

The present invention provides the compound of a kind of structure novel, shows the compounds of this invention as EGFR/HER2 after study Double target spot inhibitor show excellent drug activity.

The present invention provides a kind of general formula (II₀) compound represented or its stereoisomer, hydrate, metabolite, Solvate, pharmaceutically acceptable salt, eutectic or prodrug,

Wherein:

R²Selected from C_1-3Alkyl or 4 to 8 circle heterocyclic ring bases, the heterocycle optionally further by 0 to 2 selected from F, Cl, Hydroxyl, C_1-3Alkyl or C_1-3Replaced the substituent group of alkoxy, and the heterocycle contains 1 to 2 and is selected from N's or O Hetero atom；

Ring A is selected from

R³Selected from F, CF₃、CHF₂、CH₂F, Cl, hydroxyl or C_1-3Alkyl；

X₁ForOr X₁It is formed together with ring A

R⁴、R⁵And R⁶Respectively H；

R⁹Selected from F, Cl, hydroxyl, C_1-3Alkyl or C_2-3Alkynyl；

N, m, t each are selected from 0,1,2,3 or 4；

Restrictive condition is, when n is 0, R²Selected from C_1-3Alkyl, and m be 0 when, ring A is not

Preferably, the compound of the present invention is selected from logical formula (II) compound represented:

Wherein:

R²Selected from methyl, ethyl or

Ring A is selected from

N is 0 or 1；

R³Selected from F；

M is 0 or 1；

R⁴、R⁵And R⁶It is H；

R⁹Selected from F or Cl；

T is 3；

Restrictive condition is, when n is 0, R²Selected from methyl or ethyl, and when m is 0, ring A is not

Specifically, compound of the present invention or its stereoisomer, hydrate, metabolite, solvate, medicine Acceptable salt, eutectic or prodrug are selected from, but are not limited to:

Specific embodiment according to the present invention, the compound of the present invention or its stereoisomer, hydrate, metabolism produce Object, solvate, pharmaceutically acceptable salt, eutectic or prodrug, wherein the salt is selected from hydrochloride, hydrobromate, sulfuric acid Salt, phosphate, acetate, trifluoroacetate, rhodanate, maleate, hydroxymaleic acid salt, glutarate, mesylate, Esilate, benzene sulfonate, tosilate, benzoate, salicylate, phenylacetate, cinnamate, lactate, third Diacid salt, pivalate, succinate, fumarate, malate, mandelate, tartrate, gallate, grape Sugar lime, laruate, palmitate, pectate, picrate, citrate or their combination, it is preferred that described Salt be selected from hydrochloride, hydrobromate, sulfate, phosphate, acetate, maleate, mesylate, benzene sulfonate, trifluoro Acetate, tosilate, benzoate, salicylate, cinnamate, lactate, malonate, succinate, rich horse Hydrochlorate, malate, tartrate, citrate or their combination, more preferable hydrochloride and maleate.

The present invention also provides a kind of pharmaceutical composition, the composition includes: the of the present invention of effective dose Compound or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug, with And pharmaceutically acceptable carrier, diluent, adjuvant, medium or excipient.

Specific embodiment according to the present invention, pharmaceutical composition of the invention still further comprise it is one or more other Therapeutic agent.

Specific embodiment according to the present invention, other therapeutic agents described in pharmaceutical composition of the invention include: suitable Platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (MTX) (methotrexate), fluorouracil (fluorouracil), cytarabine (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), Topotecan (topotecan), Irinotecan (irinotecan), Etoposide (etoposide), tributidine (trabectedin), dactinomycin D (dactinomycin), Doxorubicin (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), mitomycin C (mitomycin), Ipsapirone (ixabepilone), tamoxifen (tamoxifen), fluorine His amine (flutamide), sirolimus (sirolimus), Afatinib (afatinib), alisertib, amuvatinib, A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), posupini (bosutinib), Bu Linibu (brivanib), card is rich to replace Buddhist nun (cabozantinib), Si Dinibu (cediranib), Crenolanib, gram Zhuo replace Buddhist nun (crizotinib), and dabrafenib (darafinib), dacomitinib, Da Lushe is replaced (danusertib), Dasatinib (dasatinib), more Weis replace Buddhist nun (dovitinib), Tarceva (erlotinib), Foretinib, ganetespib, gefitinib (Gefitinib) replace Buddhist nun (ibrutinib) according to Shandong, Conmana (icotinib), Imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, Linifanib, linsitinib, Masitinib (masitinib), momelotinib come that not for husky Buddhist nun (motesanib) For Buddhist nun (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib) relax Buddhist nun replaces Buddhist nun (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, Vande Thani (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, Volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximab vedotin, card Appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), difficult to understand (ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab) or their combination.

The present invention also provides the compound or its stereoisomer, hydrate, ester, metabolite, solvate, Pharmaceutically acceptable salt, eutectic or prodrug or the pharmaceutical composition are as a kind of EGFR/HER2 receptor tyrosine Kinase inhibitor is in the application for preparing pharmaceutical preparation, especially for preparing for treating and/or preventing excess proliferative disease Application in the pharmaceutical preparation of disease.

Specific embodiment according to the present invention, the compound of the present invention or its stereoisomer, hydrate, ester, metabolism In the application of product, solvate, pharmaceutically acceptable salt, eutectic or prodrug or the pharmaceutical composition, the mistake Spending proliferative diseases includes brain tumor, non-small cell lung cancer, epidermis squamous carcinoma, bladder cancer, cancer of pancreas, colon cancer, breast cancer, ovary Cancer, cervix cancer, carcinoma of endometrium, colorectal cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin's Lymthoma, liver cancer, lung cancer, in gastric cancer, cutaneum carcinoma, thyroid cancer, head and neck cancer, prostate cancer, glioma and nasopharyngeal carcinoma It is one or more, preferably one of non-small cell lung cancer, breast cancer, epidermis squamous carcinoma, gastric cancer and colon cancer or a variety of.

Detailed description of the invention

Unless there are opposite statement, the term used in the specification and in the claims has following meanings.

Carbon, hydrogen, oxygen, sulphur, nitrogen or halogen involved in group and compound of the present invention include their same position Carbon, hydrogen, oxygen, sulphur or nitrogen involved in plain situation and group of the present invention and compound are optionally further by one or more Their a corresponding isotopes are substituted, and wherein the isotope of carbon includes¹²C、¹³C and¹⁴C, the isotope of hydrogen include protium (H), deuterium (D is called heavy hydrogen), tritium (T is called superheavy hydrogen), the isotope of oxygen include¹⁶O、¹⁷O and¹⁸The isotope of O, sulphur includes³²S、³³S、³⁴S and³⁶The isotope of S, nitrogen includes¹⁴N and¹⁵The isotope of N, fluorine includes¹⁷F and¹⁹The isotope of F, chlorine includes³⁵Cl and³⁷Cl, bromine Isotope include⁷⁹Br and⁸¹Br。

" pharmaceutically acceptable salt " or " its pharmaceutically acceptable salt " refers to that the compounds of this invention keeps free alkali Biological effectiveness and characteristic, and the free alkali passes through the salt obtained with nontoxic inorganic acid or organic acid reaction.Institute The non-limiting embodiment for the inorganic acid stated include hydrofluoric acid, hydrochloric acid, hydrobromate, sulfate, phosphoric acid, hypochlorous acid, perchloric acid, Acid iodide, carbonic acid, nitrous acid, nitroxylic acid, metaboric acid, boric acid, metasilicic acid, silicic acid, metaphosphorous acid, metaphosphoric acid, pyrophosphoric acid, hydrogen sulphur Acid, sulfurous acid, thiosulfuric acid and permanganic acid；The organic acid non-limiting embodiment include formic acid, acetic acid, trifluoroacetic acid, Thiocyanic acid, maleic acid, hydroxymaleic acid, glutaric acid, methanesulfonic acid, ethanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, bigcatkin willow Acid, phenylacetic acid, cinnamic acid, lactic acid, malonic acid, pivalic acid, succinic acid, fumaric acid, malic acid, mandelic acid, tartaric acid, galla turcica Acid, gluconic acid, lauric acid, palmitinic acid, pectic acid, picric acid and citric acid.

" carrier " refer to will not to organism generate obvious stimulation and will not eliminate given compound bioactivity and The material of characteristic.

" excipient " refers to the inert substance being added in pharmaceutical composition to promote compound to be administered.Non-limiting implementation Example includes calcium carbonate, calcium phosphate, sugar, starch, cellulose derivative (including microcrystalline cellulose), gelatin, vegetable oil, polyethylene glycol Class, diluent, granulating agent, lubricant, adhesive and disintegrating agent.

" adjuvant " is nonspecific immunity strengthening agent, when injecting together with antigen or being previously implanted body, can enhance machine Immune response or change type of immune response of the body to antigen.

" diluent " is also " filler ".When raw medicine is processed into pulvis, or in order to make it easy to spray be added into The diluted inert substance of row.Such as: clay, kaolin, clay, talcum powder.

" prodrug ", which refers to, to be biologically active the compounds of this invention through biotransformationin vivo, and such conversion is by preceding Body drug hydrolyzes in blood or the influence in blood tissues through enzymatic conversion for precursor structure.Prodrug of the invention passes through modification Prepared by functional group in the compounds of this invention, which can be removed by conventional operation or in vivo, and obtain To parent compound.

" eutectic " refer to active pharmaceutical ingredient and eutectic formation under the action of hydrogen bond or other non-covalent bonds in conjunction with and At crystal, wherein the pure state of API and CCF is solid at room temperature, and there is fixed stoichiometric ratio between each component. Eutectic is a kind of multicomponent crystal, both comprising the binary eutectic formed between two kinds of neutral solids, also comprising neutral solid with or The multi-element eutectic that solvate is formed.The non-limiting example of " the eutectic formation " includes alanine, valine, bright ammonia Acid, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, junket ammonia Acid, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, L-aminobutanedioic acid, glutamic acid, pyroglutamic acid, Sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acid, formic acid, acetic acid, propionic acid, benzene sulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, ammonia Fennel acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, furancarboxylic acid, gluconic acid, glucuronic acid, glutamic acid, ethyl alcohol Acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilamide (SN) Acid, tartaric acid, p-methyl benzenesulfonic acid, malonic acid, 2 hydroxy propanoic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citron Acid, cinnamic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, Trimethylamine, diethylamine, three Ethamine, tripropylamine, diethanol amine, ethanol amine, dimethylethanolamine, 2-dimethylaminoethanol, 2- DEAE diethylaminoethanol, Dicyclohexylamine, caffeine, procaine, choline, glycine betaine, Benethamine Penicillin, ethylenediamine, gucosamine, methylglucosamine, Theobromine, triethanolamine, tromethamine, purine, piperazine, piperidines and N-ethylpiperidine.

" stereoisomer " refers to the isomers as caused by the spatially arrangement mode difference of atom in molecule, including suitable Trans isomer, enantiomter and conformer.

" optional " or " optionally " or " selective " " selectively " refer to that then described event or situation can be with But it may not occur, which includes the case where that the event or situation and wherein nonevent situation wherein occurs.For example, " selection Property by alkyl-substituted heterocycle " refer to the alkyl can with but may not exist, the description include wherein heterocycle taken by alkyl For the case where, and wherein heterocycle not by alkyl-substituted situation.

Specific embodiment

Below by way of the beneficial effect of the specific embodiment implementation process that the present invention will be described in detail and generation, it is intended to which help is read Reader more fully understands essence and feature of the invention, does not limit the scope of the present invention.

The structure of compound be by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) is come what is determined.The measurement of NMR is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, measurement solvent are deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD), inside it is designated as tetramethylsilane (TMS).

(Agilent 6120B (ESI) and Agilent 6120B (APCI)) is used in the measurement of MS.

The measurement of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100 × 4.6mm).

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and thin-layered chromatography (TLC) makes The specification that silica gel plate uses is 0.15mm~0.20mm, thin-layer chromatography isolate and purify product use specification be 0.4mm~ 0.5mm。

Column chromatography is generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.

Known starting material of the invention can be used or be synthesized according to methods known in the art, or can purchase in Safe smooth science and technology pacifies the companies such as silent resistance to Jilin Chemical, Shanghai moral, Chengdu section Long Huagong, splendid remote chemical science and technology, lark prestige science and technology.

Nitrogen atmosphere refers to that reaction flask connects the nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.

Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.

Without specified otherwise in embodiment, reaction carries out under nitrogen atmosphere.

Without specified otherwise in embodiment, solution refers to aqueous solution.

Without specified otherwise in embodiment, the temperature of reaction is room temperature.

Room temperature is optimum reaction temperature, is 20 DEG C~30 DEG C.

Other symbols used herein have following meaning:

Bn: benzyl；Me: methyl；Et: ethyl；Ts: p-toluenesulfonyl；TBS: t-Butyldimethylsilyl；Boc: tertiary fourth Oxygen carbonyl；Ac: acetyl group.

The chloro- 7- methoxy-quinazoline -6- alcohol (1d) of intermediate 1:4-

4-chloro-7-methoxy-quinazolin-6-ol

Step 1: (4- hydroxyl -7- methoxy-quinazoline -6- base) acetic acid esters (1b)

(4-hydroxy-7-methoxy-quinazolin-6-yl)acetate

Into reaction flask be added 6- hydroxyl -7- methoxyl group -3H- quinazoline-4-one 1a (40g, 208mmol, Kang Manlin) and Acetic anhydride (296mL, 211mmol) is added pyridine (67mL) after mixing evenly, is cooled to room after rising to 100 DEG C of stirrings 4 hours Temperature.Reaction solution is poured into ice water (500g), after five minutes, decompression filters for stirring, successively uses water (100mL × 2), petroleum ether (100mL × 2) wash filter cake, collect filter cake, and drying obtains 1b (36g, the yield: 73%) of gray solid shape.

Step 2: (the chloro- 7- methoxy-quinazoline -6- base of 4-) acetic ester hydrochloride (1c)

(4-chloro-7-methoxy-quinazolin-6-yl)acetate hydrochloride

1b (30g, 130mmol) and thionyl chloride (205mL, 128mmol) are added into reaction flask, trichlorine oxygen is slowly added dropwise Phosphorus (38mL, 126mmol) and n,N-Dimethylformamide (3mL) rise to 120 DEG C and stir 4 hours, be cooled to after mixing evenly Residue is concentrated under reduced pressure to obtain in room temperature.Residual species are added in toluene, rotation is concentrated under reduced pressure and removes solvent, repeats this step twice, decompression It is concentrated to get the 1c crude product (289g) of sepia solid-like, is directly used in the next step.

Step 3: the chloro- 7- methoxy-quinazoline -6- alcohol (1d) of 4-

4-chloro-7-methoxy-quinazolin-6-ol

1c (325.5g, 100mmol) and methanolic ammonia solution (7mol/L, 560mL) are added into reaction flask, is stirred at room temperature 1 Hour.Filter, wash with methanol (100mL × 2), collection filter cake, be dried to obtain gray solid shape 1d (17g, yield: 65.4%).

Intermediate 2:(3S) the fluoro- 4- hydroxy-piperdine -1- t-butyl formate (2b) of -3-

tert-butyl(3S)-3-fluoro-4-hydroxy-piperidine-1-carboxylate

3- fluorin-4-oxygen is added into reaction flask for piperidines -1- t-butyl formate 2a (20g, 92mmol) and methanol (70mL), After mixing evenly, it is cooled to 0 DEG C, sodium borohydride (7g, 184mmol) is added portionwise, is warmed to room temperature reaction 1 hour.It is concentrated under reduced pressure, Ethyl acetate (200mL) is added into residue, saturated aqueous ammonium chloride (200mL), water (300mL) uses ethyl acetate (300mL × 3) extraction, merges organic phase, and anhydrous sodium sulfate dries, filters, and filtrate decompression is concentrated to get white solid 2b (20g, yield: 90%).

It rapidly purifies chromatograph (Biotage, Isolera one, eluant, eluent: 5% ethyl acetate/petroleum ether (v/v)), obtains And the mixing of the 2b-2 and 2b-4 of white solid to mixture (8g, the yield: 40%) of the 2b-1 and 2b-3 of white solid Object (10g, yield: 50%).

Intermediate 3:4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- alcohol (3c)

4- (3-chloro-2,4-difluoro-anilino) -7-methoxy-quinazolin-6-ol

Step 1: [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] acetic acid esters (3b)

[4- (3-chloro-2,4-difluoro-anilino) -7-methoxy-quinazolin-6-yl] acetate

1c (34.0g, 0.135mol), 2,4 two fluoro- 3- chloroanilines (24.3g, 0.148mol) are sequentially added into reaction flask With isopropanol (400mL), it is heated to 85 DEG C and reacts 3 hours.It is cooled to room temperature, filters, collect filter cake, be dried to obtain gray solid The 3b (51.0g) of shape.

¹H NMR (400MHz, CDCl₃) δ 8.71 (s, 1H), 8.37 (td, 1H), 7.56 (s, 1H), 7.36 (s, 1H), 7.07 (td, 1H), 3.98 (s, 3H), 2.41 (s, 3H).

Step 2: 4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- alcohol (3c)

4- (3-chloro-2,4-difluoro-anilino) -7-methoxy-quinazolin-6-ol

The methanolic ammonia solution (400mL) of 3b (51.0g, 0.135mol) and 7M are added into reaction flask, it is small to be stirred at room temperature 1 When.Filter, wash with methanol (100mL × 2), collection filter cake, be dried to obtain gray solid shape 3c (23.0g, yield: 50.0%).

MS m/z (ESI): 338.0 [M+1].

Intermediate 4:(3aS, 6aR) -5- hydroxyl -3,3a, 4,5,6,6a- hexahydro -1H- pentamethylene [c] pyrroles -2- formic acid uncles Butyl ester (4d)

Tertbutyl- (3aS, 6aR) -5-hydroxy-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrole-2-carboxylate

Step 1: N- allyl-N- Propargyl t-butyl carbamate (4b)

tert-butyl N-allyl-N-prop-2-ynyl-carbamate

Under ice bath, N- tertbutyloxycarbonyl allylamine 4a (20g, 127.39mmoL) and N, N- dimethyl are added into reaction flask Formamide (100mL) is added sodium hydride (60% is scattered in paraffin oil, 7.6g, 191.08mmol), stirs at 0 DEG C after being added dropwise It mixes 30 minutes, is warmed to room temperature stirring 20 minutes naturally, propargyl bromide (30.3g, 245.78mmol) is added dropwise under ice bath, stirred at 0 DEG C 30 minutes, reaction solution is poured slowly into ice cube (200g), is extracted with ethyl acetate (100mL × 3), merges organic phase, saturation Drinking water (100mL × 3) washing, anhydrous sodium sulfate dry, filter, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/ V)=100: 1~50: 1) obtaining 4b (21g, the yield: 85%) of yellow liquid.

MS m/z (ESI): 140.1 [M+1].

Step 2: (3aS, 6aR) -5- oxo -1,3,3a, 4,6, the 6a- hexahydro pentamethylene simultaneously tertiary fourth of [c] pyrroles -2- formic acid Ester (4c)

Tert-butyl (3aR, 6aS) -5-oxo-1,3,3a, 4,6,6a-hexahydrocyclopenta [c] pyrrole-2-carboxylate

Sequentially added into reaction flask 4b (39g, 202.2mmoL), methyl ether (275mL), cobalt octacarbonyl (83g, It 242.7mmoL) with water (82.4mL), is heated to reflux and is stirred overnight, be concentrated under reduced pressure, saturation drinking water is added into residue The hydrochloric acid (240mL) of (500mL), ethyl acetate (250mL) and 1M, are stirred at room temperature 5 minutes, stand liquid separation, water phase acetic acid second Ester (250mL × 3) extraction merges organic phase, and saturation drinking water (250mL × 2) washing, organic phase is dry with anhydrous sodium sulfate, mistake Filter is concentrated under reduced pressure, and residue is obtained light with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=3: 1~2: 1) 4c (27.6g, the yield: 61.3%) of yellow solid.

MS m/z (ESI): 170.1 [M+1].

¹H NMR (400MHz, CDCl₃): δ 3.68-3.64 (m, 2H), 3.24-3.21 (d, 2H), 2.97-2.88 (m, 2H), 2.52-2.45 (dd, 2H), 2.20-2.14 (dd, 2H), 1.46 (s, 9H).

Step 3: (3aS, 6aR) -5- hydroxyl -3,3a, 4,5,6,6a- hexahydro -1H- pentamethylene simultaneously [c] pyrroles -2- formic acid The tert-butyl ester (4d)

Tert-butyl- (3aS, 6aR) -5-hydroxy-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrole-2-carboxylate

4c (1.5g, 6.7mmol) is added into reaction flask, after mixing evenly, ice bath is cooled to 0 DEG C, and sodium borohydride is added (0.38g, 10mmol) reacts 30 minutes for 0 DEG C after adding.Saturated ammonium chloride (20mL) is added dropwise into reaction solution, acetic acid second is added Ester (50mL), aqueous layer with ethyl acetate extract (40mL × 2), merge organic phase, are washed (40mL × 1) with saturation drinking water, organic It is mutually dried, filtered, is concentrated under reduced pressure with anhydrous sodium sulfate, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=1: 1) 4d (1.4g, the yield: 93%) of colorless oil are obtained.

¹H NMR (400MHz, CDCl₃) δ 4.30 (p, 1H), 3.50 (dd, 2H), 3.35 (dd, 2H), 2.63-2.58 (m, 2H), 2.25-2.08 (m, 2H), 1.51 (dd, 2H), 1.46 (s, 9H).

Intermediate 5:(3R) the fluoro- 4- hydroxy-piperdine -1- t-butyl formate (5c) of -3-

tert-butyl(3R)-3-fluoro-4-hydroxy-piperidine-1-carboxylate

Step 1: (R)-(5- ethyl quinine -2- base)-(6- methoxyl group -4- quinolyl) methylamine tri hydrochloride (5b)

(R)-(5-ethylquinuclidin-2-yl)-(6-methoxy-4-quinolyl)methanamine trihydrochloride

Hydroquinine is added into reaction flask and determines 5a (25g, 76.7mmol) and triphenylphosphine (30g, 115mmol), is added Tetrahydrofuran (250mL) is cooled to 0 DEG C, is added dropwise diisopropyl azodiformate (26.5g, 130.4mmol), and 0 DEG C is reacted 10 points Clock, be added dropwise diphenyl phosphate azide (36g, 130.4mmol), room temperature reaction overnight, be added portionwise triphenylphosphine (30g, 115mmol), it reacts 4 hours for 45 DEG C, is added water (25g), 45 DEG C of reactions overnight, are concentrated under reduced pressure, and are added methylene chloride (250mL) It with 2M hydrochloric acid (150mL), stirs 20 minutes, separates water layer, extracted with methylene chloride (250mL × 2), acetic acid is used in water layer concentration Ethyl ester (150mL), methanol (50mL) mashing, with ethyl acetate (150mL), methanol (30mL) washing filters out solid, is dried to obtain The 5b (26g, yield 77.8%) of white solid.

¹H NMR (400MHz, DMSO+D₂O) δ 9.04 (d, 1H), 8.24 (dt, 2H), 7.94 (t, 1H), 7.71 (dd, 1H), 6.06 (d, 1H), 4.57 (q, 1H), 4.09-4.01 (m, 3H), 3.66-3.35 (m, 4H), 1.96-1.74 (m, 4H), 1.41- 1.22 (m, 3H), 1.07-0.96 (m, 1H), 0.85 (t, 3H).

Step 2: the fluoro- 4- hydroxy-piperdine -1- t-butyl formate (5c) of (3R) -3-

tert-butyl(3R)-3-fluoro-4-hydroxy-piperidine-1-carboxylate

5b (2.03g, 4.63mmol) is taken to be dissolved in the tetrahydrofuran of 46.3mL, ice-water bath is cooling, and saturated sodium carbonate is water-soluble Liquid is adjusted to neutrality, and revolving three times with toluene band water, is added the tetrahydrofuran of 46.3mL, filters, trichloroacetic acid is added to doing (0.75g, 4.63mmol), water are configured to (R)-(5- ethyl quinine -2- base)-(6- methoxyl group -4- quinolyl) methylamine of 0.1M The tetrahydrofuran solution of single trichloroacetic acid monohydrate.Into reaction flask be added N- fluoro bis benzene sulfonamide (3.77g, 11.6mmol) -20 DEG C are cooled to, above-mentioned 0.1M is added with sodium carbonate (1.85g, 17.3mmol), addition tetrahydrofuran (33mL) (R)-((1S, 2R, 4S, 5R) -5- ethyl quinine -2- base) (6- methoxy quinoline -4- base) methylamine list trichloroacetic acid monohydrate The tetrahydrofuran solution of object, -20 DEG C are reacted 10 minutes, are added N- tertbutyloxycarbonyl -4- piperidones (4.63g, 23.1mmol), - 20 DEG C of reactions overnight, are added methyl tertiary butyl ether(MTBE) (50mL), stir 30 minutes, and filtering filtrate decompression is concentrated, silica gel column chromatography Separating-purifying (petrol ether/ethyl acetate (v/v)=5: 1) obtains the 5c (1.9g, yield 74.8%) of white solid.

¹H NMR (400MHz, CDCl₃) δ 4.84 (ddd, 1H), 4.47 (s, 1H), 4.27-4.10 (m, 1H), 3.37-3.19 (m, 2H), 2.64-2.46 (m, 2H), 1.50 (s, 9H).

¹⁹F NMR (400MHz, CDCl₃) δ -195.86~-196.43 (1F).

5c (1.9g, 8.7mmol) is dissolved in methanol (8mL), is cooled to 0 DEG C, is added sodium borohydride (0.5g, 13.0mmol), 0 DEG C reaction 2.5 hours, be added saturated aqueous ammonium chloride (20mL), stir 20 minutes, be concentrated under reduced pressure, be added water (45mL), use Ethyl acetate (25mL × 3) extraction, merges organic layer, is dried, filtered with anhydrous sodium sulfate, filtrate decompression is concentrated, silicagel column Chromatographic purification (petrol ether/ethyl acetate (v/v)=7: 1) obtains 5c-1 (0.6g, yield 30%, the ee of white solid > 99%) and 5c-2 (0.45g, yield 22.5%, ee > 99%)

Intermediate 6:4- (3, the 4 two chloro- fluoro- aniline of 2-) -7- methoxy-quinazoline -6- alcohol (6c)

4- ((3,4-dichloro-2-fluoro-anilino) -7-methoxyquinazolin-6-ol

Step 1: [4- (3, the 4 two fluoro- chloro- aniline of 2-) -7- methoxy-quinazoline -6- base] acetic acid esters (6b)

[4- (3,4-difluoro-2-chloro-anilino) -7-methoxy-quinazolin-6-yl] acetate

1c (32.4g, 0.129mol), 3,4 two fluoro- 2- chloroanilines (32.6g, 0.155mol) are sequentially added into reaction flask With isopropanol (250mL), it is heated to 100 DEG C and reacts 4 hours.It is cooled to room temperature, filters, collect filter cake, it is solid to be dried to obtain grey The 6b (51.1g) of body shape, is directly used in the next step.

MS m/z (ESI): 396.0 [M+1].

Step 2: 4- (3, the 4 two fluoro- chloro- aniline of 2-) -7- methoxy-quinazoline -6- alcohol (6c)

4- (3,4-dichloro-2-fluoro-anilino) -7-methoxyquinazolin-6-ol

The methanolic ammonia solution (250mL) of 6b (51.1g, 0.129mol) and 7M are added into reaction flask, it is small to be stirred at room temperature 1 When.Filter, wash with methanol (100mL × 2), collection filter cake, be dried to obtain gray solid shape 6c (30g, yield: 64.2%).

¹H NMR (400MHz, DMSO) δ 8.36 (s, 1H), 7.65 (s, 1H), 7.62-7.50 (m, 2H), 7.21 (s, 1H), 4.00-3.92 (m, 3H).

¹⁹F NMR (400MHz, DMSO) δ -112.23 (1F).

MS m/z (ESI): 338.0 [M+1].

Embodiment 1:1- [4- [[4- (chloro- 2, the 4- difluoro-aniline base of 3-) -7- methoxy-quinazoline -6- base] oxygroup first Base] -1- piperidyl] propyl -2- alkene -1- ketone (compound 1)

1- [4- [[4- (3-chloro-2,4-difluoro-anilino) -7-methoxy-quinazolin-6-yl] oxymethyl]-1-piperidyl]prop-2-en-1-one

Step 1: 4- [(the chloro- 7- methoxy-quinazoline -6- base of 4-) oxygroup methyl] piperidines -1- t-butyl formate (1B)

tert-butyl4-[(4-chloro-7-methoxy-quinazolin-6-yl)oxymethyl] piperidine-1-carboxylate

1d (3.0g, 14.2mmol), triphenylphosphine (5.58g, 21.3mmol) and methylene chloride are added into reaction flask (50mL), nitrogen protection, ice bath are cooled to 0 DEG C, and the dichloromethane of diisopropyl azodiformate (4.30g, 21.3mmol) is added dropwise Alkane (10mL) solution after being added dropwise, is warmed to room temperature reaction 30 minutes.4- hydroxymethyl piperidine -1- formic acid uncle is slowly added at 0 DEG C Butyl ester (4.58g, 21.3mmol) is warmed to room temperature reaction 12 hours.It is concentrated under reduced pressure, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=10: 1) obtains the 1B crude product (5.80g) of white solid, is directly used in the next step.

Step 2: 4- [[4- (3- chlorine 2,4- difluoroaniline) -7- methoxy-quinazoline -6- base] oxygen methyl] piperidines -1- first Tert-butyl acrylate (1C)

Tert-butyl 4- [[4- (3-chloro-2,4-difluoro-anilino) -7-methoxy- quinazolin-6-yl]oxymethyl]piperidine-1-carboxylate

1B (5.80g, 14.2mmol), the chloro- 3- chloroaniline (2.6g, 15.6mmol) of 2,4- bis- are sequentially added into reaction flask With isopropanol (30mL), it is heated to 120 DEG C and reacts 2 hours, be concentrated under reduced pressure, residue silica gel column chromatography separating-purifying (dichloro Methane/methanol (v/v)=100: 1~50: 1~30: 1) obtain 1C (3.80g, the yield: 50.0%) of white solid.

MS m/z (ESI): 535.1 [M+1].

Step 3: N- (chloro- 2, the 4- difluorophenyl of 3-) -7- methoxyl group -6- (4- piperidyl methyl oxygroup) quinazoline -4- amine Two (trifluoroacetic acid) salt (1D)

N- (3-chloro-2,4-difluoro-phenyl) -7-methoxy-6- (4-piperidylmethoxy) quinazolin-4-amineditrifluoroacetic acid

1C (3.80g, 0.93mmol) and methylene chloride (20mL) are added into reaction flask, trifluoroacetic acid is added dropwise under ice-water bath (20mL) is added dropwise recession and removes ice bath, react at room temperature 2 hours.It is concentrated under reduced pressure, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=10: 1) obtains 1D (3.30g, the yield: 68.0%) of white solid.

Step 4: 1- [4- [[4- (chloro- 2, the 4- difluoro-aniline base of 3-) -7- methoxy-quinazoline -6- base] oxygroup first Base] -1- piperidyl] propyl -2- alkene -1- ketone (compound 1)

1D (3.30g, 4.93mmol), triethylamine (4.1mL) and methylene chloride (15mL) are sequentially added into reaction flask, are done Ice ethanol bath is cooled to -60 DEG C, and methylene chloride (2mL) solution of acryloyl chloride (0.45mL, 5.48mmol) is added dropwise, rises to naturally Room temperature reaction 30 minutes.Saturated sodium chloride solution (20mL) is added into reaction system, is extracted with methylene chloride (20mL × 3), Merge organic phase, anhydrous sodium sulfate dries, filters, be concentrated under reduced pressure, residue with silica gel column chromatography separating-purifying (methylene chloride/ Methanol (v/v)=100: 1) obtain compound 1 (0.08g, the yield: 3.3%) of white solid.

MS m/z (ESI): 535.1 [M+1].

¹H NMR (400MHz, CDCl₃) δ 8.61 (s, 1H), 8.03 (td, 2H), 7.34 (s, 1H), 7.27 (d, 1H), 7.10-6.97 (m, 1H), 6.58 (ddd, 1H), 6.24 (dt, 1H), 5.66 (ddd, 1H), 5.30 (s, 0H), 4.74 (d, 1H), 4.10-3.81 (m, 7H), 3.51 (s, 0H), 3.15 (s, 1H), 2.72 (s, 1H), 2.25-1.61 (m, 6H), 1.43-1.16 (m, 4H)。

¹⁹F NMR (376MHz, CDCl₃): -117.92 (1F), -123.77 (1F).

Embodiment 2:1- [4- [4- (chloro- 2, the 4- difluoro-aniline base of 3-) -7- methoxy-quinazoline -6- base] oxygroup -3- Fluoro- 1- piperidyl] (compound 2, compound 2 are 1- [(3R, 4R) -4- [4- (fluoro- benzene of chloro- 2, the 4- bis- of 3- to propyl -2- alkene -1- ketone Amine) -7- methoxy-quinazoline -6- base] the fluoro- 1- piperidyl of oxygroup -3-] propyl -2- alkene -1- ketone and 1- [(3S, 4S) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] the fluoro- 1- piperidyl of oxygroup -3-] propyl -2- alkene -1- ketone Mixture)

1- [4- [4- (3-chloro-2,4-difluoro-anilino) -7-methoxy-quinazolin-6-yl] oxy-3-fluoro-1-piperidyl]prop-2-en-1-one

Step 1: 4- [4- (chloro- 2, the 4- difluoro-aniline base of 3-) -7- methoxy-quinazoline -6- base] fluoro- piperazine of oxygroup -3- (2B, 2B are (3R, 4R) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- to pyridine -1- t-butyl formate Base] oxygroup -3- fluoro-piperidine -1- t-butyl formate and (3S, 4S) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxyl group-quinoline Oxazoline -6- base] oxygroup -3- fluoro-piperidine -1- t-butyl formate mixture)

Tert-butyl4- [4- (3-chloro-2,4-difluoro-anilino) -7-methoxy-quinazolin- 6-yl]oxy-3-fluoro-piperidine-1-carboxylate

The mixture of 3c (3.0g, 8.96mmol), methylene chloride (60mL), 2b-1 and 2b-3 are sequentially added into reaction flask (3.9g, 17.91mmol) and triphenylphosphine (9.40g, 35.90mmol), nitrogen protection are cooled to dropwise addition azo two at -15 DEG C After being added dropwise, it is small to be warmed to room temperature reaction 3 for methylene chloride (36mL) solution of formic acid di tert butyl carbonate (6.20g, 26.90mmol) When.It is concentrated under reduced pressure, residue obtains yellow solid with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=100: 1) (4.1g, yield: 85.4%, 2B are (3R, 4R) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxyl groups-quinoline azoles to the 2B of shape Quinoline -6- base] oxygroup -3- fluoro-piperidine -1- t-butyl formate and (3S, 4S) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy Base-quinazoline -6- base] oxygroup -3- fluoro-piperidine -1- t-butyl formate mixture).

Step 2: N- (chloro- 2, the 4- Dichloro-phenyl of 3-) -6- [(the fluoro- 4- piperidyl of 3-) oxygen] -7- methoxy-quinazoline - (2C, 2C are N- (chloro- 2, the 4- Dichloro-phenyl of 3-) -6- [[the fluoro- 4- piperidyl of (3R, 4R) -3-] oxygen to 4- amine two (trifluoroacetic acid) salt Base] -7- methoxy-quinazoline -4- amine two (trifluoroacetic acid) and N- (chloro- 2, the 4- Dichloro-phenyl of 3-) -6- [[(3S, 4S) -3- Fluoro- 4- piperidyl] oxygroup] -7- methoxy-quinazoline -4- amine two (trifluoroacetic acid) mixture)

N- (3-chloro-2,4-difluoro-phenyl) -6- [(3-fluoro-4-piperidyl) oxy] -7- methoxy-quinazolin-4-amine

2C is N- (chloro- 2, the 4- Dichloro-phenyl of 3-) -6- [[the fluoro- 4- piperidyl of (3R, 4R) -3-] oxygroup] -7- methoxyl group - Quinazoline -4- amine two (trifluoroacetic acid) and N- (chloro- 2, the 4- Dichloro-phenyl of 3-) -6- [[the fluoro- 4- piperidyl of (3S, 4S) -3-] oxygen Base] -7- methoxy-quinazoline -4- amine two (trifluoroacetic acid) mixture.

2B (4.10g, 7.62mmol) and methylene chloride (17mL), the cooling lower dropwise addition of ice-water bath are sequentially added into reaction flask Trifluoroacetic acid (17mL) is warmed to room temperature reaction 1 hour naturally after being added dropwise, be concentrated under reduced pressure, residue silica gel column chromatography point 2C (3.00g, the yield: 60.0%) of white solid are obtained from purification (methylene chloride/methanol (v/v)=20: 1).

MS m/z (ESI): 439.0 [M+1].

Step 3: [4- [4- (chloro- 2, the 4- difluoro-aniline base of 3-) -7- methoxy-quinazoline -6- base] oxygroup -3- is fluoro- by 1- 1- piperidyl] (compound 2, compound 2 are 1- [(3R, 4R) -4- [4- (fluoro- benzene of chloro- 2, the 4- bis- of 3- to propyl -2- alkene -1- ketone Amine) -7- methoxy-quinazoline -6- base] the fluoro- 1- piperidyl of oxygroup -3-] propyl -2- alkene -1- ketone and 1- [(3S, 4S) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] the fluoro- 1- piperidyl of oxygroup -3-] propyl -2- alkene -1- ketone Mixture)

Compound 2 is 1- [(3R, 4R) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] oxygen The fluoro- 1- piperidyl of base -3-] propyl -2- alkene -1- ketone and 1- [(3S, 4S) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy Base-quinazoline -6- base] the fluoro- 1- piperidyl of oxygroup -3-] propyl -2- alkene -1- ketone mixture.

2C (2.30g, 5.25mmol) is dissolved in the mixed solution of tetrahydrofuran (90mL) and water (14mL), carbonic acid is added Hydrogen sodium (1.3g, 15.80mmol), ice bath are cooled to the tetrahydrofuran that acryloyl chloride (0.50g, 5.78mmol) is added dropwise at 0 DEG C (7mL) solution, 0 DEG C is stirred 15 minutes.Saturation drinking water (20mL) is added into reaction system, is extracted with methylene chloride (20mL × 3) It takes, merges organic phase, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, residue silica gel column chromatography separating-purifying (dichloromethane Alkane/methanol (v/v)=100: 1) obtain compound 2 (0.68g, the yield: 26.4%) of white solid.

Compound 2 (0.68g) Preparation equipment and the chiral isomers of chiral column are separated into (separation condition: chiral Column CHIRALPAKAS-H, mobile phase: A: n-hexane (0.1% diethanol amine)), B: isopropanol, A: B=50: 50 (v/v), stream Speed: 6.0mL/ minutes, UV=250nm, column temperature: 35 DEG C), obtain 1- [(3R, 4R) -4- [4- (3- chloro- 2,4- of white solid Difluoro-aniline base) -7- methoxy-quinazoline -6- base] the fluoro- 1- piperidyl of oxygroup -3-] propyl -2- alkene -1- ketone (compound 2- 1) (200mg, retention time: 40.363min, ee > 95%) and 1- [(3S, 4S) -4- [4- (chloro- 2,4- difluoro-aniline of 3- Base) -7- methoxy-quinazoline -6- base] the fluoro- 1- piperidyl of oxygroup -3-] propyl -2- alkene -1- ketone (compound 2-2) (200mg, Retention time: 39.280min, ee > 95%).

MS m/z (ESI): 493.3 [M+1].

¹H NMR (400MHz, CDCl₃): δ 8.61 (s, 1H), 7.99 (dd, 1H), 7.66 (s, 1H), 7.31 (s, 1H), 7.27 (s, 0H), 7.03 (td, 1H), 6.58 (dd, 1H), 6.25 (d, 1H), 5.71 (dd, 1H), 5.30 (s, 0H), 4.95- 4.89 (m, 1H), 4.83-4.77 (m, 1H), 4.67 (d, 1H), 4.41-4.14 (m, 2H), 4.00 (s, 3H), 3.89 (s, 0H), 3.75-3.40 (m, 2H), 3.28 (d, 1H), 2.32-2.06 (m, 2H), 1.95 (s, 1H).

¹⁹F NMR (400MHz, CDCl₃): δ -117.02 (1F), -121.91 (1F), -199.56~-200.97 (1F).

[4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] oxygroup -3- is fluoro- by embodiment 3:1- 1- piperidyl] (compound 3, compound 3 are 1- [(3R, 4S) -4- [4- (fluoro- benzene of chloro- 2, the 4- bis- of 3- to propyl -2- alkene -1- ketone Amine) -7- methoxy-quinazoline -6- base] the fluoro- 1- piperidyl of oxygroup -3-] propyl -2- alkene -1- ketone and 1- [(3S, 4R) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] the fluoro- 1- piperidyl of oxygroup -3-] propyl -2- alkene -1- ketone Mixture)

Step 1: 4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] oxygroup -3- fluoro-piperidine - (3B, 3B are (3R, 4S) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] oxygen to 1- t-butyl formate Base -3- fluoro-piperidine -1- t-butyl formate and uncle (3S, 4R) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxyl group-quinoline azoles Quinoline -6- base] oxygroup -3- fluoro-piperidine -1- butyl formate mixture)

3c (2.0g, 6.16mmol, intermediate 3), methylene chloride (40mL), 2b-2 and 2b-4 are sequentially added into reaction flask Mixture (2.7g, 12.30mmol) and triphenylphosphine (6.50g, 24.60mmol), nitrogen protection, be cooled at -15 DEG C delay Slow methylene chloride (24mL) solution that tert-butyl azodicarboxylate (4.30g, 18.50mmol) is added dropwise, it is natural after being added dropwise It is warmed to room temperature reaction 3 hours.Be concentrated under reduced pressure, residue with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=50: 1) obtaining the 3B of yellow solid, (1.40g, yield: 43.8%, 3B are (3R, 4S) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) - 7- methoxy-quinazoline -6- base] oxygroup -3- fluoro-piperidine -1- t-butyl formate and (3S, 4R) -4- [4- (chloro- 2,4- bis- of 3- Fluoro- aniline) -7- methoxy-quinazoline -6- base] oxygroup -3- fluoro-piperidine -1- t-butyl formate mixture).

Step 2: N- (chloro- 2, the 4- Dichloro-phenyl of 3-) -6- [(the fluoro- 4- piperidyl of 3-) oxygroup] -7- methoxyl group-quinoline azoles (3C, 3C are N- (chloro- 2, the 4- Dichloro-phenyl of 3-) -6- [[fluoro- 4- piperidines of (3R, 4S) -3- to quinoline -4- amine two (trifluoroacetic acid) salt Base] oxygroup] -7- methoxy-quinazoline -4- amine two (trifluoroacetic acid) salt and N- (chloro- 2, the 4- Dichloro-phenyl of 3-) -6- [[(3S, 4R) the fluoro- 4- piperidyl of -3-] oxygroup] -7- methoxy-quinazoline -4- amine two (trifluoroacetic acid) salt mixture)

3B (1.40g, 2.60mmol) and methylene chloride (7mL), the cooling lower dropwise addition trifluoro of ice-water bath are added into reaction flask Acetic acid (7mL) reacts at room temperature 1 hour.It is concentrated under reduced pressure, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/ V)=20: 1) obtaining the 3C of white solid, (0.65g, yield: 37.5%, 3C are N- (chloro- 2, the 4- Dichloro-phenyl of 3-) -6- Two (trifluoroacetic acid) salt of [[the fluoro- 4- piperidyl of (3R, 4S) -3-] oxygroup] -7- methoxy-quinazoline -4- amine and N- (3- chloro- 2, 4- Dichloro-phenyl) -6- [[the fluoro- 4- piperidyl of (3S, 4R) -3-] oxygroup] -7- methoxy-quinazoline -4- amine two (trifluoroacetic acid) The mixture of salt).

Step 3: 1- [4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] fluoro- 1- of oxygroup -3- Piperidyl] (compound 3, compound 3 are 1- [(3R, 4S) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-)-to propyl -2- alkene -1- ketone 7- methoxy-quinazoline -6- base] the fluoro- 1- piperidyl of oxygroup -3-] propyl -2- alkene -1- ketone and 1- [(3S, 4R) -4- [4- (3- Chloro- 2,4- difluoro-aniline) -7- methoxy-quinazoline -6- base] the fluoro- 1- piperidyl of oxygroup -3-] and propyl -2- alkene -1- ketone it is mixed Close object)

3C (0.65g, 0.10mmol) is dissolved in the mixed solution of tetrahydrofuran (25mL) and water (4mL), carbonic acid is added Hydrogen sodium (0.41g, 4.80mmol), ice bath are cooled to the tetrahydrofuran that acryloyl chloride (0.10g, 0.11mmol) is added dropwise at 0 DEG C (1.5mL) solution, 0 DEG C is reacted 15 minutes, saturation drinking water (20mL) is added into reaction system, with methylene chloride (20mL × 3) Extraction merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, residue silica gel column chromatography separating-purifying (dichloro Methane/methanol (v/v)=100: 1) obtain white solid compound 3 (0.18g, yield: 36.7%, HPLC: 99.70%).

Compound 3 (0.18g) Preparation equipment and the chiral isomers of chiral column are separated into (separation condition: chiral Column CHIRALPAK AD-H, mobile phase: A: n-hexane (0.1% diethanol amine), B: isopropanol, A: B=50: 50 (v/v), stream Speed: 6.0mL/ minutes, UV=254nm, column temperature: 35 DEG C), obtain white solid compound 3-1 (60mg, retention time: 9.158min, ee > 99%) and compound 3-2 (60mg, retention time: 10.662min, ee > 99%).

MS m/z (ESI): 493.3 [M+1].

¹H NMR (400MHz, CDCl₃) δ 8.61 (s, 1H), 7.99 (dd, 1H), 7.66 (s, 1H), 7.31 (s, 1H), 7.27 (s, 0H), 7.03 (td, 1H), 6.58 (dd, 1H), 6.25 (d, 1H), 5.71 (dd, 1H), 5.30 (s, 0H), 4.95-4.89 (m, 1H), 4.83-4.77 (m, 1H), 4.67 (d, 1H), 4.41-4.14 (m, 2H), 4.00 (s, 3H), 3.89 (s, 0H), 3.75- 3.40 (m, 2H), 3.28 (d, 1H), 2.32-2.06 (m, 2H), 1.95 (s, 1H).

Embodiment 4:1- [4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- [(3S)-tetrahydrofuran -3- base] oxygroup-quinoline azoles Quinoline-6- base] Oxy-1-piperidyl] propyl-2- alkene-1- ketone (compound 4)

1- [4- [4- (3-chloro-2,4-difluoro-anilino) -7- [(3S)-tetrahydrofuran-3-yl] oxy-quinazolin-6-yl]oxy-1-piperidyl]prop-2-en-1-one

Step 1: the fluoro- 2- nitrobenzoic acid (4B) of 5- benzyloxy -4-

5-benzyloxy-4-fluoro-2-nitro-benzoic acid

The fluoro- 2- Nitro-benzoic acid 4A (25g, 123mmol) of 4,5- bis- and tetrahydrofuran (400mL) are added into reaction flask, After mixing evenly, benzylalcohol (29.3g, 270.6mmol) is added, ice bath is cooled to 0 DEG C, and bis- (trimethylsilyl) Sodamides of 2M are added dropwise Tetrahydrofuran solution (197mL, 394mmol) reacts 1 hour for 0 DEG C after being added dropwise.The hydrochloric acid that 2M is added dropwise into reaction solution is adjusted System pH is added ethyl acetate (400mL) to 1-2, separates organic phase after stirring, water phase be extracted with ethyl acetate (100mL × 3), merge organic phase, anhydrous sodium sulfate is dried, filtered, is concentrated under reduced pressure into residual acetic acid ethyl ester about (100mL), and 0 DEG C of standing 2 is small When, decompression filters, and collects filter cake, and drying obtains 4B (17g, the yield: 47.5%) of yellow solid.

MS m/z (ESI): 292.0 [M+1].

¹H NMR (400MHz, DMSO) δ 7.70 (d, 1H), 7.39-7.31 (m, 6H), 5.28 (s, 2H).

Step 2: the fluoro- 2- nitrobenzene methyl (4C) of 5- benzyloxy -4-

methyl 5-benzyloxy-4-fluoro-2-nitro-benzoate

4B (17g, 58.4mmol) and n,N-Dimethylformamide (170mL), after mixing evenly, ice are added into reaction flask Bath cooling, is added potassium carbonate (24.2g, 175.2mmol) and iodomethane (24.8g, 175.2mmol), adds and be warmed to room temperature reaction 2 Hour.Reaction solution is poured into ice water, is extracted with ethyl acetate (100mL × 4), organic phase is merged, be washed with water (100mL × 1), organic phase is dried, filtered with anhydrous sodium sulfate, is concentrated under reduced pressure, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/ V)=10: 1~8: 1) obtaining the 4C (15.9g, yield 89%) of yellow solid.

MS m/z (ESI): 306.1 [M+1].

¹H NMR (400MHz, CDCl₃) δ 7.79 (d, 1H), 7.42-7.35 (m, 5H), 7.25 (d, 1H), 5.23 (s, 2H), 3.91 (s, 3H).

Step 3: the 2- amino fluoro- methyl benzoate of -5- benzyloxy -4- (4D)

methyl 2-amino-5-benzyloxy-4-fluoro-benzoate

4C (18.4g, 60.3mmol) is dissolved in the mixed solution of isopropanol (294mL) and tetrahydrofuran (74mL), is stirred It after mixing uniformly, is added iron powder (18.1g, 324.1mmol), is heated to 100 DEG C, the water-soluble of ammonium chloride (12g, 3.75mmol) is added Liquid (15mL), 100 DEG C are reacted 7 hours.It filters while hot, washs filter cake with ethyl acetate (100mL × 2), filtrate decompression is concentrated, Ethyl acetate (400mL) is added to residual species, is washed (50mL × 2) with saturated sodium bicarbonate, organic phase anhydrous sodium sulfate It dries, filters, is concentrated under reduced pressure, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=8: 1~7: 1) obtains grey The 4D (15g, yield 90.4%) of solid-like.

MS m/z (ESI): 276.1 [M+1].¹H NMR (400MHz, CDCl₃) δ 7.53 (d, 1H), 7.47-7.28 (m, 5H), 6.42 (d, 1H), 5.03 (s, 2H), 3.85 (s, 3H).

Step 4: the fluoro- 3H- quinazoline-4-one (4E) of 6- benzyloxy -7-

6-benzyloxy-7-fluoro-3H-quinazolin-4-one

4D (15g, 54.5mmol) and formamide (50mL) are added into reaction flask, n,N-Dimethylformamide is added (0.5mL) is heated to 180 DEG C and reacts 7 hours.Reaction solution is cooled to room temperature, and reaction solution is poured slowly into water (250mL), stirring 30 minutes, filtering collected filter cake, obtains the 4E (13g, yield 88%) of yellow solid.

MS m/z (ESI): 271.1 [M+1].

¹H NMR (400MHz, DMSO) δ 12.33 (brs, 1H), 8.07 (s, 1H), 7.78 (d, 1H), 7.56 (d, 1H), 7.50 (d, 2H), 7.40 (dt, 3H), 7.24-7.05 (m, 1H), 5.33 (s, 2H).

Step 5: 6- benzyloxy -7- [(3S)-tetrahydrofuran -3- base] oxygroup -3H- quinazoline-4-one (4F)

6-benzyloxy-7-[(3S)-tetrahydrofuran-3-yl]oxy-3H-quinazolin-4-one

(S) -3- hydroxyl tetrahydrofuran (20mL) and metallic sodium (2g, 88.9mmol) are added into reaction flask, is warming up to 120 DEG C reaction 1.5 hours, be added 4E (4g, 14.8mmol), be warming up to 150 DEG C react 2.5 hours.Reaction solution is cooled to room temperature, will Reaction solution pours into ice water, with concentrated hydrochloric acid regulation system pH value to neutrality, is added ethyl acetate (10mL), and filter cake is collected in filtering, Obtain the 4F (4.5g, yield 90%) of gray solid shape.

MS m/z (ESI): 339.1 [M+1].

¹H NMR (400MHz, DMSO) δ 7.98 (s, 1H), 7.55 (s, 1H), 7.47 (d, 2H), 7.40 (t, 2H), 7.34 (d, 1H), 7.14 (s, 1H), 5.24 (s, 2H), 3.95 (dd, 1H), 3.87 (q, 2H), 3.77 (td, 1H), 2.31 (td, 1H), 2.06-2.01 (m, 1H).

Step 6: the chloro- 7- of 6- benzyloxy -4- [(3S)-tetrahydrofuran -3- base] oxygroup-quinazoline (4G)

6-benzyloxy-4-chloro-7-[(3S)-tetrahydrofuran-3-yl]oxy-quinazoline

4F (2.5g, 7.4mmol) and thionyl chloride (25mL) are added into reaction flask, is added DMF (0.5mL), reflux is anti- It answers 2.5 hours.It is concentrated to dryness, methylene chloride (50mL) and water (50mL) is added, adjust pH value to 9-10 with ammonium hydroxide, separate Organic phase, water phase are extracted with dichloromethane (30mL × 2), merge organic phase, successively with water (30mL × 1), saturation drinking water (30mL × 1) it washs, organic phase is dried, filtered with anhydrous sodium sulfate, is concentrated under reduced pressure, silica gel column chromatography separating-purifying (methylene chloride/first Alcohol (v/v)=100: 1), obtain the 4G (2g, yield 77%) of pale-yellow solid.

MS m/z (ESI): 357.0 [M+1].

¹H NMR (400MHz, CDCl₃) δ 8.86 (s, 1H), 7.50 (d, 3H), 7.42 (t, 2H), 7.36 (t, 1H), 7.27 (d, 1H), 5.29 (s, 2H), 5.20-5.07 (m, 1H), 4.14 (d, 2H), 4.06 (dd, 1H), 3.96 (td, 1H), 2.45- 2.22 (m, 2H).

Step 7: 6- benzyloxy-N- (chloro- 2, the 4- difluorophenyl of 3-) -7- [(3S)-tetrahydrofuran -3- base] oxygroup-quinoline Oxazoline -4- ammonia (4H)

6-benzyloxy-N- (3-chloro-2,4-difluoro-phenyl) -7- [(3S)-tetrahydrofuran- 3-yl]oxy-quinazolin-4-amine

4G (3g, 8.4mmol) and chloro- 2, the 4- difluoroaniline (2.7g, 16.9mmol) of 3- are added into reaction flask, is added different Propyl alcohol (60mL), heating reflux reaction 3 hours.Reaction solution is cooled to room temperature, and filtering collects filter cake, obtains faint yellow solid shape 4H (3.3g, yield 81%).

MS m/z (ESI): 484.1 [M+1].

¹H NMR (400MHz, DMSO) δ 11.74 (s, 1H), 8.85 (s, 1H), 8.54 (s, 1H), 7.64 (dd, 1H), 7.58-7.34 (m, 7H), 5.36 (s, 2H), 5.26 (s, 1H), 3.97 (d, 2H), 3.90 (dd, 1H), 3.80 (dd, 1H), 2.38 (td, 1H), 2.19-1.94 (m, 1H).

Step 8: 4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- [(3S)-tetrahydrofuran -3- base] oxygroup-quinazoline -6- alcohol (4I)

4- (3-chloro-2,4-difluoro-anilino) -7- [(3S)-tetrahydrofuran-3-yl] oxy- quinazolin-6-ol

4H (1.1g, 2.28mmol), trifluoracetic acid (10mL) and thioanisole (1mL) are sequentially added into reaction flask, are added Hot back flow reaction 2.5 hours.It is concentrated to dryness, is added ether (15mL), extremely with the methanolic ammonia solution regulation system pH value of 7M 9, it is concentrated under reduced pressure, is added water (20mL), filtering collects filter cake, is dried to obtain 4I (740mg, the yield of faint yellow solid shape 83%).

MS m/z (ESI): 394.1 [M+1].

¹H NMR (400MHz, DMSO) δ 9.64 (s, 1H), 9.56 (s, 1H), 8.34 (s, 1H), 7.67 (s, 1H), 7.54 (dd, 1H), 7.38 (t, 1H), 7.16 (s, 1H), 5.24 (s, 1H), 4.04-3.86 (m, 3H), 3.79 (dd, 1H), 2.32 (td, 1H), 2.18-2.05 (m, 1H).

Step 9: 4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- [(3S)-tetrahydrofuran -3- base] oxygen-quinazoline -6- Base] oxygroup piperidines -1- t-butyl formate (4J)

Tert-butyl-4- [4- (3-chloro-2,4-difluoro-anilino) -7- [(3S) - tetrahydrofuran-3-yl]oxy-quinazolin-6-yl]oxypiperidine-1-carboxylate

Sequentially added into reaction flask 4I (600mg, 1.53mmol), N-Boc-4- hydroxy piperidine alcohol (615mg, 3.06mmol) and triphenylphosphine (1.6g, 6.12mmol), addition methylene chloride (12mL) are cooled to -15 DEG C, and azo two is added dropwise The dichloromethane solution (6mL) of formic acid di tert butyl carbonate (615mg, 3.06mmol) drips off and is warmed to room temperature reaction 3 hours.It depressurizes dense Contracting, residue obtain white solid 4J with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=50: 1 → 30: 1) (750mg, yield 85%).

MS m/z (ESI): 577.0 [M+1].

¹H NMR (400MHz, DMSO) δ 9.62 (s, 1H), 8.37 (s, 1H), 7.93 (s, 1H), 7.57 (td, 1H), 7.40 (t, 1H), 7.22 (s, 1H), 5.26 (s, 1H), 4.64 (d, 1H), 4.00-3.93 (m, 1H), 3.92-3.74 (m, 3H), 3.61 (d, 2H), 3.30 (s, 1H), 2.32 (td, 1H), 2.12-1.85 (m, 4H), 1.69 (d, 2H), 1.42 (s, 9H).

Step 10: N- (chloro- 2, the 4- difluorophenyl of 3-) -6- (4- piperidyl oxygroup -7- [(3S)-tetrahydrofuran -3- base] Oxygroup quinazoline -4- amine (4K)

N- (3-chloro-2,4-difluoro-phenyl) -6- (4-piperidyloxy) -7- [(3S) - tetrahydrofuran-3-yl]oxy-quinazolin-4-amine

4J (750mg, 1.3mmol), trifluoracetic acid (3mL) and methylene chloride (10mL) are sequentially added into reaction flask, are dripped It adds and is reacted at room temperature 3 hours after finishing.It is concentrated under reduced pressure, ether (15mL) is added into residue, adjusted with the methanolic ammonia solution of 7M System pH is concentrated under reduced pressure to 9, residue with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=10: 1 → 5: 1) saturated sodium bicarbonate solution (20mL) and chloroform (30mL), are added into residue, separates organic layer, water layer is extracted with chloroform (10mL × 3) merge organic phase, and anhydrous sodium sulfate dries, filters, filtrate decompression is concentrated, and obtain the 4K of faint yellow solid shape (575mg, yield 93%).

MS m/z (ESI): 477.0 [M+1].

¹H NMR (400MHz, DMSO) δ 9.62 (s, 1H), 8.36 (d, 1H), 7.88 (s, 1H), 7.56 (dd, 1H), 7.40 (td, 1H), 7.20 (s, 1H), 5.25 (s, 1H), 4.65-4.42 (m, 1H), 3.98 (dd, 1H), 3.93-3.85 (m, 2H), 3.80 (td, 1H), 3.06-2.95 (m, 2H), 2.61 (dd, 2H), 2.32 (td, 1H), 2.13-1.89 (m, 3H), 1.58 (d, 2H), 1.23 (s, 1H).

Step 11: 1- [4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- [(3S)-tetrahydrofuran -3- base] oxygroup quinoline azoles Quinoline-6- base] Oxy-1-piperidyl] propyl-2- alkene-1- ketone (compound 4)

Sequentially added into reaction flask 4K (310mg, 0.65mmol), tetrahydrofuran (12mL) and sodium bicarbonate (164mg, Aqueous solution (1.8mL) 1.95mmol), ice bath are cooled to 0 DEG C, and it is molten that acryloyl chloride (65mg, 0.72mmol) tetrahydrofuran is added dropwise Liquid (1mL) adds 0 DEG C and reacts 15 minutes, be added dropwise saturated sodium bicarbonate aqueous solution (20mL), is added chloroform (50mL), separated Machine layer, water layer extract (20mL × 3) with chloroform, merge organic phase, anhydrous sodium sulfate dries, filters, filtrate decompression is concentrated, residual Object is stayed to obtain the chemical combination of white solid with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=100: 1 → 30: 1) Object 4 (207mg, yield: 60%).

MS m/z (ESI): 531.0 [M+1].

¹H NMR (400MHz, CDCl₃) δ 8.61 (s, 1H), 8.08 (dd, 1H), 7.51 (s, 1H), 7.25 (s, 1H), 7.04 (td, 1H), 6.60 (dd, 1H), 6.27 (d, 1H), 5.70 (d, 1H), 5.11 (s, 1H), 4.68 (s, 1H), 4.08 (d, 2H), 4.05-3.89 (m, 2H), 3.85-3.76 (m, 3H), 3.59 (s, 1H), 2.36 (td, 1H), 2.28-2.18 (m, 1H), 2.03- 1.95 (m, 3H), 1.37-1.22 (m, 3H).

Embodiment 5:1- [(3aR, 6aS) -5- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- [(3S)-tetrahydrofuran -3- base] Oxygroup-quinazoline -6- base] oxygroup -3,3a, 4,5,6,6a- hexahydro -1H- pentamethylene simultaneously [c] pyrroles -2- base] propyl -2- alkene -1- Ketone (compound 5)

1- [(3aR, 6aS) -5- [4- (3-chloro-2,4-difluoro-anilino) -7- [(3S) - Tetrahydrofuran-3-yl] oxy-quinazolin-6-yl] oxy-3,3a, 4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrol-2-yl]prop-2-en-1-one

Step 1: (3aR, 6aS) -5- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- [(3S)-tetrahydrofuran -3- base] oxygen Base-quinazoline -6- base] oxygroup -3,3a, 4,5,6,6a- hexahydro -1H- pentamethylene [c] pyrroles -2- t-butyl formates (5B)

Tert-butyl- (3aR, 6aS) -5- [4- (3-chloro-2,4-difluoro-anilino) -7- [(3S) - Tetrahydrofuran-3-yl] oxy-quinazolin-6-yl] oxy-3,3a, 4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-2-carboxylate

It is sequentially added into reaction flask 4I (300mg, 0.75mmol), 4d (339mg, 1.50mmol, intermediate 4) and triphen Base phosphine (786mg, 3.00mmol) is added methylene chloride (6mL), is cooled at -15 DEG C and tert-butyl azodicarboxylate is added dropwise The dichloromethane solution (3mL) of (518mg, 2.25mmol) is warmed to room temperature reaction 2 hours after being added dropwise.It is concentrated under reduced pressure, residual Object obtains the 5B of white solid with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=100: 1 → 50: 1) (353mg, yield: 78%).

MS m/z (ESI): 603.0 [M+1].

¹H NMR (400MHz, DMSO) δ 9.62 (s, 1H), 8.36 (s, 1H), 7.76 (s, 1H), 7.57 (dd, 1H), 7.40 (t, 1H), 7.19 (s, 1H), 5.22 (s, 1H), 5.08 (s, 1H), 3.96 (dd, 1H), 3.88 (d, 2H), 3.83-3.72 (m, 1H), 3.48 (td, 2H), 3.13 (d, 2H), 2.84 (s, 3H), 2.32 (dt, 1H), 2.12-2.01 (m, 4H), 1.97-1.90 (m, 2H), 1.39 (s, 9H).

[[(3aR, 6aS) -1,2,3,3a, 4,5,6,6a- octahydro pentamethylene simultaneously [c] pyrroles -5- base] oxygen step 2: 6- Base]-N- (chloro- 2, the 4- difluorophenyl of 3-) -7- [(3S)-tetrahydrofuran -3- base] oxygroup-quinazoline -4- ammonia (5C)

6- [[(3aR, 6aS) -1,2,3,3a, 4,5,6,6a-octahydrocyclopenta [c] pyrrol-5-yl] Oxy]-N- (3-chloro-2,4-difluoro-phenyl) -7- [(3S)-tetrahydrofuran-3-yl] oxy- quinazolin-4-amine

It is sequentially added into reaction flask 5B (470mg, 0.78mmol), trifluoracetic acid (2mL) and methylene chloride (6mL) add Complete room temperature reaction 30 minutes.It is concentrated to dryness, is added ether (15mL), with the methanolic ammonia solution regulation system pH value of 7M to 9, It is concentrated under reduced pressure, residue is with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=10: 1~7: 1), into residue Saturated sodium bicarbonate solution (20mL) and chloroform (30mL) is added, separates organic layer, water layer extracts (10mL × 3) with chloroform, closes And organic phase, anhydrous sodium sulfate dry, filter, and are concentrated under reduced pressure, obtain 5C (340mg, the yield: 87%) of yellow solid.

MS m/z (ESI): 503.0 [M+1].

¹H NMR (400MHz, DMSO) δ 8.36 (s, 1H), 7.91 (d, 1H), 7.56 (d, 1H), 7.41-7.36 (m, 1H), 7.20 (s, 1H), 5.23 (s, 1H), 5.10 (d, 1H), 3.97 (dd, 1H), 3.88 (d, 2H), 3.83-3.73 (m, 1H), 3.24 (dd, 1H), 3.13-2.99 (m, 2H), 2.88 (t, 3H), 2.32 (td, 1H), 2.21-1.96 (m, 3H), 1.87 (d, 2H).

Step 3: 1- [(3aR, 6aS) -5- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- [(3S)-tetrahydrofuran -3- base] Oxygroup-quinazoline -6- base] oxygroup -3,3a, 4,5,6,6a- hexahydro -1H- pentamethylene simultaneously [c] pyrroles -2- base] propyl -2- alkene -1- Ketone (compound 5)

Sequentially added into reaction flask 5C (340mg, 0.68mmol), tetrahydrofuran (12mL) and sodium bicarbonate (171mg, Water (1.8mL) solution 2.04mmol) is cooled to 0 DEG C, and the tetrahydrofuran (1mL) that acryloyl chloride (68mg, 0.75mmol) is added dropwise is molten Liquid, 0 DEG C is reacted 30 minutes, and saturated sodium bicarbonate solution (10mL) is added dropwise into reaction system, is added methylene chloride (30mL), point Organic layer out, water layer are extracted with dichloromethane (10mL × 2), merge organic phase, saturation drinking water washing (20mL × 1), anhydrous sulphur Sour sodium dries, filters, be concentrated under reduced pressure, residue with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=100: 1~ 30: 1) obtaining the compound 5 (100mg, yield: 27%, HPLC:97%) of yellow solid.

MS m/z (ESI): 557.0 [M+1].

¹H NMR (400MHz, CDCl₃) δ 8.60 (s, 1H), 7.41 (s, 1H), 7.19 (s, 1H), 7.03 (td, 1H), 6.41 (dd, 1H), 6.32 (dd, 1H), 5.66 (dd, 1H), 5.14-5.01 (m, 2H), 4.08 (d, 2H), 4.03 (dd, 1H), 3.93 (td, 1H), 3.74 (ddd, 2H), 3.52-3.36 (m, 3H), 3.14-3.00 (m, 1H), 3.00-2.85 (m, 1H), 2.33- 2.19 (m, 4H), 1.91 (ddd, 3H).

Embodiment 6:1- [(3aR, 6aS) -5- [4- [(chloro- 2, the 4- difluorophenyl of 3-) amino] -7- methoxy-quinazoline - 6- yl] oxygroup-hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl] propyl -2- alkene -1- ketone (compound 6)

1- ((3aR, 5s, 6aS) -5- ((4- ((3-chloro-2,4-difluorophenyl) amino) -7- methoxyquinazolin-6-yl)oxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1- one

((the chloro- 7- methoxy-quinazoline -6- base of 4-) oxygroup-hexahydro pentamethylene simultaneously [c] pyrrole step 1: (3aR, 6aS) -5- Cough up -2 (1H) -- t-butyl formate (6B)

(3aR, 5s, 6aS)-tert-butyl 5- ((4-chloro-7-methoxyquinazolin-6-yl) oxy) hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

1d (1.1g, 5.2mmol), 4d (1.7g, 7.8mmol, intermediate 4) and triphenylphosphine are sequentially added into reaction flask (2.1g, 7.8mmol), after mixing evenly, ice-water bath are cooled to 0 DEG C, by diisopropyl azodiformate (1.6g, 7.8mmol) Methylene chloride (5mL) solution be added dropwise in system, be warmed to room temperature and be stirred overnight naturally.It is concentrated under reduced pressure, residue silicon Rubber column gel column chromatographic isolation (petrol ether/ethyl acetate (v/v)=3: 2 → 2: 3) obtains the 6B (2.2g) of colorless oil.

MS m/z (ESI): 420.3 [M+1].

Step 2: (3aR, 6aS) -5- [[4- [(chloro- 2, the 4- difluorophenyl of 3-) amino] -7- methoxy-quinazoline -6- Base] oxygroup]-hexahydro pentamethylene [c] pyrroles -2 (1H)-t-butyl formate (6C)

(3aR, 5s, 6aS)-tert-butyl 5- ((4- ((3-chloro-2,4-difluorophenyl) amino) -7- methoxyquinazolin-6-yl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Sequentially added into reaction flask chloro- 2, the 4- difluoroaniline of 6B (4g, 9.5mmol), 3- (3g, 19mmol, finish) and Isopropanol (65mL) rises to 100 DEG C and reacts 3 hours, is concentrated under reduced pressure, and residue separates (methylene chloride/methanol with silica gel column chromatography (v/v)=30: 1~10: 1 6C (1.7g, the yield: 32.7%) of pale yellowish oil) are obtained.

MS m/z (ESI): 547.2 [M+1].

¹H NMR (300MHz, CDCl₃) δ 8.30 (s, 2H), 7.40 (m, 2H), 6.83 (m, 1H), 5.38 (m, 1H), 3.98 (s, 3H), 3.52 (m, 2H), 3.25 (m, 2H), 2.90 (m, 2H), 2.22 (m, 2H), 2.05 (m, 2H), 1.43 (s, 9H).

Step 3: [[(3aR, 6aS)-octahydro pentamethylene is simultaneously [c] by N- (chloro- 2, the 4- difluorophenyl of 3-) -7- methoxyl group -6- Pyrroles -5- base] oxygroup] bis- (trifluoroacetic acid) salt (6D) of quinazoline -4- amine

N- (3-chloro-2,4-difluorophenyl) -7-methoxy-6- (((3aR, 5s, 6aS) - octahydrocyclopenta[c]pyrrol-5-yl)oxy)quinazolin-4-amine

6C (0.59g, 1.1mmol), methylene chloride (4.5mL) and trifluoroacetic acid are sequentially added under ice-water bath into reaction flask (2.2mL) is stirred at room temperature 2 hours.Be concentrated under reduced pressure, residue with silica gel column chromatography separate (methylene chloride/methanol (v/v)=20: 1~5: 1) obtaining 6D (0.6g, the yield: 82%) of pale-yellow solid.

Step 4: 1- [(3aR, 6aS) -5- [[4- [(chloro- 2, the 4- difluorophenyl of 3-) amino] -7- methoxy-quinazoline - 6- yl] oxygroup-hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl] propyl- 2- alkene -1- ketone (compound 6)

Successively 6D (0.257g, 0.38mmol), triethylamine (0.116g, 1.14mmol) and methylene chloride into reaction flask (12mL), dry ice ethanol bath, which is cooled at -40 DEG C, to be added dropwise acryloyl chloride (0.041g, 0.46mmol), and -40 DEG C are stirred 50 points Clock.Reaction solution is poured into saturated sodium bicarbonate solution (60mL), is extracted with chloroform (60mL × 3), organic phase, anhydrous slufuric acid are merged Sodium dries, filters, and is concentrated under reduced pressure, and residue silica gel column chromatography separates (methylene chloride/methanol (v/v)=60: 1~30: 1) and obtains To the compound 6 (0.06g, yield: 36.6%, HPLC:98.46%) of colorless oil.

MS m/z (ESI): 501.0 [M+1].

¹H NMR (300MHz, CDCl₃) δ 8.59 (s, 1H), 7.90 (m, 1H), 7.44 (s, 1H), 7.27 (d, 1H), 7.03 (m, 1H), 6.30 (m, 2H), 5.66 (m, 1H), 5.10 (m, 1H), 3.99 (s, 3H), 3.71 (m, 2H), 3.42 (m, 2H), 3.01 (m, 2H), 2.28 (m, 3H), 1.96 (m, 3H).

Embodiment 7:1- [(3R, 4R) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] oxygen The fluoro- 1- piperidyl of base -3-] propyl -2- alkene -1- ketone maleate (compound 7)

1- [(3R, 4R) -4- [4- (3-chloro-2,4-difluorophenyl) amino) -7- methoxyquinazolin-6-yl]oxy-3-fluoropiperidin-1-yl]prop-2-en-1-one maleic acid salt

Be added into reaction flask compound 2-1 (200mg, 0.41mmol), methanol (2.0mL) and maleic acid (47.1mg, 0.41mmol), it is stirred at room temperature 5 hours.Compound 7 (90mg, the yield: 36%) of pale-yellow solid is obtained by filtration.

¹H NMR (400MHz, DMSO) δ 8.53 (s, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 7.60 (td, 1H), 7.43 (td, 1H), 7.28 (s, 1H), 6.85 (dd, 1H), 6.21 (s, 2H), 6.15 (dd, 1H), 5.73 (dd, 1H), 4.96-4.74 (m, 2H), 4.03-3.91 (m, 5H), 3.75 (s, 1H), 3.62 (s, 1H), 2.23-2.00 (m, 1H), 1.85-1.73 (m, 1H).

¹⁹F NMR (400MHz, DMSO) δ -114.82, -188.00, -188.82.

Embodiment 8:1- [(3R, 4S) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] oxygen The fluoro- 1- piperidyl of base -3-] propyl -2- alkene -1- ketone maleate (compound 8)

1- [(3R, 4S) -4- [4- (3-chloro-2,4-difluorophenyl) amino) -7- methoxyquinazolin-6-yl]oxy-3-fluoropiperidin-1-yl]prop-2-en-1-one maleic acid salt

Be added into reaction flask compound 3-2 (170mg, 0.35mmol), ethyl alcohol (2.0mL) and maleic acid (40.1mg, 0.35mmol), it is stirred at room temperature 5 hours.Compound 8 (80mg, the yield: 37.7%) of pale-yellow solid is obtained by filtration.

¹H NMR (400MHz, DMSO) δ 8.51 (s, 1H), 7.96 (s, 1H), 7.59 (td, 1H), 7.43 (td, 1H), 7.27 (s, 1H), 6.85 (d, 1H), 6.21 (s, 2H), 6.14 (dd, 1H), 5.72 (dd, 1H), 5.09 (d, 1H), 4.88-4.70 (m, 1H), 4.34 (s, 2H), 3.98 (s, 4H), 3.43 (dt, 3H), 3.05 (d, 1H), 2.05 (dd, 2H).

¹⁹F NMR (400MHz, DMSO) δ -114.62, -114.79, -201.63.

Embodiment 9:1- [(3R, 4R) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] oxygen The fluoro- 1- piperidyl of base -3-] propyl -2- alkene -1- keto hydrochloride (compound 9)

1- [(3R, 4R) -4- [4- (3-chloro-2,4-difluorophenyl) amino) -7- methoxyquinazolin-6-yl]oxy-3-fluoropiperidin-1-yl]prop-2-en-1-one hydrochloric acid salt

Be added into reaction flask compound 2-1 (400mg, 0.81mmol), methanol (2.8mL) and hydrochloric acid (0.1mL, Methanol (0.5mL) solution 1.23mmol), is stirred at room temperature 4 hours.It is concentrated under reduced pressure to give the compound 9 of white solid (395mg, yield: 93.4%).

¹H NMR (400MHz, DMSO) δ 12.16 (s, 1H), 8.91-8.68 (m, 2H), 7.67-7.56 (m, 1H), 7.49 (t, 1H), 7.42 (s, 1H), 6.86 (dd, 1H), 6.14 (dd, 1H), 5.72 (dd, 1H), 5.16 (s, 1H), 4.96-4.64 (m, 1H), 4.03 (s, 3H), 3.82 (s, 1H), 3.63 (s, 2H), 3.47 (s, 2H), 2.24 (d, 1H), 1.68 (d, 1H).

¹⁹F NMR (400MHz, DMSO) δ -112.89 (1F), -113.91 (1F), -187.52~-188.50 (1F).

Embodiment 10:1- [(3R, 4S) -4- [4- (chloro- 2, the 4- difluoro-aniline of 3-) -7- methoxy-quinazoline -6- base] oxygen The fluoro- 1- piperidyl of base -3-] propyl -2- alkene -1- keto hydrochloride (compound 10)

1- [(3R, 4S) -4- [4- (3-chloro-2,4-difluorophenyl) amino) -7- methoxyquinazolin-6-yl]oxy-3-fluoropiperidin-1-yl]prop-2-en-1-one hydrochloric acid salt

Be added into reaction flask compound 3-2 (150mg, 0.30mmol), methanol (0.8mL) and hydrochloric acid (16mg, Methanol (0.3mL) solution 0.45mmol), is stirred at room temperature 5 hours.It is concentrated under reduced pressure to give the compound 10 of white solid (135mg, yield: 84.3%).

¹H NMR (400MHz, DMSO) δ 10.58 (s, 1H), 8.55 (s, 1H), 8.25 (s, 1H), 7.67-7.19 (m, 3H), 6.97-6.69 (m, 1H), 6.17-6.01 (m, 1H), 5.71 (d, 1H), 5.12 (d, 1H), 5.00-4.86 (m, 1H), 4.38 (t, 1H), 3.99 (d, 3H), 3.69-3.49 (m, 1H), 3.36 (dd, 3H), 3.05 (dd, 1H), 2.05 (dt, 1H), 2.00-1.76 (m, 1H).

¹⁹F NMR (376MHz, DMSO) δ -114.51 (1F), -114.61 (1F), -201.01~-202.20 (1F).

Embodiment 11:1- [(3R, 4R) -4- [4- (3, the 4- bis- chloro- fluoro- aniline of 2-) -7- methoxy-quinazoline -6- base] oxygen The fluoro- 1- piperidyl of base -3-] propyl -2- alkene -1- ketone (compound 11)

1- [(3R, 4R) -4- [4- (3,4-dichloro-2-fluoro-anilino) -7-methoxy-quinazolin- 6-yl]oxy-3-fluoro-1-piperidyl]prop-2-en-1-one

Step 1: (3R, 4R) 4- [4- (3, the 4- bis- chloro- fluoro- aniline of 2-) -7- methoxy-quinazoline -6- base] oxygroup -3- Fluoro-piperidine -1- t-butyl formate (11B)

(3R, 4R)-tert-butyl4- ((4- ((3,4-dichloro-2-fluorophenyl) amino) -7- methoxyquinazolin-6-yl)oxy)-3-fluoropiperidine-1-carboxylate

Sequentially added into reaction flask 6c (2.6g, 7.3mmol, intermediate 6), methylene chloride (18mL), 5c-1 (0.53g, 2.43mmol) and triphenylphosphine (1.91g, 7.3mmol), nitrogen protection is cooled to the dropwise addition tertiary fourth of azoformic acid two at -15 DEG C Methylene chloride (18mL) solution of ester (1.27g, 7.3mmol) after being added dropwise, is warmed to room temperature reaction 18 hours.It is concentrated under reduced pressure, Residue obtains the 11B of yellow solid with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=100: 1) (0.2g, yield: 15%).

Step 2: N- (3,4- bis- chloro- 2- fluoro-phenyl) -6- [[the fluoro- 4- piperidyl of (3R, 4R) -3-] oxygroup] -7- methoxy Base-quinazoline -4- amine two (trifluoroacetic acid) salt (11C)

N- (3,4-dichloro-2-fluorophenyl) -6- (((3R, 4R) -3-fluoropiperidin-4-yl) oxy)-7-methoxyquinazolin-4-amine(ditrifluoroacetic acid)

11B (0.2g, 0.35mmol) and methylene chloride (3mL), the cooling lower dropwise addition of ice-water bath are sequentially added into reaction flask Trifluoroacetic acid (3mL) is warmed to room temperature reaction 1 hour naturally after being added dropwise, be concentrated under reduced pressure, and residue is separated with silica gel column chromatography Purification (methylene chloride/methanol (v/v)=20: 1) obtains 11C (0.16g, the yield: 99%) of white solid.

Step 3: 1- [(3R, 4R) -4- [4- (3, the 4- bis- chloro- fluoro- aniline of 2-) -7- methoxy-quinazoline -6- base] oxygen The fluoro- 1- piperidyl of base -3-] propyl -2- alkene -1- ketone (compound 11)

1- ((3R, 4R) -4- ((4- ((3,4-dichloro-2-fluorophenyl) amino) -7- methoxyquinazolin-6-yl)oxy)-3-fluoropiperidin-1-yl)prop-2-en-1-one

11C (0.7g, 1.04mmol) is dissolved in the mixed solution of tetrahydrofuran (25mL) and water (5mL), carbonic acid is added Hydrogen sodium (0.44g, 5.22mmol), ice bath are cooled to dropwise addition acryloyl chloride (0.11g, 1.14mmol) at -30 DEG C, -15 DEG C of stirrings 30 minutes.Saturation drinking water (20mL) is added into reaction system, is extracted with methylene chloride (35mL × 3), merges organic phase, it is anhydrous Sodium sulphate dries, filters, and filtrate decompression is concentrated, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v) =100: 1) obtaining the compound 11 (0.12g, yield: 23%, HPLC:94.80%) of white solid.

MS m/z (ESI): 509.0 [M+1].

¹H NMR (400MHz, CDCl₃): δ¹H NMR (400MHz, CDCl₃) δ 8.69 (s, 1H), 8.35 (t, 1H), 7.43 (s, 1H), 7.32 (dd, 2H), 6.59 (dd, 1H), 6.30 (d, 1H), 5.74 (dd, 1H), 4.74 (dd, 2H), 4.18-3.45 (m, 7H), 2.19 (s, 1H), 1.95 (m, 1H).

¹⁹F NMR (400MHz, CDCl₃): δ -123.08 (1F), -188.63~-189.44 (1F).

Embodiment 12:1- [(3R, 4S) -4- [4- (3, the 4- bis- chloro- fluoro- aniline of 2-) -7- methoxy-quinazoline -6- base] oxygen The fluoro- 1- piperidyl of base -3-] propyl -2- alkene -1- ketone (compound 12)

1- ((3R, 4S) -4- ((4- ((3,4-dichloro-2-fluorophenyl) amino) -7- methoxyquinazolin-6-yl)oxy)-3-fluoropiperidin-1-yl)prop-2-en-1-one

Step 1: (3R, 4S) -4- [4- (3, the 4- bis- chloro- fluoro- aniline of 2-) -7- methoxy-quinazoline -6- base] oxygroup -3- Fluoro-piperidine -1- t-butyl formate (12B)

(3R, 4S)-tert-butyl4- ((4- ((3,4-dichloro-2-fluorophenyl) amino) -7- methoxyquinazolin-6-yl)oxy)-3-fluoropiperidine-1-carboxylate

Sequentially added into reaction flask 6c (7.8g, 21.9mmol, intermediate 6), methylene chloride (60mL), 5c-2 (1.6g, 7.3mmol) and triphenylphosphine (5.7g, 21.9mmol), nitrogen protection is cooled to the dropwise addition tertiary fourth of azoformic acid two at -15 DEG C Ester (3.8g, 21.9mmol) after being added dropwise, is warmed to room temperature reaction 18 hours.It is concentrated under reduced pressure, residue silica gel column chromatography point The 12B crude product (4.0g) of yellow solid is obtained from purification (methylene chloride/methanol (v/v)=100: 1), it is anti-to be directly used in lower step It answers.

Step 2: N- (3,4- bis- chloro- 2- fluoro-phenyl) -6- [[the fluoro- 4- piperidyl of (3R, 4S) -3-] oxygroup] -7- methoxy Base-quinazoline -4- amine two (trifluoroacetic acid) salt (12C)

N- (3,4-dichloro-2-fluorophenyl) -6- (((3R, 4S) -3-fluoropiperidin-4-yl) oxy)-7-methoxyquinazolin-4-amine(ditrifluoroacetic acid)

12B (4.0g, 7.3mmol) and methylene chloride (10mL), the cooling lower dropwise addition of ice-water bath are sequentially added into reaction flask Trifluoroacetic acid (10mL) is warmed to room temperature reaction 1 hour naturally after being added dropwise, be concentrated under reduced pressure, residue silica gel column chromatography point 12C (1.3g, the first step and the second step total recovery of white solid are obtained from purification (methylene chloride/methanol (v/v)=20: 1) For 27%).

Step 3: 1- [(3R, 4S) -4- [4- (3, the 4- bis- chloro- fluoro- aniline of 2-) -7- methoxy-quinazoline -6- base] oxygen The fluoro- 1- piperidyl of base -3-] propyl -2- alkene -1- ketone (compound 12)

12C (1.2g, 1.8mmol) is dissolved in the mixed solution of tetrahydrofuran (40mL) and water (8mL), bicarbonate is added Sodium (0.8g, 9.0mmol), ice bath are cooled to dropwise addition acryloyl chloride (0.2g, 2.2mmol) at -30 DEG C, and -15 DEG C are stirred 30 minutes. Saturation drinking water (50mL) is added into reaction system, is extracted with methylene chloride (50mL × 3), merges organic phase, anhydrous sodium sulfate It dries, filters, is concentrated under reduced pressure, residue is obtained with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=100: 1) Compound 12 (0.21g, the yield: 22.8%) of white solid.

MS m/z (ESI): 509.0 [M+1].

¹H NMR (400MHz, CDCl₃): δ¹H NMR (400MHz, CDCl₃) δ 8.64 (s, 1H), 8.16 (t, 1H), 7.63 (s, 1H), 7.38-7.18 (m, 2H), 6.58 (dd, 1H), 6.26 (dd, 1H), 5.72 (dd, 1H), 5.00-4.57 (m, 2H), 4.40-4.06 (m, 2H), 4.00 (s, 3H), 3.95-3.21 (m, 2H), 2.27-2.10 (m, 1H), 1.96 (s, 1H).

¹⁹F NMR (400MHz, CDCl₃): δ -121.02 (1F), -197.39~-198.96 (1F).

Embodiment 13:1- ((3R, 4R) -4- ((4- ((3,4- bis- chloro- 2- fluorine) amino) -7- methoxy quinazoline -6- base) oxygen Base) -3- fluorine resources -1- base) propyl -2- alkene -1- keto hydrochloride (compound 13)

1- ((3R, 4R) -4- ((4- ((3,4-dichloro-2-fluorophenyl) amino) -7- methoxyquinazolin-6-yl)oxy)-3-fluoropiperidin-1-yl)prop-2-en-1-one Hydrochloric acid salt

Compound 11 (80mg, 0.16mmol), methanol (1mL) and (0.1mL, 0.23mmol) hydrochloric acid are added into reaction flask Methanol solution (2.3M), be stirred at room temperature 4 hours, be concentrated under reduced pressure to give white solid compound 13 (73mg, yield: 90.4%).

¹H NMR (400MHz, DMSO-d₆) δ 12.19 (d, 1H), 8.96-8.68 (m, 2H), 7.78-7.53 (m, 2H), 7.41 (s, 1H), 6.86 (dd, 1H), 6.14 (dd, 1H), 5.72 (dd, 1H), 5.15 (s, 1H), 4.96-4.57 (m, 1H), 4.36-3.93 (m, 5H), 3.82 (d, 2H), 2.34-2.10 (m, 1H), 1.68 (d, 1H).

¹⁹F NMR (400MHz, DMSO-d₆): δ -111.12 (1F), -187.67~-188.44 (1F).

Embodiment 14:1- ((3R, 4S) -4- ((4- ((3,4- bis- chloro- 2- fluorine) amino) -7- methoxy quinazoline -6- base) oxygen Base) -3- fluorine resources -1- base) propyl -2- alkene -1- keto hydrochloride (compound 14)

1- ((3R, 4S) -4- ((4- ((3,4-dichloro-2-fluorophenyl) amino) -7- methoxyquinazolin-6-yl)oxy)-3-fluoropiperidin-1-yl)prop-2-en-1-one Hydrochloric acid salt

Compound 12 (78mg, 0.15mmol), methanol (1mL) and (0.1ml, 0.23mmol) hydrochloric acid are added into reaction flask Methanol solution (2.3M), be stirred at room temperature 5 hours.It is concentrated to get compound 14 (73mg, the yield: 85%) of white solid.

¹H NMR (400MHz, DMSO) δ 12.43 (s, 1H), 8.86 (s, 1H), 7.84-7.49 (m, 2H), 7.39 (s, 1H), 6.80 (dd, 2H), 6.22-6.00 (m, 2H), 5.32-5.02 (m, 1H), 4.72-3.92 (m, 8H), 2.07 (s, 1H), 1.42 (ddd, 1H).

¹⁹F NMR (400MHz, DMSO): δ -110.94 (1F), -186.83~-187.43 (1F).

Embodiment 15

7- ((4- ((3,4- bis- chloro- 2- fluorophenyl) amino) -7- methoxyquinazoline hydrochloride -6- base) oxygroup) tetrahydro -1H- oxazole And [3,4-a] pyridine -3 (5H) -one (compound 15)

7- ((4- ((3,4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) Oxy) tetrahydro-1H-oxazolo [3,4-a] pyridin-3 (5H)-one

Step 1: 1- tert-butyl 2- methyl 4- hydroxy piperidine -1,2- dicarboxylic acid esters (15B)

1-tert-butyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate

1- tert-butyl 2- methyl 4- oxo-piperidine -1,2- dicarboxylic acid esters 15A (6.1g, 24mmol) is added in reaction flask, Methanol 60mL is added, ice bath is cooling, and sodium borohydride (1.4g, 36mmol) is added portionwise, adds, insulation reaction 30 minutes.It is added dropwise Saturated aqueous ammonium chloride 50mL is concentrated under reduced pressure, and ethyl acetate is added and each 100mL of water, liquid separation, water phase are extracted with ethyl acetate 50mL × 2 merge organic phase, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=3: 1~2: 1 colorless oil 15B (5.8g, yield 94%)) is obtained.

MS m/z (ESI): 160.1 [M+1].

¹H NMR (400MHz, CDCl₃) δ 4.93 (d, 1H), 4.21-3.90 (m, 1H), 3.73 (s, 3H), 3.66 (t, 1H), 2.99 (d, 1H), 2.44 (t, 1H), 1.91 (dd, 1H), 1.60 (t, 1H), 1.46 (s, 9H).

Step 2: 1- tert-butyl 2- methyl 4- ((4- ((3,4- bis- chloro- 2- fluorophenyl) amino) -7- methoxyquinazoline hydrochloride - 6- yl) oxo) piperidines -1,2- dicarboxylic acid esters (15C)

1-tert-butyl 2-methyl 4- ((4- ((3,4-dichloro-2-fluorophenyl) amino) -7- Methoxyquinazolin-6-yl) oxy) piperidine-1,2-dicarboxylate

By 15B (2.0g, 7.71mmol), 4- ((3,4- bis- chloro- 2- fluorophenyl) amino) -7- methoxyquinazoline hydrochloride -6- alcohol (1.37g, 3.86mmol), triphenylphosphine (4.05g, 15.42mmol) are added in reaction flask, are added methylene chloride (60mL), drop Temperature is added dropwise the dichloromethane solution 10mL of azo-2-carboxylic acid's di tert butyl carbonate (2.66g, 11.57mmol), drips off, rise to -20 DEG C Room temperature reaction 4 hours.It is concentrated under reduced pressure, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=100: 1~50: 1) To faint yellow solid 15C (1.5g, yield 65%).

MS m/z (ESI): 595.0 [M+1].

¹H NMR (400MHz, DMSO) δ 9.77 (s, 1H), 8.41 (s, 1H), 7.82 (s, 1H), 7.69-7.54 (m, 2H), 7.20 (s, 1H), 4.92 (s, 1H), 4.67 (d, 1H), 3.93 (s, 3H), 3.81 (s, 1H), 3.52 (d, 3H), 2.68 (t, 1H), 2.02 (dd, 2H), 1.81 (t, 1H), 1.41 (d, 9H), 1.24 (s, 1H).

Step 3: tert-butyl 4- ((4- ((3,4- bis- chloro- 2- fluorophenyl) amino) -7- methoxyquinazoline hydrochloride -6- base) oxygen Generation) -2- (methylol) piperidines -1- formic acid esters (15D)

Tert-butyl 4- ((4- ((3,4-dichloro-2-fluorophenyl) amino) -7- methoxyquinazolin-6-yl)oxy)-2-(hydroxymethyl)piperidine-1-carboxylate

15C (0.5g, 0.8mmol) is added in reaction flask, is added tetrahydrofuran (4mL), is cooled to -78 DEG C, is added dropwise two The toluene solution (4mL, 1.5mol/L) of isobutylaluminiumhydride drips off and is slowly increased to room temperature reaction 4 hours.Reaction solution is poured into hydrogen In aqueous solution of sodium oxide (100mL, 1mol/L) and the mixture of ice, it is added ethyl acetate (30mL), liquid separation, water phase is with acetic acid second Ester extracts (20mL × 2), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, silica gel column chromatography separating-purifying (two Chloromethanes/methanol (v/v)=100: 1~20: 1) obtain yellow oil 15D (0.3g, yield 60%).

MS m/z (ESI): 567.1 [M+1].

Step 4: 7- ((4- ((3,4- bis- chloro- 2- fluorophenyl) amino) -7- methoxyquinazoline hydrochloride -6- base) oxygroup) tetrahydro - 1H- oxazole [3,4-a] pyridine -3 (5H) -one (compound 15)

15D (0.25g, 0.44mmol) is added in reaction flask, is added n,N-Dimethylformamide (2.5mL), ice bath is cold But, sodium hydride (0.07g, 1.8mmol) is added, adds, be warmed to room temperature reaction 1 hour.Reaction solution is poured into ice water, second is added Acetoacetic ester (20mL), liquid separation, water layer extract 20mL × 2 with ethyl acetate, merge organic phase, with saturated common salt water washing (20mL × 4), anhydrous sodium sulfate dries, filters, be concentrated under reduced pressure, prepare liquid phase separating-purifying, obtain compound as white solid 15 (0.044g, Yield 20%).

MS m/z (ESI): 492.9 [M+1].

¹H NMR (400MHz, DMSO) δ 9.69 (s, 1H), 8.41 (s, 1H), 7.89 (s, 1H), 7.60 (s, 2H), 7.25 (s, 1H), 5.76 (s, 1H), 4.67 (tt, 1H), 4.40 (t, 1H), 4.06-3.97 (m, 1H), 3.97 (s, 3H), 3.80 (dd, 1H), 3.08 (td, 1H), 2.36 (d, 1H), 2.21 (d, 1H), 1.47 (q, 2H).

Embodiment 16

7- ((4- ((3,4- bis- chloro- 2- fluorophenyl) amino) -7- methoxyquinazoline hydrochloride -6- base) oxygroup) tetrahydro -1H- oxazole [3,4-a] pyridine -3 (5H)-thioketones (compound 16)

7- ((4- ((3,4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) Oxy) tetrahydro-1H-oxazolo [3,4-a] pyridin-3 (5H)-thione

Step 1: tertiary butyl-4-hydroxy -2- (methylol) piperidines -1- formic acid esters (16B)

tert-butyl 4-hydroxy-2-(hydroxymethyl)piperidine-1-carboxylate

15B (1.35g, 5.21mmol) is added in reaction flask, is added ethyl alcohol (15mL), is cooled to 0 DEG C, hydroboration is added Sodium (0.99g, 26mmol) adds and is slowly increased to room temperature reaction 8 hours.Reaction solution is poured into the aqueous solution of sodium hydroxide It in (100mL, 1mol/L), is added ethyl acetate (30mL), stirs liquid separation, separate organic phase, water phase is extracted with ethyl acetate (30mL × 2) merge organic phase, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=50: 1-10: 1 colorless oil 16B (0.7g, yield 60%)) is obtained.

MS m/z (ESI): 254.1 [M+23].

¹H NMR (400MHz, CDCl₃) δ 4.45 (dd, 1H), 4.15-4.00 (m, 1H), 3.96-3.77 (m, 2H), 3.73 (dd, 1H), 3.62 (dd, 1H), 2.92 (t, 1H), 2.16-1.76 (m, 3H), 1.59-1.20 (m, 9H).

Step 2: 2- (methylol) piperidines -4- alcohol trifluoroacetate (16C)

2-(hydroxymethyl)piperidin-4-ol trifluoroacetic acid salt

16B (0.26g, 1.12mmol) is added in reaction flask, is added methylene chloride (1.5mL), ice bath is cooling, is added three Fluorine acetic acid (1.5mL) adds and is warmed to room temperature reaction 1 hour.It is concentrated under reduced pressure, it is not purified to be directly used in the next step.

MS m/z (ESI): 132.1 [M+1].

Step 3: 7- hydroxy tetrahydro -1H- oxazole [3,4-a] pyridine -3 (5H)-thioketones (16D)

7-hydroxytetrahydro-1H-oxazolo [3,4-a] pyridine-3 (5H)-thione

16C (0.147g, 1.12mmol) is added in reaction flask, is added methylene chloride (3mL), ice bath is cooling, is added three Ethamine (0.34g, 3.36mmol) is added thiocarbonyldiimidazole (0.24g, 1.34mmol), adds, and is warmed to room temperature reaction 2 hours. Aqueous hydrochloric acid solution (10mL, 1mol/L) is added into reaction solution, stirs liquid separation, water layer extracts (5mL × 7) with methylene chloride, closes And organic phase, anhydrous sodium sulfate dry, filter, and are concentrated under reduced pressure, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)= 100: 1-70: 1) obtaining yellow oil 16D (0.07g, yield 40%).

MS m/z (ESI): 174.1 [M+1].

¹H NMR (400MHz, CDCl₃) δ 4.65 (t, 1H), 4.40-4.25 (m, 3H), 4.12-4.01 (m, 1H), 3.59- 3.46 (m, 1H), 2.05 (ddd, 1H), 1.86-1.74 (m, 2H), 1.68-1.55 (m, 1H).

Step 4: 7- ((4- ((3,4- bis- chloro- 2- fluorophenyl) amino) -7- methoxyquinazoline hydrochloride -6- base) oxygroup) tetrahydro - 1H- oxazole [3,4-a] pyridine -3 (5H)-thioketones (compound 16)

By 16D (0.18g, 1.0mmol), 4- ((3,4- bis- chloro- 2- fluorophenyl) amino) -7- methoxyquinazoline hydrochloride -6- alcohol (0.74g, 2.0mmol), triphenylphosphine (1.1g, 4.0mmol) are added in reaction flask, are added methylene chloride (10mL), cooling To -20 DEG C, the dichloromethane solution (5mL) of azo-2-carboxylic acid's di tert butyl carbonate (0.72g, 3.1mmol) is added dropwise, drips off, rises to room Temperature reaction 4 hours.It is concentrated under reduced pressure, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=100: 1~70: 1) obtains Compound as white solid 16 (0.127g, yield 24%).

MS m/z (ESI): 509.0 [M+1].

¹H NMR (400MHz, DMSO) δ 9.63 (s, 1H), 8.41 (s, 1H), 7.89 (s, 1H), 7.69-7.50 (m, 2H), 7.26 (s, 1H), 4.80-4.56 (m, 2H), 4.41-4.13 (m, 3H), 3.95 (s, 3H), 3.36-3.24 (m, 1H), 2.45 (d, 1H), 2.31 (d, 1H), 1.57 (d, 2H).

Biological test example

Biological test example 1:SRB cell proliferation experiment

SRB experiment is the proliferative conditions for detecting cell under drug effect.After dosing 72 hours, pass through SRB dyeing and enzyme Instrument 490nm reading is marked, reflects the proliferative conditions of cell.

96 orifice plate of plating cells, every empty 8000 cells of H1975 cell line, every empty 10000 cells of A431 cell line, 37 DEG C incubator, 5%CO₂Overnight incubation.Before dosing, every kind of cell takes 6 holes that 30 μ l, 50% trichloroacetic acid is added and fixes.Compound It is configured to solution with DMSO, 10 μM of maximum concentration, 5 times dilute totally ten gradients, with the culture medium gradient dilution containing 0.1%FBS Untested compound, and make 2 times of its final concentration.96 porocyte culture plates culture mediums of NCI-H1975, A431 cell are changed to fresh Culture medium (every 100 μ l of hole) containing 0.1%FBS, add 100 μ l contain 2 times of final concentrations untested compound, 37 DEG C of incubators, 5% CO₂Culture 72 hours.After incubation, 50 μ l 50%TCA are added, is placed in 4 DEG C of refrigerators and fixes 1h.Abandon liquid, 300 μ lddH₂O It washes 5 times, drying at room temperature 1h or more long.50 μ l 0.4%SRB of every empty addition, dye 15min.Dye liquor is abandoned, washes 6-7 with 1% acetic acid Secondary, drying at room temperature is saturating.It is dissolved with 200 μ l 10mM unbuffered Trisbase (pH=10.5), Oscillating Flat 2h.Enzyme mark Instrument measures 490nm absorbance.

Table 1:SRB cell proliferation experiment result

Conclusion: the compounds of this invention, which has, significantly inhibits H1975 (L858R/T790M), A431 (EGFRwt amplification) thin Born of the same parents' proliferation function.

Biological test example 2: Pharmacokinetic Evaluation

Male SD rat (purchased from dimension experimental animal Co., Ltd, tonneau China) 180-240g, fasting water supply are stayed overnight, 3 rats Oral administration gavage 5mg/kg, 3 rat intravenous injection 1mg/kg.Oral administration group, compound are molten with 0.5% methylcellulose (MC) Liquid (containing 0.4% Tween 80) is configured to 0.5mg × mL^-1Suspension, before administration and upon administration 30 minutes and 1,2,4, 6, it takes a blood sample within 8,12 and 24 hours；Intravenously administrable group, compound with 10% DMA, 20%Solutol HS-15 (30%, w/v) and 70% normal saline is at 0.2mg × mL^-1Solution, before administration and upon administration 5,15 and 30 minutes and 1,2,4,8, It takes a blood sample within 12 and 24 hours.Anticoagulant heparin.5500 revs/min of blood sample are centrifuged 10 minutes, collect blood plasma, save in -80 DEG C.It takes Each 10 μ L of time point rat plasma, after 500 μ L of the acetonitrile solution mixing of containing the internal standard is added, vortex mixed 4 minutes, 3700 revs/min Zhongli's heart 18 minutes, 70 μ L of supernatant is taken to mix with 70 μ L water, 5 μ L of mixed liquor is taken to carry out LC-MS/MS analysis.In main medicine generation, is dynamic Mechanics parameter is analyzed with the non-compartment model of 6.3 software of WinNonlin, and Pharmacokinetic Evaluation test result is shown in Table 2.

2 Pharmacokinetic Evaluation test result of table

Conclusion: the compounds of this invention shows the Pharmacokinetic Characteristics for being substantially better than control drug Afatinib.

Biological test example 3: nude mouse tumor cell transplantation tumor measuring

(1) experimental animal:

BALB/cA-nude nude mouse, 4-6 week old, female are purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.. Quality certification number: SCXK (capital) 2012-0001.

(2) tumor cell transplantation:

NCI-H1975 cell: after nude mouse laboratory environment adapts to 3 days, right flank subcutaneous vaccination H1975 cell 5 × 10⁶/ only.Tumour growth is to 200-250mm³When, random to be grouped, every group of 10 mouse.

A431 cell: after nude mouse laboratory environment adapts to 3 days, right flank inoculates A431 cell 5 × 10⁶/ only.It is swollen Tumor grows to 200-250mm³When, random to be grouped, every group of 10 mouse.

(3) dosage and method:

NCI-H1975 cell transplantation tumor nude mouse: test-compound with PEG400/Tween80 be configured to 0.15mg/ml and Two dosage of 0.5mg/ml.Animal distinguishes gastric infusion test-compound 1.5mg/kg and 5mg/kg after weighing in； Afatinib is configured to 1.2mg/ml and 4mg/ml with PEG400/Tween80.It is tested that animal distinguishes gastric infusion after weighing in Compound 12mg/kg and 40mg/kg.Blank control group gives the PEG400/Tween80 solution of same volume not drug containing.Often Its single administration, successive administration 10 days.

A431 cell transplantation tumor nude mouse: test-compound with PEG400/Tween80 be configured to 0.03mg/ml and 0.1mg/ml.Animal distinguishes gastric infusion test-compound 0.3mg/kg and 1mg/kg after weighing in；Afatinib with PEG400/Tween80 is configured to 0.3mg/ml and 1mg/ml.Animal distinguishes gastric infusion test-compound 3mg/ after weighing in Kg and 10mg/kg blank control group gives the PEG400/Tween80 solution of same volume not drug containing.It is administered once a day, even Continuous administration 10 days.

(4) transplantable tumor volume and nude mouse body weight determination

After tumor cell inoculation nude mouse on every Mondays, four knurl product (calculation formula is seen below) is respectively surveyed with vernier caliper, And it weighs in.

(5) data statistics

Average and standard deviation (SD) is calculated using Office Excel software, SEM (STDEV/SQRT).Group difference with T-testj is examined, and P < 0.05 is significant difference standard

Gross tumor volume (V) calculation formula are as follows: V=1/2 × major diameter × minor axis × minor axis

Relative volume (RTV)=VT/V0

Tumour inhibiting rate (%)=(CRTV-TRTV)/CRTV × 100%)

Wherein V0, VT are respectively the gross tumor volume before starting administration and after last time administration.CRTV, TRTV are respectively time The relative tumour volume of blank control group and experimental group after being finally administered.It the results are shown in Table 3,4.

Table 3: to the suppression result of A431 cell transplantation tumor

Table 4: to the suppression result of H1975 cell transplantation tumor

Conclusion: the compounds of this invention more can obviously inhibit containing EGFR wild type compared with control drug Afatinib The growth of the human lung cancer NCI-H1975 of human epithelial cells cancer A431 and EGFR T790M mutation is only sun in dosage respectively Property control 1/10,1/8 dosage under, control drug is significantly stronger than to A431, H1975 transplantable tumor effect respectively.

Biological test example 4: effect of the manual patch-clamp detection the compounds of this invention of electro physiology to hERG potassium-channel

This test cell used is that transfection has hERG cDNA and stablizes the CHO cell line in the expression channel hERG.Using hand Dynamic diaphragm forceps system (German HEKAEPC-10 signal amplifier and digital switching system) makees the record of full cell currents.Surface is raw Round slide with CHO hERG cell is placed in the electrophysiological recording slot under inverted microscope.With cell in track External solution makees continuous perfusion (1 milliliter about per minute).Experimentation uses conventional whole-cell patch-clamp electric current recording technique.Cell It clamps down under the voltage of -80mV.Cell Clamping voltages are depolarized to+20mV to activate hERG potassium channel, clamped down on again after 5 seconds- 50mV is to eliminate inactivation and generate tail current.Tail current peak value is used as the numerical value of hERG size of current.What above-mentioned steps were recorded Perfusion drug to be tested can be then superimposed after stablizing by reaching under hERG potassium current extracellular fluid perfusion lasting in track, Until inhibiting effect of the drug to hERG electric current reaches stable state.It is later straight with extracellular fluid perfusion wash to reach stable situation Size to before hERG current reverts to dosing object.

Untested compound concentration is 30,10,3,1,0.3,0.1 and 0.03 μM, to test.Before the test, it uses first DMSO is diluted to the stock solution of 30,10,3,1,0.3 and 0.1mM, then final μM concentration is diluted to extracellular fluid.Each concentration The ultimate density of DMSO is all 0.1% in compound solution.The test concentrations of positive control Cisapride (Cisapride) are 0.1μM。

The number that test data is provided by HEKA Patchmaster, Microsoft Excel and Graphpad Prism It is analyzed according to analysis software, as a result such as table 5.

Table 5: to the exercising result of hERG potassium-channel

Compound number	hERG IC₅₀(μM)
		Afatinib	2.40
9	5.84
		13	3.55
14	2.12

Conclusion: the compounds of this invention inhibits weak, safety with higher, especially compound to hERG potassium-channel 9 and 13, weaker is inhibited to hERG potassium-channel, has greater security.

Claims

1. a kind of logical formula (II) compound represented or its stereoisomer or pharmaceutically acceptable salt

Wherein:

R²Selected from methyl or ethyl；

Ring A is selected from

N is 0 or 1；

R³Selected from F；

M is 1；

R⁴、R⁵And R⁶It is H；

R⁹Selected from F or Cl；

T is 3.

2. compound according to claim 1 or its stereoisomer or pharmaceutically acceptable salt, wherein the change Object is closed to be selected from:

3. compound according to claim 1 or its stereoisomer or pharmaceutically acceptable salt, wherein its pharmacy Salt described in upper acceptable salt is selected from hydrochloride, hydrobromate, sulfate, phosphate, acetate, trifluoroacetate, sulphur Cyanate, maleate, hydroxymaleic acid salt, glutarate, mesylate, esilate, benzene sulfonate, p-methyl benzenesulfonic acid Salt, benzoate, salicylate, phenylacetate, cinnamate, lactate, malonate, pivalate, succinate, rich horse Hydrochlorate, malate, mandelate, tartrate, gallate, gluconate, laruate, palmitate, pectin Hydrochlorate, picrate, citrate or their combination.

4. compound according to claim 1 or its stereoisomer or pharmaceutically acceptable salt, wherein described Salt is selected from hydrochloride, hydrobromate, sulfate, phosphate, acetate, maleate, mesylate, benzene sulfonate, trifluoro second Hydrochlorate, tosilate, benzoate, salicylate, cinnamate, lactate, malonate, succinate, fumaric acid Salt, malate, tartrate, citrate or their combination.

5. a kind of pharmaceutical composition, the composition includes: effective dose according to claim 1 described in any one of -2 Compound or its stereoisomer or pharmaceutically acceptable salt and pharmaceutically acceptable carrier, diluent, adjuvant, matchmaker Jie's object or excipient；The composition can also further comprise one or more other therapeutic agents.

6. pharmaceutical composition according to claim 5, wherein the other therapeutic agents are cis-platinums, carboplatin, oxaliplatin, Dacarbazine, Temozolomide, procarbazine, methotrexate (MTX), fluorouracil, cytarabine, gemcitabine, purinethol, fluorine reach Draw shore, vincaleukoblastinum, vincristine, vinorelbine, taxol, Docetaxel, topotecan, Irinotecan, Etoposide, song It is fixed that shellfish is replaced, dactinomycin D, Doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, and Yi Sha It is grand, tamoxifen, Flutamide, sirolimus, Afatinib, alisertib, amuvatinib, Ah pa replace Buddhist nun, Axitinib, Bortezomib, posupini, Bu Linibu, card is rich to replace Buddhist nun, Si Dinibu, crenolanib, and gram Zhuo replaces Buddhist nun, darafinib, Dacomitinib, Da Lushe are replaced, Dasatinib, more Weis replace Buddhist nun, Tarceva, foretinib, ganetespib, Gefitinib, according to Shandong replace Buddhist nun, Conmana, Imatinib, iniparib, Lapatinib, lenvatinib, linifanib, Linsitinib, Masitinib, momelotinib, for husky Buddhist nun, linatinib, nilotinib, niraparib, Oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, Rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, Sorafenib, Sutent, Tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, Vande Thani, Veliparib, Wei Luofeini, vismodegib, volasertib, alemtuzumab, bevacizumab, Brentuximabvedotin, catumaxomab, Cetuximab, ground promise monoclonal antibody, lucky trastuzumab, her monoclonal antibody, the appropriate pearl of Buddhist nun Monoclonal antibody, difficult to understand, Victibix, Rituximab, tositumomab, Herceptin or their combination.

7. compound of any of claims 1-4 or its stereoisomer or pharmaceutically acceptable salt or power Benefit requires pharmaceutical composition described in any one of 5-6 preparing medicine as EGFR/HER2 receptor tyrosine kinase inhibitors Application in object preparation.

8. application according to claim 7, wherein the pharmaceutical preparation is for treating and/or preventing excess proliferative disease The pharmaceutical preparation of disease.

9. application according to claim 8, wherein the excess proliferative disease include brain tumor, non-small cell lung cancer, Squamous cell, bladder cancer, cancer of pancreas, colon cancer, breast cancer, oophoroma, cervix cancer, carcinoma of endometrium, colorectal cancer, Kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin lymphoma, liver cancer, lung cancer, cutaneum carcinoma, thyroid cancer, One of head and neck cancer, prostate cancer, epidermis squamous carcinoma, gastric cancer, glioma and nasopharyngeal carcinoma are a variety of.